Epidemiology
:
-
history :
-
arose from SIV and moved
into humans around 1930 by butchering chimpanzees (Pan
spp.
)
for bushmeat in West-Central Africa. Apes are traditionally hunted in Africa
and are offered for sale in open-air meat markets. The bloody carcasses
are regularly covered with blood-feeding flies, amongst them possibly the
stable or biting house fly (Stomoxys
calcitrans), a cosmopolitically occurring biting fly. This fly
is the effective vector for the retrovirus causing equine infectious anemia.
According to laboratory experiments, the infectivity of ingested HIV is
not reduced in the regurgitates of this fly.
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arrived in the USA around 1968
-
one hypothesis suggests that Canadian air steward Gaetan Dugas - dubbed
Patient Zero - brought in the disease and spread it to many homosexual
partners
-
according to a recent study the disease entered many different times independently.
Even early in the epidemic the viruses in different cities were distinct
from one another. This supports another popular theory: that HIV may have
hitched a ride with tourists arriving from Haitiref
-
epidemic in 1974 near Lake Victoria (Kinshasa, Zaire)
-
retrospectively recognized as having struck in the late 1970s
-
first reported in 1981 : this is compatible with HIV's roughly 10-year
incubation period. It was discovered by an epidemiological research that
showed increase in sales of pentamidine chlorhydrate in New York and San
Francisco districts : the drug was used to treat opportunistic Pneumocystis
carinii
infections (see below).
-
prevalence : 42 million people at November 2002, 38 million people in 2003.
In 2003, nearly 50% of all people infected between the ages of 15 and 49
are women. In Africa, the proportion is almost 60%. In 2004 nearly 50%
of the estimated 39.4 million people living with HIV, the virus that causes
AIDS, are women and girls, whether married or single, promiscuous or faithful.
The trend is that more young women are being infected than young men :
if they are married, they can't abstain. They are faithful but the husband
is not faithful. Women need information, including how to use a female
condom to protect themselves. Men and women between 15 and 24 years old
are the hardest hit by the pandemic
-
Asia (with 60% of the world's population) : 7.4 million people in 2003.
An estimated 10 million people will carry the virus by 2010 unless effective
action is taken
-
India : 5.1 million infected individuals (0.9%) in 2003. According to the
CIA, the number of cases in India could top 20 million by 2010. The people
hit by AIDS in India are not the ones you would expect. About 86% of cases
are a result of sexual transmission, most of it heterosexual. Intravenous
drug use accounts for only 2.4% of infections, except in Nagaland and Manipur,
2 states where HIV infection is highly prevalent. The earliest cases appeared
in high-risk groups: among the country's 3 million sex workers or the 5
million truckers who haul the virus up and down the highways. During 2004,
there were just 28,000 new cases of HIV infection, down 95% from the previous
year — proof that its strategies are working. But even in the United States
there are an estimated 40,000 new cases each year. So do you believe that
Indian number? Of course not, that would be ridiculous. Compared with South
Africa, where the prevalence of HIV is 21.5%, India's prevalence is just
0.91%. That is < 1% generally considered to be the tipping point, beyond
which the epidemic will escalate out of control. It took just 7 years for
South Africa's prevalence to rise from 1% to 20%. But the statistics are
sobering. 6 states in India already have a prevalence > 1%, and in 2004
the number of high-prevalence districts jumped from 49 to 116. Even in
the low-prevalence or 'highly vulnerable' states, as they are now dubbed,
there are pockets where > 4% of adults are infected. Over the next 5 years,
it plans to expand its 670 voluntary testing sites to 24,000 and increase
the number of people on antiretroviral therapy from an estimated 8,000
to 188,000. But in the world's most populous democracy, good intentions
don't go very far. Despite doubling its AIDS budget since 2003-04, India
still only spends about 29 US cents per person on AIDS. In contrast, Uganda,
credited with curbing its AIDS crisis, dedicates US$1.85 per person. Already,
India accounts for > 13% of the world's AIDS burden but with its prevalence
so close to the tipping point. In Mumbai, the bustling metropolis on India's
west coast, there are nearly 100,000 sex workers. Volunteers from non-governmental
organizations (NGOs) walk through the streets of Kamathipura, the red-light
district, handing out condoms and leaflets. But in the southern states,
where prevalence is highest, there are no red-light districts to canvass.
Instead, sex workers — many of whom are married women — work out of their
homes, hotels or on the highways, earning themselves the nickname 'highway
queens'. Some towns, such as Peddapuram and Amalapuram in the state of
Andhra Pradesh, are like one big red-light district. For US$230, you can
stay there for 1 month and be treated like a mappillai, a son-in-law, who
is treated like a prince by the girl's family. In Andhra Pradesh, HIV prevalence
jumped from 1.25% in 2003 to 2.25% in 2004. Experience has shown that the
best way to reach these unconventional sex workers is through their peers.
There are 638,000 villages in India, many of them with bad roads, no running
water and no medical care. The best estimates are that 59% of those infected
with HIV live in rural areas, but because there is limited surveillance
there, the real number is likely to be higher. Compounded by ignorance
and illiteracy, myriad myths about AIDS have taken root: that eating chicken
and brinjal (aubergine) is harmful, for example, or that the virus can
be transmitted by mosquito bites. Some largely rural states such as Uttar
Pradesh and Bihar have all the ingredients for a massive epidemic — illiteracy,
poverty, migrant labour and sex traffic — but have so far received little
attention either from the government or from donor agencies. The model
of success for those states is perhaps Tamil Nadu, where the epidemic spawned
dozens of NGOs that conduct education programmes and provide counselling
and support. As a result, it is the only state where prevalence has dropped
— from 1.13% in 2001 to 0.63% at the last count. Truckers go home
only once every few months. On the road, they have multiple sexual partners
and often abuse drugs and alcohol. Many believe that if they don't have
sex they will build up garmi, a Hindi word meaning heat, and will go blind.
In recent years, they've become accustomed to being chased by volunteers
with flipcharts and penis models in their pockets. Selvaraj works with
the HOPE Foundation, which has counsellors and doctors at several stops
along a 60-km stretch on the highway. But the message has not entirely
got through. Believing that AIDS can only be transmitted by women, many
truckers now have sex with 'cleaners', the young boys who travel with them.
Homosexuality is illegal in India, so the government's campaigns mostly
neglect men who have sex with men. These truckers have ample access to
condoms, but many use the condoms to plug pipes in the trucks. According
to a report by India's comptroller and auditor-general, 75% of the 1.5
billion condoms made each year are used as sealants for leaky roofs, as
lubricants in weaving gold-embroidered saris, or are mixed with concrete
and tar to pave roads.
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China : 840,000 HIV-positive people and 80,000 with full-blown AIDS. In
the mid-1990s, the Chinese government established a system of centres to
screen donated blood and its products for HIV. But the low cost and ready
availability of unregulated rural samples kept demand high, and contaminated
blood continued to slip through the net. In some provinces, including Anhui,
Henan and Shandong, the disease took off in the early 1990s when poor farmers
began selling their blood plasma. Without clean needles the disease spread,
and in some villages up to 60% of people are now infected. 3 new laws,
passed at the 11th session of the Standing Committee of the National People's
Congress, builds on earlier regulations governing blood safety and made
it illegal to buy and sell blood and discriminate against victims of infectious
diseases, and guarantee funds for preventing infectious disease. China
passed a law in August 2004 to make it illegal to buy and sell blood in
an effort to stem the country's growing AIDS epidemic, the first time the
disease has been targeted in a law. Officialsof relevant United Nations
organizations warned that the number could hit 10 million if the epidemic
goes unchecked. As part of the measures to curb the disease, China has
made AIDS prevention a compulsory course of schools ranging from junior
high schools to colleges. China also launched pilot clinics last year to
provide methadone maintenance therapy to intravenous drug users and programs
to promote the use of condoms at hotels, universities and nightclubs. Shanxi
Province in North China will conduct HIV testing among people who have
sold blood since 1990 during the first 4 months of 2005. A senior official
at the department said that some people infected with the HIV virus have
yet to be traced after the blood-sale scandal. The department also requested
local health bureaus to conduct antibody testing on the spouses and children
of previous blood sellers who were found HIV positive and to offer timely
anti-retroviral treatment to the patients. To prevent possible discrimination,
the department asked health institutions to protect HIV carriers' privacy
and keep the testingresults secret.
