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HIV

2007 Schools Wikipedia Selection. Related subjects: Health and medicine

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   Human immunodeficiency virus
   Image:Aids_virus.jpg
   Stylized rendering of a cross section
   of the human immunodeficiency virus
            Virus classification

   Group:   Group VI ( ssRNA-RT)
   Family:  Retroviridae
   Genus:   Lentivirus
   Species: Human immunodeficiency virus 1
   Species: Human immunodeficiency virus 2

   CAPTION: International Statistical Classification of Diseases and
   Related Health Problems Codes
   Classifications and external resources

   ICD- 10 B20-B24
   ICD- 9  042- 044

   Human immunodeficiency virus or HIV is a retrovirus that causes
   Acquired Immune Deficiency Syndrome (AIDS), a condition in which the
   immune system begins to fail, leading to life-threatening opportunistic
   infections. Previous names for the virus include Human T-Lymphotropic
   Virus-III (HTLV-III) and lymphadenopathy-associated virus (LAV).

   Infection with HIV occurs by the transfer of blood, semen, vaginal
   fluid, Cowper's fluid or breast milk. Within these body fluids HIV is
   present as both free virus particles and virus within infected immune
   cells. The three major routes of transmission are unprotected sexual
   intercourse, contaminated needles and transmission from an infected
   mother to her baby at birth or through breast milk. Screening of blood
   products for HIV in the developed world has largely eliminated
   transmission through blood transfusions or infected blood products in
   these countries.

   HIV infection in humans is now pandemic. As of January 2006, the Joint
   United Nations Programme on HIV/AIDS (UNAIDS) and the World Health
   Organization (WHO) estimate that AIDS has killed more than 25 million
   people since it was first recognized on December 1, 1981, making it one
   of the most destructive pandemics in recorded history. In 2005 alone,
   AIDS claimed an estimated 2.4-3.3 million lives, of which more than
   570,000 were children. A third of these deaths are occurring in
   sub-Saharan Africa, retarding economic growth and increasing poverty.
   According to current estimates, HIV is set to infect 90 million people
   in Africa, resulting in a minimum estimate of 18 million orphans.
   Antiretroviral treatment reduces both the mortality and the morbidity
   of HIV infection, but routine access to antiretroviral medication is
   not available in all countries.

   HIV primarily infects vital cells in the human immune system such as
   helper T cells (specifically CD4^+ T cells), macrophages and dendritic
   cells. HIV infection leads to low levels of CD4^+ T cells through three
   main mechanisms: firstly, direct viral killing of infected cells;
   secondly, increased rates of apoptosis in infected cells; and thirdly,
   killing of infected CD4^+ T cells by CD8 cytotoxic lymphocytes that
   recognize infected cells. When CD4^+ T cell numbers decline below a
   critical level, cell-mediated immunity is lost, and the body becomes
   progressively more susceptible to opportunistic infections. If
   untreated, eventually most HIV-infected individuals develop AIDS and
   die; however about one in ten remain healthy for many years, with no
   noticeable symptoms. Treatment with anti-retrovirals, where available,
   increases the life expectancy of people infected with HIV. It is hoped
   that current and future treatments may allow HIV-infected individuals
   to achieve a life expectancy approaching that of the general public
   (see Treatment).

Origin and discovery

   The AIDS epidemic was discovered June 5, 1981, when the U.S. Centers
   for Disease Control and Prevention reported a cluster of Pneumocystis
   carinii pneumonia (now classified as Pneumocystis jiroveci pneumonia)
   in five homosexual men in Los Angeles. The disease was originally
   dubbed GRID, or Gay-Related Immune Deficiency, but health authorities
   soon realized that nearly half of the people identified with the
   syndrome were not homosexual men. In 1982, the CDC introduced the term
   AIDS to describe the newly recognized syndrome, though it was still
   casually referred to as GRID.