-
> 1.5 million people are now HIV+ in eastern Europe and central
Asia, compared with just 30 000 in 1995. > 1 in 100 people in Estonia,
Russia, and Ukraine are infected with the virus : the result could see
the annual growth in gross domestic product reduced by 1%. Just as in some
CIS countries today, only 12 years ago South Africa too saw < 1% of
its adult population infected--now that rate is 20 times higher. Lessons
can be learned from successes in countries such as Poland, the Czech Republic,
and Slovakia. Currently only 7000 people in eastern Europe and central
Asia receive antiretroviral therapy for HIV--9% of those who need the drugs
in the region
-
some 27 companies in Asia make generic versions of patented antiretroviral
medications. But of 1.3 million Asians who need the drugs, only 7% have
access to them, the report states. Computer models predict that HIV will
spread most rapidly in countries where > 20% of men visit sex workers :
Thailand, which saw an early and rapid rise in infections in the late 1980s,
increased condom use among Thai sex-workers to nearly 90% and halved the
number of men who visited them. As a result, the number of new people testing
positive for HIV in the country fell from 142,819 in 1991 to 21,260 this
year.
-
Africa : 7 countries in southern Africa report prevalence rates > 15%.
They are Botswana, Swaziland, Lesotho, Zimbabwe, South Africa, Namibia,
and Zambia (a prevalence rate > 1% is considered to be a generalized epidemic)
-
South Africa : the world's largest number of HIV-positive people – 5.3
million people (18%). 20% of people aged 15-49 are infected
-
Botswana : 38.8% of adult population is infected (the world highest rate)
-
Tanzania : 10% of population
-
Uganda : there are 70% fewer cases of HIV in 2004 compared with 10 years
ago (500,000 Ugandans are HIV positive in 2004, compared with 1.5 million
a decade ago) because there is 60% less casual sex. In 1984, when infection
was at its peak, billboards, radio shows and concerts shouted a coordinated
anti-HIV message. Public figures, including politicians, religious leaders
and health workers, promoted safe sex and people began to use condoms more
often. But similar strategies in other African countries did little to
lower the prevalence of HIV. The difference is that in Uganda people became
engaged with the epidemic at the community level : local care groups, religious
movements, non-governmental organisations and care networks all spread
the message. Families, friends and neighbours began talking about HIV prevention
and care, and sexually transmitted diseases stopped being a taboo topic.
The issue also became personal : most people now know someone who has AIDS
or has died from the disease and this has motivated people to change their
behaviour. The situation echoes San Francisco in the late 80's when HIV
had a stranglehold on the gay community : the best predictor of behavioural
change back then was knowing someone with HIV or AIDS.
-
USA : between 1,039,000 and 1,185,000 people were living with HIV in December
2003; 40,000 new cases a year. The previous estimate from 2002 showed that
between 850,000 and 950,000 people had the AIDS virus. The jump reflects
the role of medicines that have allowed people infected with the virus
to live longer. Of those, almost 25% are unaware of their infection, and
400,000 have full blown AIDS. For the first 2 decades of the AIDS epidemic
in the USA, HIV-1 subtype B has been the predominant isolate throughout
the country. In recent years, non-B HIV-1 subtypes have been spreading
in parts of Europe. In 2003, the Minnesota Department of Health piloted
HIV-1 subtyping with routine surveillance to describe and monitor non-B-subtype
HIV-1 isolates. In Minnesota, African-born persons make up < 1% of the
population, but in 2002 accounted for 21% of the state’s new cases of HIV
infection. All of those infected with non-B subtypes were African immigrants
attending health clinics in the Minneapolis-St. Paul area. Of the 98 African-born
HIV-1-infected patients, 87 were successfully subtyped and 95% of these
were infected with non-B subtypes. 7 different subtypes were identified,
all consistent with strains endemic to the patients’ regions of birth.
Of the non-African HIV-1-infected patients, 25 were successfully subtyped
and all were infected with subtype B. These results underestimate the prevalence
of non-B subtypes in Minnesota because recent immigrants are less likely
than assimilated immigrants to have access to the American health care
system. Since their estimates are based solely on patients from health
care facilities, they probably missed recent immigrants with HIV infection.
The findings of a high prevalence of non-B subtypes in a state where African-born
individuals make up < 1% of the population suggest that it may be time
to consider implementing HIV subtype surveillance in states with larger
immigrant populations and throughout the USA. In the 1990s, the CDC and
other agencies generally agreed that between 600,000 and 900,000 people
had the virus, according to the University of California-San Francisco's
Center for HIV Information. Previous estimates -- as high as 1.5 million
people -- from the 1980s were later determined to be too high. For example,
the CDC estimated in 1986 that between 1 million and 1.5 million people
had HIV. In 1987, that was revised to 945,000 to 1.4 million and was refined
in 1990 to 800,000 to 1.2 million. The CDC's latest estimates indicate
blacks account for 47% of HIV cases; gay and bisexual men make up 45% of
those living with the virus that causes AIDS, the health agency believes.
In 2003, the rates of AIDS cases were 58 per 100,000 in the black population,
10 per 100,000 Hispanics, 6 per 100,000 whites, 8 per 100,000 American
Indian/Alaska native population, and 4 per 100,000 Asian/Pacific Islanders.
The CDC also warned those demographics may soon change because heterosexual
blacks, women and others infected after having high-risk sex (such as with
someone with HIV, an injection-drug user or a man who has sex with other
men) now account for a larger proportion of those living with HIV than
those who are living with full-blown AIDS. Of 156,000 new cases of HIV
infection between 2001 and 2004, 51% were in non-Hispanic blacks — although
blacks made up just 13% of the population in those states : the rate of
HIV diagnosis fell by 6.8% annually among black women and 4.4 percent annually
among black men between 2001 and 2004. The HIV diagnosis rate even fell
by 9.7% every year on average among black male users of injected drugs.
32% of black men in Baltimore who had sex with other men, which includes
homosexual and bisexual activity, were infected with HIV
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Brazil : the nation of about 170 million slashed Aids deaths to 24,8% of
the infected population in 1999 from 73,7% in 1990. In absolute numbers,
Latin America's largest country suffers from a high rate of HIV infection,
with 200,000 registered cases of HIV, and estimates of up to 540,000 total
cases. But only 0,6% of the adult population is infected. Currently, there
are almost 600,000 HIV-infected individuals in Brazil. From 1984 to 2004,
362,364 AIDS cases were officially reported and 155,000 patients are under
HAART treatmentref
-
incidence : 4.9 millions in 2004, 4.8 millions in 2003 (25% is Asian; 3
million people in sub-Saharan Africa)
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there will be 45 million new infections by 2010
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India : in 2003 there were 520,000 new cases of HIV infection, 28,000 in
2004 (???), but 2 of India's most populous states -- Uttar Pradesh and
Bihar with a combined population of > 250 million -- had poor surveillance.
This is 85% of the 2002 figure of 610,000 new infections.
-
Thailand : in 2003, 21,000 people became infected, compared with 140,000
people in 1996; an increase in condom use and a decrease in the sex trade
have contributed to the trendref
-
UK : there has been a 20% increase in new diagnoses of HIV infection between
2002 and 2003 : new diagnoses in heterosexuals have risen by 27% in the
same period, with most infections contracted outside of the UK in countries
with a high rate of infection with HIV. The increase in rates is also though
to be related to an increase in other STD, which might influence the transmission
of HIV
-
USA : 40,000 new HIV infections have occurred every year since the 1990s.
However, recent outbreaks of HIV and sexually transmitted diseases in major
cities around the country offer a hint that new infections may be as high
as 60,000 cases a year
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mortality : 3.1 millions in 2004
-
there will be nearly 70 million deaths from the disease by 2010
Genomics :
viral genome transcription initially depends on
NFkB
,
generating a double-spliced 2 kb transcript. LPS stimulation of
TLR4
induces
TIRAP and MyD88 activation => RAC1 activation and RAC1 stimulates
trans-activation
of the HIV long-terminal repeat (HIV-LTR)
ref.
Although HIV-1 infects quiescent and proliferating CD4
+ lymphocytes,
the virus replicates poorly in resting T cells : in the latter
MURR1
inhibits HIV-1 growth in part through its ability to inhibit basal and
cytokine-stimulated NF
kB
activity
ref
Strains from A to I exist (3 subgroups (M, N, and O)) : A/E mosaic
is the most virulent strain. Biological phenotype may be classified according
to ..
-
non-syncitia-inducing (NSI) strains are usually those which are
acquired in infection.
-
syncitia-inducing (SI) strains are more virulent and usually develop
at the end of the disease : anyway when cotransmitted together with NSI
strains, they worse the prognosis. They are characterized by amino acid
substitutions in codons 11 (?=>Arg) and 25 (Gly=>?) within V3 loop of env.
-
env sequence => coreceptor usage => cell tropism :
-
macrophage-tropic (M-tropic) / non-T-cell-line-tropic / R5 strains
infect macrophages and primary CD4+ T lymphocytes. They use
CCR5
/ CD195
as coreceptor. Proliferation kinetics in U937-2, CEM, MT-2 and Jurkat-tat
cell lines is slow/low (S/L), with pattern 1, 2 or 3. In lymph nodes,
CXCR4-bearing cells are found almost exclusively inside GCs and in the
medulla.
-
T-cell-line-tropic (T-tropic) / X4 strains infect macrophage and
CD4+ T lymphocytes. They mainly use CXCR4
/ CD184 / fusin / LESTR
as coreceptor, but can also use CCR5 /
CD195
,
CCR3
and CCR2B
.
Proliferation kinetics in U937-2, CEM, MT-2 and Jurkat-tat cell lines is
rapid/high
(R/H). In lymph nodes, CCR5-bearing cells exist primarily in the medulla
and extrafollicular areas of the cortex, surrounding the FDC reservoir
of infectious virus : FDC themselves upregulate CXCR4 expression.
-
dual-tropic / R5X4 strains use CXCR4
/ CD184 / fusin / LESTR
,
CCR5
/ CD195
and CCR2B as coreceptors
Although in vitro studies have identified HIV-1 strains that can
use other co-receptors, infection of human cervical tissue using co-receptors
other than CXCR4 or CCR5 is unlikely. In contrast to infection of cervical
tissue, uptake of HIV-1 by migratory DCs is not inhibited by a combination
of CXCR4 and CCR5 inhibitors, but is inhibited when CD4-specific antibodies
and mannan are present. Presence of DC-SIGN-specific antibody also inhibit
the capture of infectious virus by migratory cells, albeit to a lesser
extent, indicating an important but not exclusive role for this receptor
in virus capture and transmission. By targeting HIV-1 directly with neutralizing
gp120-specific antibodies and a CD4-Ig fusion protein, both localized infection
of cervical tissue and transfer of infectious virus by migratory cells
are inhibitedref.
Resulting phenotypes may be :
-
common variants :
-
S/L M-tropic NSI
-
R/H T-tropic SI
-
rare variants :
Lentiviral strains capable of only one round of infection
in vitro
and
in vivo to investigate the dynamics and pathogenesis of HIV
and SIV have been created by mutating the ribosomal frameshifting site
between the
gag and
pol reading frames
ref.
Proteomics
:
-
Env
/ gp160 / transmembrane (TM) envelope gp
-
gp120 : 3 molecules of gp120 are non-covalently
linked to trimeric gp41, forming heteroligomeric spikes on the surface
of the virus particle. Different regions of gp120 interact with CD4 and
chemokine receptors found on the surface of target cells. These interactions
lead to a series of conformational changes in gp120, and subsequently allow
the conformational changes in gp41 that lead to formation of the coiled-coil
form and exposure of the fusion peptide
-
CD4
-binding
domain (CD4bd) : composed of several parts of the gp120 molecule, forming
a binding pocket into which a region of CD4 fits
-
bridging sheet : composed of 4 anti-parallel b strands from the
V1/V2 stem and the C4 regions of gp120. This region is involved in the
binding of gp120 to chemokine receptors, triggering subsequent conformational
changes in gp120 and gp41. Because this region forms or is exposed after
binding of gp120 to CD4, it is known as the "CD4-induced epitope".
-
V2 loop : a highly variable region that is proximal to the CD4bd
and is part of the bridging sheet. The V2 loop (together with the V1 loop)
seems to shield partially the CD4bd, the bridging sheet and part of the
V3 loop until conformational changes in gp120 are induced by CD4.
-
V3 loop : a semi-conserved region of gp120 that is structurally
constrained by its requisite participation in virus infectivity. The V3
loop interacts with chemokine receptors on the sruface of target cells.
It also binds to CD209 / dendritic-cell-specific
ICAM-3 grabbing non-integrin (DC-SIGN) / CIRE
,
macrophage
mannose receptor
and langerin
on DCs. In primary immature DCs, internalized virus particles are rapidly
degraded in and endo-lysosomal compartment. MHC class-I-restricted peptides
are derived from a small number of virions that enter the cytosol (after
membrane fusion) and are degraded by the proteasome, rather than from the
majority of virions that are degraded in the endo-lysosomal compartment.
Tight contact with permissive CD4+ T lymphoctes in antigen-independent
structured immunological synapses allows infection of the latter, but DCs
also induce IFN-g production by the CD8+
effector T cells and formation of high levels of antibodies whose neutralization
ability is impaired by a receptor-binding site conformational masking mechanism.
Cell contact between DCs and T cells in lymph nodes might make the transmission
process so efficient that only small amounts of virus that avoid degradation
are required. Alternatively, HIV-1 could replicate in DCs at low levels,
so that progeny virions rather than captured virions could be transmitted
to T cellsref.
-
gp41 transmembrane glycoprotein is found as a
homotrimeric complex in the envelope of the viurs; it interacts non-covalently
with gp120 on the exterior of the virus particle
-
immunodominant region (includes gp41 epitope cluster I) :
induces high levels of antibodies, most of which are not neutralizing but
might mediate other functions, such as ADCC and aggregation of and complement
deposition on virus particles
-
transmembrane-proximal region : poorly exposed on the surface of
the virus and is thought to be a transitional epitope, exposed for a brief
period of time during the confromational changes that occur in gp41 that
lead to the fusion of virus and cell membranes
-
amino-terminal and carboxy-terminal heptad repeat regions: the repeating
motifs in these regions form leucine zippers, which are involved in the
formation of the coiled-coil form of gp41 after conformational changes
are induced in gp120 by its interaction with CD4 and chemokine receptors
-
fusion peptide : the amino-terminal region of gp41, which is exposed
after formation of the coiled-coil form. This region is inserted into the
membrane of the target cell, resulting in fusion of virus and cell membranes
Virions of wild-type HIV-1 and a mutant SIV had 14 and 73 spikes per particle,
respectively, with some clustering of HIV-1 spikes. 3D averaging showed
that the surface glycoprotein (gp120) 'head' of each subunit of the trimeric
SIV spike contains a primary mass, with 2 secondary lobes. The transmembrane
glycoprotein 'stalk' of each trimer is composed of 3 independent legs that
project obliquely from the trimer head, tripod-like. Reconciling available
atomic structures with the 3D whole spike density map yields insights into
the orientation of Env spike structural elements and possible structural
bases of their functionsref.
-
Gag
/ p2 / p6 / p55 / nucleocapsid (NU) / matrix (MA) : a 30-residue
coiled-coil motif at the N-terminus is required for targeting free and
structured capsids to the microtubule organizing center (MTOC)—or centrosome—
via dynein-dynactin retrograde microtubule motor (with Gag directly
interacting with dynein light chain 8 prior to nuclear translocation of
the viral genome. It intreracts with endophilin 1 and 2 (cytosolic proteins
converting lysophosphatidic acid by addition of the fatty acid arachidonate
into phosphatidic acid, involved in the formation of endocytic vesicles),
which remain as minor components of virions : also a-adaptin)
becomes included in the virion . Gag is sufficient to produce a virus-like
particle, during which Gag is cleaved into four structural proteins :
-
MA
-
p12
-
capsid protein (CA) : interaction of CA with the host cell protein
cyclophilin
A (CypA)
prevents inhibition by the restriction factor REF1
/ APEX nuclease (multifunctional DNA repair enzyme) 1 (APEX1). Alterations
in protection upon maturation provide evidence for the maturation-induced
formation of an interaction between the N- and C-terminal domains in half
of the capsid molecules, indicating that only half of the capsid protein
is assembled into the conical coreref.
-
NC
-
Pol
/ protease / integrase
(IN) / reverse transcriptase (RT) / p160. HIV-1 preferentially integrates
into transcribed regions. Host p300 acetylates K264, K266, and K273 in
the carboxy-terminus of IN, a region that is required for DNA binding,
increasing IN affinity to DNA, and promoting the DNA strand transfer activity
of the proteinref
-
accessory genes :
-
Nef
/ p27 is found in virion and has NLS. Macrophages that express
Nef or that are stimulated through the CD40 receptor release sCD23 and
sICAM that render CD4+ T lymphocytes permissive to HIV-1 infection
without progressing through the cell cycle. Then Nef triggers CD4 endocytosis
preventing overinfection and signal tranduction. It interacts with the
N3 subunit (impairing binding of PA28 but not of the 19S regulator) of
the 26S proteasome
.