   In 1983, scientists led by Luc Montagnier at the Pasteur Institute in
   France first discovered the virus that causes AIDS. They called it
   lymphadenopathy-associated virus (LAV). A year later a team led by
   Robert Gallo of the United States confirmed the discovery of the virus,
   but they renamed it human T lymphotropic virus type III (HTLV-III). The
   dual discovery led to considerable scientific disagreement, and it was
   not until President Mitterrand of France and President Reagan of the
   USA met that the major issues were resolved. In 1986, both the French
   and the US names for the virus itself were dropped in favour of the new
   term, human immunodeficiency virus (HIV).

   HIV was classified as a member of the genus lentivirus, part of the
   family of retroviridae. Lentiviruses have many common morphologies and
   biological properties. Many species are infected by lentiviruses, which
   are characteristically responsible for long-duration illnesses with a
   long incubation period. Lentiviruses are transmitted as
   single-stranded, positive-sense, enveloped RNA viruses. Upon entry of
   the target cell, the viral RNA genome is converted to double-stranded
   DNA by a virally encoded reverse transcriptase that is present in the
   virus particle. This viral DNA is then integrated into the cellular DNA
   by a virally encoded integrase so that the genome can be transcribed.
   Once the virus has infected the cell, two pathways are possible: either
   the virus becomes latent and the infected cell continues to function,
   or the virus becomes active and replicates, and a large number of virus
   particles are liberated that can then infect other cells.

   Two species of HIV infect humans: HIV-1 and HIV-2. HIV-1 is thought to
   have originated in southern Cameroon after jumping from wild
   chimpanzees (Pan troglodytes troglodytes) to humans during the
   twentieth century. HIV-2 may have originated from the Sooty Mangabey
   (Cercocebus atys), an Old World monkey of Guinea-Bissau, Gabon, and
   Cameroon. HIV-1 is the most virulent. It is easily transmitted and is
   the cause of the majority of HIV infections globally. HIV-2 is less
   transmittable and is largely confined to West Africa. HIV-1 is the
   virus that was initially discovered and termed LAV.

   Three of the earliest known instances of HIV-1 infection are as
   follows:
    1. A plasma sample taken in 1959 from an adult male living in what is
       now the Democratic Republic of Congo.
    2. HIV found in tissue samples from a 15 year old African-American
       teenager who died in St. Louis in 1969.
    3. HIV found in tissue samples from a Norwegian sailor who died around
       1976.

   Although a variety of theories exist explaining the transfer of HIV to
   humans, no single hypothesis is widely accepted, and the topic remains
   controversial. Freelance journalist Tom Curtis discussed one
   controversial possibility for the origin of HIV/AIDS in a 1992 Rolling
   Stone magazine article. He put forward what is now known as the OPV
   AIDS hypothesis, which suggests that AIDS was inadvertently caused in
   the late 1950s in the Belgian Congo by Hilary Koprowski's research into
   a polio vaccine. Although subsequently retracted due to libel issues
   surrounding its claims, the Rolling Stone article motivated another
   freelance journalist, Edward Hooper, to probe more deeply into this
   subject. Hooper's research resulted in his publishing a 1999 book, The
   River, in which he alleged that an experimental oral polio vaccine
   prepared using chimpanzee kidney tissue was the route through which
   simian immunodeficiency virus (SIV) crossed into humans to become HIV,
   thus starting the human AIDS pandemic. This theory is contradicted by
   an analysis of genetic mutation in primate lentivirus strains that
   indicates with 95% certainty that the origin of the HIV-1 strain dates
   to about 1930.