One action of Nef is to down-regulate surface MHC I molecules, helping
infected cells to evade immunity. Nef also down-regulates the macrophage-expressed
MHC-Ib protein HFE, which regulates iron homeostasis and is mutated in
the iron-overloading disorder hemochromatosis. In model cell lines, Nef
reroutes HFE to a perinuclear structure that overlaps the trans-Golgi network,
causing a 90% reduction of surface HFE. This activity requires a Src-kinase-binding
proline-rich domain of Nef and a conserved tyrosine-based motif in the
cytoplasmic tail of HFE. HIV-1 infection of ex vivo macrophages
similarly down-regulates naturally expressed surface HFE in a Nef-dependent
manner. The effect of Nef expression on cellular iron was explored; iron
and ferritin accumulation were increased in HIV-1-infected ex vivo
macrophages expressing wild-type HFE, but this effect was lost with Nef-deleted
HIV-1 or when infecting macrophages from hemochromatosis patients expressing
mutated HFE. The iron accumulation in HIV-1-infected HFE-expressing macrophages
was paralleled by an increase in cellular HIV-1-gag expression. Through
Nef and HFE, HIV-1 directly regulates cellular
iron metabolism
,
possibly benefiting viral growthref
-
transcription
activator (Tat) / p14 (86 and 101 amino acid isoforms in different
strains) functions through binding to a short leader RNA, called transactivation
responsive element (TAR) together with HIV
TAT specific factor 1 (HTATSF1), a cofactor required for Tat activation
of HIV-1 transcription. Within nucleus it
activates the HIV-1 long terminal repeat (LTR), mainly by adapting co-activator
complexes, such as p300/CBP,
pCAF
and the positive transcription elongation factor P-TEFb (cyclin
T1 + CDK9),
to the promoter, promoting phosphorylation of the CDD on RNA polymerase
II. The protein-protein interface involves hydrophobic interactions between
the P/CAF ZA loop and the Tat core domain. In particular, tyrosines 760
and 761 of P/CAF, 2 residues that are highly conserved in most known bromodomains,
play an essential role for the bindingref.
The proto-oncoprotein Hdm2
interacts with Tat and mediates its ubiquitination enhancing Tat-mediated
transactivation via a non-proteolytic function. Tat
also interacts with the a-rings (impairing binding
of PA28 but not of the 19S regulator) of the 26S
proteasome
.
Tat also binds to HIV-1
Tat interactive protein, 60kDa (HTATIP) and HIV-1
Tat interactive protein 2, 30kDa (HTATIP2). TAR is also bound by TAR
(HIV) RNA binding protein 1 (TARBP1), TAR
(HIV) RNA binding protein 2 (TARBP2) and TAR
DNA binding protein (TARDBP). Tat 48-60 and Tat 47-57
are used as cell-penetrating
peptides (CPPs)
.
It has a basic domain for binding to cell membranes after secretion. Interaction
between HIV-1 Tat and pRb2/p130 is a possible mechanism in the pathogenesis
of AIDS-related neoplasmsref.
-
Rev
/ p19 is produced by the 2 kb transcript. It binds to importin
b
to enter nucleus, where it is detached by RanGTP and binds to Rev-responsive
elements (RRE) within env and protects the pre-mRNA from being spliced
by protecting donor and acceptor splicing sites. The NES of Rev binds crm1
allowing export into cytosol, where RanBP1 and RanGAP detach the viral
pre-mRNA from Rev and crm1 allowing the transcription of longer polypeptides
-
a single spliced 4.3 kb transcript which codes for Tat, Rev and Nef.
-
an unspliced 9.2 kb transcript which codes for gag and pol and represents
the genomic RNA
Such splicing impairment is
It also binds to HIV-1
Rev binding protein (HRB) and HIV-1
rev binding protein 2 (HRB2). Rev 34-50 is used as a cell-penetrating
peptide (CPPs)
.
-
virion
infectivity factor (Vif) / p23 protein inhibits the cellular cytidine
deaminase APOBEC3G /
CEM15 cytidine deaminase
and APOBEC3F
in nonpermissive cell lines by inhibiting mRNA translation and enhancing
proteasomal degradation independently of other viral proteinsref1,
ref2,
ref3,
allowing HIV-1 multiplication even in these cells. HIV-1 deleted for the
vif
accessory gene encapsidates the APOBEC3G. Upon infection, the encapsidated
APOBEC3F and APOBEC3G induce G=>A mutations in the viral reverse transcripts
-
Vpr
/ p15 protein is found in virions, is peculiar to most evoluted
retroviruses, and blocks cell cycle in G2 phase upregulating
viral genome transcription. It also has glucocorticoid
receptor
coactivator activity, potently increasing the sensitivity of glucocorticoid
target tissues to cortisol, leading patients with AIDS and normal cortisol
secretion to manifestations compatible with glucocorticoid hypersensitivity
of the immune system, such as suppression of innate and cellular immunities.
-
viral
protein U (Vpu) / p16 is an integral membrane protein which detaches
CD4 from Env during unproper binding in the ER or Golgi, allowing Env to
reach the plasma membrane. It can disrupt NFkB
-mediated
innate responses.
The emergence of HIV-1 escape mutations (due to both lack of proof-reading
activity of HIV-1 reverse transcriptase and activity of human
APOBEC3G
/ CEM15 cytidine deaminase
)
depends on the balance of selective pressure - exerted by numerous factors,
such as CTL frequency (up to 19% of host CD8
+ CTL are specific
for Tat and up to 37% of CD8
+ CTLs are specific for Rev : anyway
CD8
+ CTLs are no longer effective in late stages due to antigenic
shift of wild-type virions), epitope specificiy, properties of the TcR
and the functional state of CTL - and the cost of the mutation to virus
fitness. Reduced B-cell expression of
CD25
/ IL-2R
results in reduced ability to proliferate. Anyway, even when present, the
viral inhibitory activity of neutralizing antibodies results in complete
replacement of neutralization-sensitive virus by successive populations
of resistant virus with mutations in the
env gene : these mutations
are unexpectedly sparse, don't map generally to known neutralization epitopes,
and primarily involve changes in
N-linked glycosylation. The neutralizing
HIV-specific antibody
2G12 - isolated from an infected patient -
rather than binding gp120 as a monomer, forms a dimer in which their VH
domains are swapped : the result is an extended multivalent antigen-binding
site that can recognize the close repeating pattern of oligomannose residues
that mask the surface of gp120 (a conventional antibody could never achieve
this due to steric constraints). Whereas the sugars on the surface of gp120
are closely clustered, on host proteins the same sugars tend to be widely
spaced, so the unusual antibody structure allows the recognition of a unique
feature of the virus.
In absence of escape mutants low-level rebound may have originated
from activated reservoirs of previously infected cells, with the activation
caused by infection with syphilis.
HIV-1 has been reported to acquire a considerable number of cell surface
proteins (including CD3
deg,
CD11a
/ LFA-1,
CD11b
/ Mac-1,
CD18,
CD25,
CD28,
CD43,
CD44,
CD54
/ ICAM-1,
CD55
/ DAF,
CD59
/ protectin,
CD63,
CD71
/ TfR, and
class II MHC molecules
)
upon budding at the site of cell-to-cell contact. The physical presence
of host-encoded CD55 and CD59 was found to protect from complement-mediated
virolysis. The incorporation of ICAM-1 renders HIV-1 virions less susceptible
to Ab-mediated neutralization.
Susceptibility / rapid progression to AIDS:
-
homozygosis for class I MHC loci
-
HLA-A1
-
HLA-Aw19
-
HLA-A24
-
HLA-B7 supertype : variation in viral set-point, in absolute CD4 count
and, by inference, in rate of disease progression, is strongly associated
with particular HLA-B but not HLA-A allele expression. Moreover, substantially
greater selection pressure is imposed on HIV-1 by HLA-B alleles than by
HLA-A. Furthermore, HLA-B gene frequencies in the population are those
likely to be most influenced by HIV disease, consistent with the observation
that B alleles evolve more rapidly than A allelesref.
-
HLA-B8
-
HLA-B35
-
HLA-Cw*04
-
HLA-C7
-
HLA-DR3
-
HLA-DR4
-
HLA-DQ1
-
HLA-DQB1*0302
-
HLA-A1-B8-DR3
-
TAP1
-
TAP2
-
CX3CR1
I249 or M280
-
IL-10
-5'592A
-
abuse of exogenous opioids agonists
play a significant role in the susceptibility of the CNS to HIV-1 infection
and subsequent encephalopathy by inhibiting local production of HIV-1-protective
chemokines (CXCL8 / IL-8
and CCL-4 / MIP-1b
)
and enhancing expression of HIV-1 entry coreceptor genes (CCR3
,
CD195
/ CCR5
,
and CXCR2
)
within the CNS. These effects of opioids appear to be mediated through
the opioid m
receptor
that is expressed on astroglial cells.
-
opsonization of HIV-1 by semen C3a enhances infection of CR3-expressing
cells
-
superinfection from a different strain may occur even in individuals who
have immunity to their initial infection
-
human
immunodeficiency virus type 1 (HIV-1) expression (elevated) 1 (HIVE1)
Resistance :
-
resistance to infection :
-
homozygous CCR5
-D32
(resulting in a truncated protein that remains within the cell; this alteration
doesn't affect the health of homozyogous carriers, indicating that its
functions are dispensable; this allele has been positively selected in
Caucasians 700 years ago : although the allele confers resistance against
HIV-1, HIV has not existed in the human population long enough to account
for this selective pressure. The prevailing hypothesis is that the selective
rise of CCR5-D32 to its current frequency can
be attributed to bubonic plague but CCR5 knockout mice (a species which
is susceptible to pulmonary but not to bubonic plague) are not protected
against Yersinia pestis
infection after allref
: smallpox is more consistent
with this historical roleref,
but it has only been a serious threat in Europe since the 1600s, which
may not have been enough time to have such a big genetic effect. But the
influence of smallpox over the centuries may have been underestimated,
because it largely affected children. The average frequency of this allele
is 10% in European populations. A mathematical model based on the changing
demography of Europe from 1000 to 1800 AD demonstrates how plague epidemics,
1347 to 1670, could have provided the selection pressure that raised the
frequency of the mutation to the level seen today. The original single
mutation appeared over 2,500 years ago and that persistent epidemics of
a haemorrhagic fever that struck at the early classical civilisations served
to force up the frequency to about 5x10-5 at the time of the
Black Death in 1347. Around 1900, historians spread the idea that the plagues
of Europe were not a directly infectious disease but were outbreaks of
bubonic plague, overturning an accepted belief that had stood for 550 years.
Professor Duncan and Dr Scott illustrated in their book, Return of the
Black Death (2004, Wiley), that this idea was incorrect and the plagues
of Europe (1347-1660) were in fact a continuing series of epidemics of
a lethal, viral, haemorrhagic fever that used the CCR5 as an entry port
into the immune system. Using computer modeling, they demonstrated how
this disease provided the selection pressure that forced up the frequency
of the mutation from 1 in 20,000 at the time of the first Black Death epidemic
(which killed some 40% of Europeans between 1347 and 1350) to values today
of 1 in 10. Lethal, viral haemorrhagic fevers were recorded in the Nile
valley from 1500 BC and were followed by the plagues of Mesopotamia (700-450BC),
the plague of Athens (430BC), the plague of Justinian (AD541-700) and the
plagues of the early Islamic empire (AD627-744). These continuing epidemics
slowly raised the frequency from the original single mutation to about
1 in 20,000 in the 14th century simply by conferring protection from an
otherwise certain deathref.
Haemorrhagic plague did not disappear after the Great Plague of London
in 1665-66 but continued in Sweden, Copenhagen, Russia, Poland and Hungary
until 1800 : this maintenance of haemorrhagic plague provided continuing
selection pressure on the CCR5-D32 mutation
and explains why it occurs today at its highest frequency in Scandinavia
and Russia : people in Finland and Russia have the highest level, around
16%, whereas a mere 4% of Sardinians possess it
-
individuals carrying extra copies of CCL3L1
gene (one of several cytokine genes clustered on 17q whose product binds
to several chemokine receptors including CCR9
/ chemokine binding protein 2
and CCR5 / CD195
,
a co-receptor for HIV, and binding of this protein to CCR5 inhibits HIV
entry. The copy number of this gene varies among individuals; most individuals
have 1-6 copies in the diploid genome, although rare individuals have 0
or > 6 copies. The human genome reference assembly contains two full copies
of the gene and a partial pseudogene. This record represents the more telomeric
full-length gene.) are less likely to contract HIV or to progress to full-blown
AIDS. African populations have an average of 6 copies, whereas non-African
populations have half that number. Regardless of the absolute number of
gene copies in a population, those with a below-average number within their
population are more likely than their fellows to contract HIV, and more
likely to develop AIDS if they are infected. This heightened disease susceptibility
is exacerbated in those who also have a 'high-risk' variation of the CCR5
gene. The team estimates that around 40% of the risk of HIV infection can
be explained by these two genes.
-
HLA-A28
-
HLA-Bw70
-
HLA-Aw69
-
HLA-B18
-
rhesus macaques with SNPs in TRIM5a,
which intereferes with coat shedding. TRIM-Cyp fusion protein arose after
the divergence of New and Old World primates when a LINE-1 retrotransposon
catalysed the insertion of a cyclophilin A (CypA) complementary DNA into
the TRIM5 locus : this retrotransposition explains owl monkey post-entry
restriction to HIV-1ref.
The mouse retroviral-restriction factor Friend-virus-susceptibility
factor 1 (Fv1), derived from an endogenous retroviral Gag protein,
protects against infection with murine leukaemia virus (MLV), with the
2 main alleles, Fv1n and Fv1b, conferring
resistance to different strains of MLV (B-MLV and N-MLV, respectively).
Although the mechanism of action of Fv1 is unknown, it seems to involve
an effect on viral capsid (CA) proteins, because polymorphism at position
110 of MLV CA determines the B- or N-tropism. Since the description of
Fv1 more than 30 years ago, it has been shown that cells from other mammals
can also restrict N-MLV, but not B-MLV, infection in a CA110-dependent
manner; the corresponding human activity is known as restriction
factor 1 (Ref1) and the simian activity is known as lentiviral-susceptibility
factor 1 (Lv1). Ref1 and Lv1 are actually species-specific variants
of TRIM5aref1,
ref2
: Fv1 lies upstream of and depends on TRIM5a
for its activity. In addition to MLV, TRIM5a
can also restrict infection with other retroviruses, depending on the species.
For example, TRIM5a from African green monkeys,
but less so from humans, could restrict HIV-1ref.
Also, TRIM5a from African green monkeys could
restrict infection with a strain of simian immunodeficiency virus (SIV)
from macaques but not an SIV strain from African green monkeys. Therefore,
TRIM5a might have evolved to prevent cross-species
retroviral transmission and that for a particular retrovirus to colonize
a new species requires adaptation to avoid species-specific TRIM5a-mediated
restriction — probably by mutations in the CA proteinref.
Given that the TRIM motif is shared by proteins encoded by > 30 genes in
the human genome, this interest in TRIM5a might
lead to the discovery of a family of TRIM factors that restrict different
viruses : indeed, TRIM1 from African green monkeys, humans and owl monkey
kidney cells could restrict N-MLVref.
-
rapid elimination of HIV-1 infection :
-
HLA-A26
-
HLA-B38
-
TAB1
-
TAB4
-
TAP2
-
TAP3
-
long term survivors : alive > 10 years after infection
-
slow progressor (SP) : CD4+ lymphocyte count has declined
to 500 cells / mL.
-
long-term non progressors (LTNP) (< 5%) : always remained asymptomatic
with a CD4+ lymphocyte count > 500 / mL
without antiretroviral drugs.
-
defects in HIV-1 nef gene and/or U3
-
heterozygous CCR5-D32 or other CCR5
promoter SNPs
-
heterozygous CCR2-V64I (due to ability to heterodimerize with CXCR4
/ CD184 / fusin / LESTR
,
downregulating its surface expression)
-
homozygous 3'UTR-A801 SDF-1 (its upregulation allows more effective competitive
inhibition of HIV-1 binding to CXCR4
/ CD184 / fusin / LESTR
)
-
CCL-5 / RANTES
-28G
(its upregulation allows more effective competitive inhibition of HIV-1
binding to CD195 / CCR5
)
-
maximal heterozygosis in class I HLA genes
-
HLA-A11 haplotype
-
HLA-A32 haplotype
-
HLA-Bw4-80Ile
-
HLA-B13 haplotype
-
HLA-B27 haplotype / supertype
-
HLA-B51 haplotype
-
HLA-B57 haplotype
-
HLA-B58 supertype
-
HLA-C2 haplotype
-
HLA-DQA1*0301
-
HLA-DQB1*0302
-
HLA-DQB1*0303
-
HLA-DRB1*0400
-
HLA-DRB4*0101
-
in 1986, Levy's lab described an activity in nonprogressors' CD8+
T lymphocytes that halted the replication of the virus without killing
the infected cells : the CD8+ cell antiviral factor (CAF)ref
has been identified partly with b-chemokines
CCL3
/ MIP-1a
,
CCL-4
/ MIP-1b
and CCL-5 / RANTES
(competitive inhibitors of binding to CCR5
/ CD195
,
so expecially effective against M-tropic / R5 strains). HIV-specific CD8+
T lymphocytes from LTNPs have incresed proliferation rate and perforin
expression compared to those from progressors.
-
neutrophils produce a-defensins
-1,
-2 and -3 (effective against both strains)
-
co-infection with HTLV-2
can potentially interfere with the replicative capacity of HIV-1 by up-regulating
the secretion of HIV-1 suppressive chemokines, in particular CCL3
/ MIP-1a
.
-
co-infection with Hepatitis GB
virus C (HGBV-C)
Transmission
:
-
horizontal transmission :
-
blood and derivatives : viremia is higher during the acute and very late
stages
-
sexual route : strains transmitted by this route express a shorter gp120
isoform which increases attachment to cell surface but increases susceptibility
to antibodies by 10-folds. Peripheral blood CD4+ T cells isolated
from women who have unprotected sexual intercourse with the same man for
> 1 year (and to a much lesser extent men with the same female partner)
are highly resistant to both CCR5 and CXCR4 binding strains of HIV-1 in
vitro: mucosal alloimmunisation might be a novel vaccination strategy
to induce protection against HIV-1. A link between reactivity to foreign
histocompatibility antigens and resistance to infection with simian
immunodeficiency virus (SIV) was first observed in the early 1990s.
Macaques immunised with inactivated SIV cultivated in a human T-cell line
or with the uninfected cells had equal protection on challenge with virus
grown in the same cell line, indicating that protection was mediated by
xenoimmunisation against host-cell proteins in the vaccine. SIV and HIV-1
can incorporate considerable quantities of selected host-cell antigens,
including MHC class I and II molecules, as they bud from infected cellsref1,
ref2,
ref3
and the frequency of antibodies against these components correlate with
protection against SIVref.
Xenoimmunisation of macaques and alloimmunisation of women also induces
significant quantities of CD8+ T-cell-derived antiviral factors,
including CC-chemokinesref1,
ref2
and an increase in resistance of CD4+ T cells to in-vitro
HIV-1 infectionref.
That reduced mother-to-infant transmission of HIV-1 correlates with an
increased MHC class I disparity and that HIV transmission is more frequent
in uniparous compared with multiparous women supports the idea that natural
alloimmunisation may also decrease susceptibility to HIV-1ref1,
ref2.
Alloimmunisation has been proposed as one such strategy because it could
provide sterilising immunity through induction of antibodies and cellular
immunity that together might eliminate free virus, productively infected
cells, and pro-virally infected cells during a transmission eventref.
If infection did occur, alloimmunisation would also provide a second line
of defence via induction of CD8+ T-cell-derived antiviral factorsref.
However, the overall effect of allostimulation on HIV-1 infection is complex,
and alloresponses, in general, may not always lead to protection or control.
Both in-vitro and in-vivo exposure to allogeneic leucocytes
is reported to stimulate HIV-1 replication in already infected cellsref1,
ref2,
ref3.
HIV-1 immunogen (inactivated envelope-depleted HIV-1 coupled with incomplete
Freund's adjuvant), an immunological modifier which contains substantial
amounts of host-cell proteins, did not increase HIV-1 progression-free
survival when used as a therapeutic vaccine in a large clinical trialref.
Furthermore, a study in serodiscordant couples, albeit in small numbers,
failed to show that histocompatibility discordance was a major factor in
non-transmitting couplesref.
It could also be argued that individuals who have unprotected intercourse
with multiple partners should generate an extensive primed allorepertoire.
Although a small cohort of highly exposed persistently seronegative female
sex-workers have been identified, most epidemiological evidence indicates
that unprotected intercourse dangerously exposes most individuals to HIV-1
infection. Peters and colleagues did not show data about the allospecific
immune response in the genital tract, the main site of transmission of
HIV-1, where sterilising immunity must occur and yet where the immune repertoire
in the female needs to be tolerant to paternal (partner) transplantation
antigens. Certainly their findings suggest that regular sex, like pregnancy,
results in a boosting of the MLR to partner antigens in the peripheral
blood. Because the seminal antigens of a male partner are, however, by
definition, shared with those of the fetus of an ensuing pregnancy, the
strength and quality of the local immune response would be expected to
be of paramount importance. Successful pregnancy may, in fact, be associated
with repeated exposure to semen from a specific materef1,
ref2,
ref3
and is characterised by an influx of immune cells and subsequent hypertrophy
of lymph nodes draining the genital tract which is suggestive of induction
of an immune responseref1,
ref2,
ref3,
ref4.
Experiments in mice suggest this finding is due to the generation of active
immunological tolerance, and that seminal-fluid priming prevents rejection
of tumours with the same male background, even in the absence of an ensuing
pregnancyref.
Such an effect is probably due to the presence of extraordinary concentrations
of TGF-ß found in semen (and also 19-hydroxy-PGE in human semen),
which can skew local immune responses to a Th2 phenotype, induce
suppressive Th3 and Tr1 lymphocytes subsets, and
down-regulate the activity of any Th1-effector cellsref1,
ref2,
ref3.
Hence the post-coital immune recognition of male alloantigen in the female
genital tract might routinely result in active local tolerance. Reproduction-driven
cervical immune privilege prevents rejection of other antigenically foreign
cells, such as preneoplastic and neoplastic cells infected with HPV. It
is more difficult to conceive whether down-regulation of the local male
response to female transplantation antigens would be evolutionarily warranted.
However, the natural tendency in the male genital tract, as a component
of the mucosal immune system, could be towards tolerance in the absence
of danger signals. Immune responses, when they occur in the mucosae, might
also be compartmentalised and not reflect events in the peripheral bloodref.
These observations must never, of course, be interpreted as a suggestion
for individuals to have unprotected intercourse for the purpose of alloimmunisationref.
Newly infected cells were detected in the cervical submucosa 3-4 days after
exposure to a primary HIV isolate. At earlier times, extensive and stable
binding occurred when cervical surfaces were exposed to virions or seminal
cells. Cervical mucus provided some protection for the endocervical surface,
by physically trapping virions and seminal cells. Confocal microscopy combined
with 3D surface reconstruction revealed that virions could both bind to
the external surface of the cervical epithelium and actually penetrate
beneath the epithelial surface. In quantitative assays, pretreatment with
a blocking antibody directed against b1
integrin reduced HIV virion binding. Collectively, these results highlight
a continuum of complex interactions that occurs when natural sources of
HIV infectivity are deposited onto mucosal surfaces in the female reproductive
tractref.
-
blood transfusion (tested by Procleix®) (rare nowadays)
-
scintigraphy with radiotracer-labelled leucocytes
-
piercing, tattooing
-
other biological fluids (> 400 mL saliva, ...)
-
zooanthroponosis (resérvoir : Pan
troglodytes troglodytes
)
-
laboratory infection
-
HIV-1 can not replicate in arthropod salivary gland cells (mosquito (Toxorhynchites
amboinensisref),
bed bug (Cimex hemipterusref),
flea, Ornithodoros
moubata
ref)
due to lack of T4 antigen on cell surface; low viral titres in body fluids
and the short survival of the virus in the mosquito (1-2 days, the time
required for the mosquito to digest the blood-meal) render the risk of
mechanical transmission extremely low or nonexistent : It has been calculated
that, for mechanical transmission, an AIDS-free individual would have to
be bitten by 10 million mosquitoes that had been feeding on an HIV carrier
to receive a single unit of HIV from contaminated mosquito mouthparts
-
vertical transmission :
-
the HIV virus cannot penetrate the sperm cells, but is contained in seminal
fluid and at times white blood cells. Sperm washing uses centrifugal force
to separate out the different cellular components of the semen. The healthiest
of the motile sperm will swim up to the top of the solution where they
are harvested and tested for HIV. The final sample of sperm is free of
the fluid and non-sperm cells which can carry the virus. This is then inseminated
into the female partner at her most fertile time of the month. This is
done either through in vitro fertilization in a laboratory culture dish,
or directly injected into a woman's uterus (intrauterine inseminations).
-
CDC estimates that some 300 or so U.S. infants are born each year infected
with HIV, despite recommendations for prenatal HIV testing and for use
of AIDS drugs during pregnancy in infected women. An estimated 700,000
children worldwide developed HIV infections last year, most in Africa and
from mother-to-child transmission during childbirth or early infancy. The
problem is especially acute in southern Africa, where about 1 in 5 pregnant
women has HIV but is unaware of it and many don't see a doctor until giving
birth.Without drug treatment before birth for mothers and shortly thereafter
for newborns, babies born to infected women have a 25-30% chance of becoming
infected. With optimal treatment of the mother, the transmission rate drops
to < 2%. The odds increase if the mother isn't treated until she's in
labor, but that's still better than no treatment at all.
-
placental route (the placenta protects most unborn children from HIV. Infection
only becomes likely if the placenta is damaged, or after it breaks naturally,
during labor => prevention by Caesarian section)
-
lactation : babies of HIV-positive mothers stand a 15% chance of becoming
infected during breast-feeding. Milk formula isn't available to many in
poorer countries. And a lack of breast milk has long-term health effects,
including increased susceptibility to respiratory diseases - a major killer
of infants in the developing world. Additionally, if there's not enough
food or if you can't afford the formula or if people are diluting down
the formula, what you get is a baby that dies of malnutrition. Anyway a
baby's chance of contracting HIV falls to <1% if they receive antiretroviral
drugs while being nursed and the doses needed to protect babies are a fraction
of those used to treat adults, and they are only necessary for the first
6-12 months of a child's life. So some might argue that treating infants
is an affordable alternative to treating their mothers, but nursing mothers
must also receive medication so that they can live to look after their
children. But researchers estimate that only 1% of adults in sub-Saharan
Africa have access to antiretroviral drugs. Breastfeeding causes nearly
40% of all pediatric HIV infections, yet also prevents millions of child
deaths every year by protecting infants from diarrhea and other infections.
Exclusive breastfeeding substantially reduces the transmission of HIV from
mother to infant and infant death, compared with partial breastfeeding.
Infants who were introduced to solid foods or animal milk within the first
three months were at four times greater risk of contracting HIV through
breastfeeding compared to those who were exclusively breastfedref.
International guidelines currently recommend that HIV-infected mothers
should avoid all breastfeeding, but only if replacement feeding is acceptable,
feasible, affordable, sustainable and safe : for the large majority of
African women, this isn’t the case and breastfeeding is the only choice.
These findings indicate that for these mothers, delaying introduction of
all non-breast milk foods will substantially reduce the risk of HIV and
death for their infants
Prevention : an HIV+ mother is
given a single dose of nevirapine
during labor and her baby gets one dose within 48 hours of birth. The baby
has active levels in its bloodstream for at least the first week of life,
hence being protected even during the early period of breastfeeding. Researchers
are looking at the benefits of giving babies a drug such as nevirapine
once a day for the first 6 months while they're breastfeeding, then having
an early weaning. The ability to screen women rapidly for HIV infections
and offer antiretroviral therapy has the potential to prevent HIV transmission
to hundreds of thousands of infants that otherwise might occur. Orasure
Technologies' OraQuick test involves a finger-prick blood test and
was approved for U.S. use in 2002 : it takes an average of 66 minutes to
test, get results and explain them to the women - plenty of time to begin
treatment while labor is still progressing. High sensitivity but poor specificity
require confiration with conventional tests. Treatment for HIV-exposed
infants is generally AZT (zidovudine) syrup every 6 hours for 6 weeks;
some also get a single dose of nevirapine, an inexpensive AIDS drug shown
to help prevent mother-to-child transmission. Infected mothers also get
AZT and some received nevirapine, too.
Pathogenesis
:
-
anti-lymphocyte antibodies (ALA), mainly IgM, have been detected
in the plasma of 53.8ref-75%
(of 78)ref
of HIV-positive patients tested. ALA bind to both CD4+, CD8+,
and B lymphocytes, but not to monocytes. ALA could not be detected in the
plasma of normal subjects, patients with acute renal failure undergoing
renal dialysis, or patients with high levels of circulating immune complexesref
: antigenic specificities of ALA in HIV infection are resistant to pronase
treatment and are not related to CD4 and CD8 moleculesref
-
anti-lymphocytic ganglioside antibodies were detected in 23 out of 49 AIDS
patients sera (46.9%). All positive sera reacted selectively with the GM3
comigrating band from AIDS lymphocytes. 22 out of the 23 anti-lymphocytic
GM3 positive sera also had antibodies against CD4+
T cells, versus 17/26 anti-GM3 negative. Furthermore, patients
with lymphocytic GM3 antibodies showed a significantly higher
antibody reactivity against CD4+ T cells than patients in which
these antibodies were not detected.The absorption tests revealed that preincubation
of positive sera with GM3 was followed by a decrease in the
reaction with target lymphocytes. These findings suggest that anti-GM3
antibodies are a portion, but not the majority, of antibodies reacting
with CD4+ T cellsref.
-
MHC class II- T cells showed a stronger reaction with anti-lymphocyte
antibodies than B cells or MHC class II+ T cells. Patients with
antibodies against CD4 lymphocytes showed a significantly higher antibody
reaction with the retroviral antigen gp41 than patients without these antibodies.
An association between anti-lymphocyte antibodies and antibody reactivity
against other HIV-1 antigens was not noticedref.
-
antibodies elicited by HIV infection can interact with antibodies elicited
by cofactor infections (HIV-CMV; HIV-HBV; HIV-tuberculosis; HIV-mycoplasmas;
HIV-S. aureus; and CMV-mycoplasmas) to form CIC, and some of these
antibodies mimic ALA so that they may function as LCTAref
-
directed against OKT4+ or OKT11+ cells whereas OKT8+
cells showed no detectable reactivity (a population of T cells that is
predominantly composed of helper cells and does not include suppressor
cells)ref
ALA proved to be useful prognostic indicators for the course of the HIV
infectionref.
There was a statistically significant correlation of increased Ig+ cells
with HIV infection, decreased CD4/CD8 ratios, increased serum neopterin
levels, and abnormal in-vitro responses to pooled allogeneic stimulator
cells or CD3 monoclonal antibody. Patients with ALA were lymphopenic, had
decreased absolute counts of CD4+, CD25+, CD21+
and OKM5+ cells, and higher percentages of CD8+ and
OKIa1+ cells in their blood than patients without ALAref.
ADCC against non-T cells and lymphoblastoid cell lines (P3HR-1K and Raji)
were detected in AIDS patients and in homosexuals and haemophiliacs with
positive or negative HIV serology. Anti-class II antigen specificity was
revealed by experiments in which class II antigens on target cells were
blocked with monoclonal anti-class II antibody (DA6,231) and the cytotoxic
reaction induced by patient's sera was abolished. In contrast, ADCC was
not impaired by preincubating the target cells with anti-class I monoclonal
antibody (W6/32)ref.
Of homosexuals individuals whose sera contained ALA, 71% of ARC patients
and 83% of healthy (anti-HIV Ab negative) homosexuals had antibodies recognizing
a 73 kDa molecule. ALA present in ARC sera reacted with CD3+,
CD4+ and CD8+ lymphocytes while little reactivity
with B cells was observed. Our results indicate that ALA appear in homosexuals
prior to HIV infection and are reactive primarily with T lymphocytes. A
73 kD structure associated with the T cell membrane is frequently the target
for these antibodiesref.
The sperm has been proposed to be the cause of AIDS, selectively accepting
into its interior only macrophage-tropic HIV through its CD4+
antigens and carrying this HIV into a person through 4 possible pathways:
rectum (anal sex), genital ulcers, blood transfusions, and female circumcision.
Then the sperm acts as a 'Trojan horse' by entering HLA-DR+
CD4+ T cells and releasing the HIV into these cells. The released
HIV in turn mutates to a form capable of attacking CD4+ T cells.
Thus the sperm by a 'Trojan horse' mechanism has changed the tropism of
HIV. However, experimental evidence indicates that this mutated HIV is
essentially non-toxic. In contrast, it is concluded that the sperm is extremely
toxic since it is capable of inducing autoimmune reactions (by means of
its CD4+ antigens) and is capable of entering and destroying
HLA-DR+ CD8+ and HLA-DR+ CD4+
T cells in either the presence or absence of HIV (AIDS or ICL
).
Hence, the mysteries of AIDS can be explained by the presence of the toxic
sperm and its complicated interactions with HIV (the 'Trojan horse' mechanism)ref.
-
antibody-dependent
enhancement (ADE)
of viral infection
-
astrocytes can be infected by primary HIV-1 isolates via a mechanism independent
of CD4 or major chemokine receptors
-
Hin-1
protein is found only in HIV-1 infected cells
-
HIV-specific CD8+ T cells produce antiviral cytokines but are
impaired in cytolytic function : they express significantly lower levels
of perforin and have persistent CD27 expression (suggesting impaired maturation)ref
-
individuals with advanced HIV-1 infection have higher proportions of T
cells that are short lived, in both the CD4+ and CD8+
memory/effector T-cell subpopulations, compared by healthy controls. In
advanced HIV-1 infection, total pool sizes of short-lived cells are only
moderately affected, whereas the size of the long-lived pool is reduced
by a factor > 4. This indicates that patients with HIV-1 have a reduced
ability to generate long-lived progenitor cells for maintaining the T-cell
pool. Effective treatment with HAART is able to restore the capacity to
generate these progenitor cells, by reducing the levels of T-cell proliferation
and T-cell death in infected individuals. These data provide evidence against
a model in which the characteristic depletion of CD4+ T cells
that occurs in HIV-1 infection results from direct HIV-mediated cell killing,
as long-lived progenitors of both CD4+ and CD8+ T-cell
subpopulations are reduced in patients infected with HIV-1. Moreover, they
favour a model in which increased levels of proliferation of effector/memory
T cells in HIV infection reflect chronic activationref
-
A146P SNP in Gag is more common in patients expressing the MHC class I
molecule HLA-B57 as the result of selection pressure (may arise in an HIV+
HLA-B57+ child of an infected HLA-B57- mother), and
is associted with a 22-fold increase in viral load compared with wild-type
virus, resulting in an increased risk of progression to AIDS. The A146P
mutation affects the pathway by which proteins become processed (ERAP1
/ARTS1 can not cut amino-terminal extended ISW9 peptides that contain
proline rather than alanine at residue 146) and presented on MHC molecules,
and therefore indirectly prevents lysis by CTLS specific for the epitope
ISW9 (residues 147-155), which doesn't contain residue 149ref.
-
given that the gastrointestinal tract and other lymphoid tissues harbour
most of the body’s CD4+ T cells and that, in the gut, a large
number of these cells are activated and express the HIV co-receptor CCR5
,
the intestinal CD4+ T cells are potentially highly susceptible
to infection with HIV. In fact the gastrointestinal tract has the most
marked depletion of CD4+ T cells. Specifically, deletion mainly
occurred in the effector sites (the lamina propria) as opposed to the inductive
sites (Peyer’s patches and lymphoid follicles) of the gut mucosa. This
deletion occurs rapidly and at all stages of HIV infection (before changes
observed in the blood), regardless of administration of HAART
for up to 5 years, which on the other side restores normal CD4+
T-cell numbers in the blood. Disrupted lymphoid architecture (increased
T-cell activation is associated with collagen deposition in the lymph nodes)
might disturb normal lymphoid-tissue homeostasis, which might then impair
CD4+ T-cell reconstitution of the gut following depletion by
infection with HIVref1,
ref2.
In monkeys, within a few days of infection, SIV infects up to 60% of memory
CD4+ lymphocytes, and it goes on to kill about 50% of them.
These cells are responsible for remembering infectious agents and triggering
the immune system to attack them. The virus worms its way into all of the
cells it kills, but also triggers cell suicide in many cells without actually
invading them. The idea that HIV inflicts severe damage very early in infection
stemmed from a 1998 paper showing that SIV quickly obliterates CD4+
cells in the guts of monkeys : the slow crumbling of patients' immune systems,
and their increased vulnerability to infection, is triggered by the early
viral damage. You have a massive wound in the first 3 months of infection
and the patient dies slowly as a result : if this is true, then the number
of immune cells killed by HIV in its first few days might be used to predict
how quickly the disease will advance in a particular patient. The realization
could also prompt changes in the way experimental vaccines are devised
and tested. It suggests that a jab must stop the infection at its earliest
stages: perhaps by working in the gut, where the destruction of immune
cells is most dramatic. The results also back the case for giving
drugs as a preventative measure to groups at very high risk of infection,
such as sex workers, to prevent the virus gaining a foothold. And researchers
may need to find ways of supplementing existing antiviral drugs with treatments
that regenerate the devastated population of memory CD4+ cells
-
aberrant polyclonal B cell activation and hypergammaglobulinemia with many
autoantibodies : B cells from patients show impaired reactivity to immunisation
and in vitro activation signalsref.
During frank loss of immunocompetence, autoimmune diseases that are predominantly
T cell subtype CD8 driven predominate. In stage I there is the acute HIV
infection, and the immune system is intact. In this stage, autoimmune diseases
may develop. Stage II describes the quiescent period without overt manifestations
of AIDS. However, there is a declining CD4 count indicative of some immunosuppression.
Autoimmune diseases are not found. During stage III there is immunosuppression
with a low CD4 count and the development of AIDS. CD8 T cells predominant
and diseases such as psoriasis and diffuse immune lymphocytic syndrome
(similar to Sjogren's syndrome) may present or even be the initial manifestation
of AIDS. Also during this stage no autoimmune diseases are found. In stage
IV there is restoration of immune competence following HAART
.
In this setting, there is a resurgence of autoimmune diseases. The frequency
of reported rheumatological syndromes in HIV-infected patients ranges from
1 to 60%. The list of reported autoimmune diseases in HIV/AIDS include
systemic
lupus erythematosus (SLE)
,
anti-phospholipid
syndrome
,
vasculitis
,
primary
biliary cirrhosis (PBC)
,
polymyositis
,
Graves'
disease
,
and idiopathic
thrombocytopenic purpura (ITP)
.
Also, there is an array of autoantibodies reported in HIV/AIDS patients
which include anti-cardiolipin, anti-b2
GPI, anti-DNA, anti-small nuclear ribonucleoproteins (snRNP), anti-thyroglobulin,
anti-thyroid peroxidase, anti-myosin, and anti-erythropoietin antibodies.
The association of autoantibodies in HIV-infected patients to clinical
autoimmune disease is yet to be established. With the upsurge of HAART,
the incidence of autoimmune diseases in HIV-infected patients is increasingref.
-
HIV infection leads to a state of chronic immune activation and progressive
deterioration in immune function, manifested most recognizably by the progressive
depletion of CD4+ T cells. A substantial percentage of NK cells
from patients with HIV infection are activated and express the natural
cytotoxicity receptor (NCR) NKp44. A cellular ligand for NKp44 (NKp44L)
is expressed during HIV-1 infection and is correlated with both the progression
of CD4+ T cell depletion and the increase of viral load. CD4+
T cells expressing this ligand are highly sensitive to the NK lysis activity
mediated by NKp44+ NK cells. The expression of NKp44L is induced
by the linear motif NH2-SWSNKS-COOH of the HIV-1 envelope gp41
protein. This highly conserved motif appears critical to the sharp increase
in NK lysis of CD4+ T cells from HIV-infected patients. These
studies strongly suggest that induction of NKp44L plays a key role in the
lysis of CD4+ T cells by activated NK cells in HIV infection
and consequently provide a framework for considering how HIV-1 may use
NK cell immune surveillance to trigger CD4+ T cells. Understanding
this mechanism may help to develop future therapeutic strategies and vaccines
against HIV-1 infectionref.
-
HIV-1 meninges and temporal lobe subpopulations evolve about 30 and 100
times faster, respectively, than the other viral populations in the brain.
However, maximum likelihood codon-based substitution models did not detect
any site under significant positive selective pressure, and the main cause
of HIV-1 genetic variation appeared to be random genetic drift. Therefore,
the higher evolutionary rate in the meninges and temporal lobe could be
due to an enhanced infection/expansion rate of macrophages as a consequence
of the immune system failure. In conclusion, in this case study, viral
infection in the brain progressed with a nonspecific genetic evolution,
recurrent migration events, and an expansion of macrophage-tropic sequences.
The data suggest that after immune failure newly produced viral variants,
which would be rapidly cleared under normal conditions, begin to productively
infect macrophages in a "self-amplifying" cycle of infection/inflammatory
response that could be at the origin of HIV-associated dementiaref
-
HIV-1 evolves in vivo under selective pressure from CD8+
T-lymphocyte (CTL) responses, which are in turn determined by host and
viral genetic factors, such as restricting MHC molecules and the available
viral epitope sequences. Identical twins infected with HIV-1 as neonates
from a common blood transfusion, with subsequently similar environmental
exposures, allows controlled comparisons of CTL targeting and viral evolution.
17 years after infection, their CTL targeting of HIV-1 was remarkably similar.
In contrast, their overall TCR profiles were highly dissimilar,
and a dominant epitope was recognized by distinctly different TCR in each
twin. Furthermore, their viral epitopes had diverged, and there was ongoing
viral phylogenetic divergence between the twins between 12 and 17 years
after infection. These results indicate that while CTL targeting is predominately
genetically determined, stochastic influences render the interaction of
HIV-1 and host immunity, and therefore viral escape and CTL efficacy, unpredictableref.
-
latency occurs in CD4+ lymphocytes because RNA polymerase II
cannot bind to the proviral long terminal repeat (LTR) because of alterations
in the chromatin structure that had been induced by the binding of the
histone deacetylase enzyme HDAC1 to the LTR. Inhibition of HDAC1 or knockdown
of NF-kB p50 (which recruits and complexes with
HDAC1) were sufficient for the production of short nonproductive viral
transcripts, and full viral transcription could be achieved by coexpressing
the viral transactivating protein Tat. Establishing this mechanism in primary
CD4 T cells will be the next step in determining whether combinations of
HDAC1 inhibition and Tat activation will prove viable as a means of overcoming
latency in the clinicref
-
The adverse effects of immune activation on CD4+ T-cell recovery
and the relationship between CD4+ T-cell counts and effector
T-cell function were examined in HIV-1 patients receiving long-term effective
ART. Patients with nadir CD4+ T-cell counts <100/ml,
> 12 months on ART and >6 months with <50 HIV RNA copies/ml were stratified
by current CD4+ T-cell counts and patients from the lowest (n
= 15) and highest (n = 12) tertiles were studied. Proliferation (Ki67),
activation (HLA-DR, CD38) and replicative senescence (CD57) were assessed
by flow cytometry and CD4+ T-cell responses to CMV by IFN-g
ELISpot. Proportions of CD4+ T-cells expressing HLA-DR or CD57
were strong univariate predictors of total (P = 0.0002 and P = 0.002) and
naive
(P < 0.0001 and P < 0.0001, respectively) CD4+ T-cell
counts, suggesting that CD4+ T-cell activation drives the depletion
of naive CD4+ T-cells. This was clearest in patients with a
small/undetectable thymus. IFN-g responses to
CMV were similar in patients with low or high CD4+ T-cell countsref.
=> a
chronic
syndrome
CDC staging, 1987 :