Transmission

   Estimated per act risk for acquisition of HIV-1
   by exposure route
   Exposure Route Estimated infections per 10,000 exposures to an infected
   source
   Blood Transfusion 9,000
   Childbirth 2,500
   Needle-sharing injection drug use- 67
   Receptive anal intercourse^* 50
   Percutaneous needle stick 30
   Receptive penile-vaginal intercourse^* 10
   Insertive anal intercourse^* 6.5
   Insertive penile-vaginal intercourse^* 5
   Receptive fellatio^* 1
   Insertive fellatio^* 0.5
   ^* assuming no condom use

   Since the beginning of the pandemic, three main transmission routes for
   HIV have been identified:
     * Sexual route. The majority of HIV infections are acquired through
       unprotected sexual relations. Sexual transmission can occur when
       infected sexual secretions of one partner come into contact with
       the rectal, genital or oral mucous membranes of another.
     * Blood or blood product route. This transmission route can account
       for infections in intravenous drug users, hemophiliacs and
       recipients of blood transfusions (though most transfusions are
       checked for HIV in the developed world) and blood products. It is
       also of concern for persons receiving medical care in regions where
       there is prevalent substandard hygiene in the use of injection
       equipment, such as the reuse of needles in Third World countries.
       Health care workers such as nurses, laboratory workers, and
       doctors, have also been infected, although this occurs more rarely.
       People who give and receive tattoos, piercings and scarification
       procedures can also be at risk of infection.
     * Mother-to-child transmission (MTCT). The transmission of the virus
       from the mother to the child can occur in utero during the last
       weeks of pregnancy and at childbirth. In the absence of treatment,
       the transmission rate between the mother and child is 25%. However,
       where drug treatment and Cesarian section are available, this can
       be reduced to 1%. Breast feeding also presents a risk of infection
       for the baby.

   HIV-2 is transmitted much less frequently by the MTCT and sexual route
   than HIV-1.

   HIV has been found at low concentrations in the saliva, tears and urine
   of infected individuals, but the risk of transmission by these
   secretions is negligible. The use of physical barriers such as the
   latex condom is widely advocated to reduce the sexual transmission of
   HIV. Spermicide when used alone or with vaginal contraceptives like a
   diaphragm actually increases the male to female transmission rate due
   to inflammation of the vagina, and should not be considered a barrier
   to infection. Current research is clarifying the relationship between
   male circumcision and HIV in differing social and cultural contexts.
   Even though male circumcision may lead to a reduction of infection risk
   in heterosexual men by up to 60%, UNAIDS believes that it is premature
   to recommend male circumcision as part of HIV prevention programs.
   South African medical experts are concerned that the repeated use of
   unsterilized blades in the ritual circumcision of adolescent boys may
   be spreading HIV.

Structure and genome

   Diagram of HIV
   Enlarge
   Diagram of HIV

   HIV is different in structure from other retroviruses. It is about
   120 nm in diameter (120 billionths of a meter; around 60 times smaller
   than a red blood cell) and roughly spherical.

   It is composed of two copies of positive single-stranded RNA that codes
   for the virus's nine genes enclosed by a conical capsid composed of
   2,000 copies of the viral protein, p24. The single-stranded RNA is
   tightly bound to nucleocapsid proteins, p7 and enzymes needed for the
   development of the virion such as reverse transcriptase, proteases and
   integrase. A matrix composed of the viral protein p17 surrounds the
   capsid ensuring the integrity of the virion particle. This is, in turn,
   surrounded by the viral envelope which is composed of two layers of
   fatty molecules called phospholipids taken from the membrane of a human
   cell when a newly formed virus particle buds from the cell. Embedded in
   the viral envelope are proteins from the host cell and about 70 copies
   of a complex HIV protein that protrudes through the surface of the
   virus particle. This protein, known as Env, consists of a cap made of
   three molecules called glycoprotein (gp) 120, and a stem consisting of
   three gp41 molecules that anchor the structure into the viral envelope.
   This glycoprotein complex enables the virus to attach to and fuse with
   target cells to initiate the infectious cycle. Both these surface
   proteins, especially gp120, have been considered as targets of future
   treatments or vaccines against HIV.

   Of the nine genes that are encoded within the RNA genome, three of
   these genes, gag, pol, and env, contain information needed to make the
   structural proteins for new virus particles. env, for example, codes
   for a protein called gp160 that is broken down by a viral enzyme to
   form gp120 and gp41. The six remaining genes, tat, rev, nef, vif, vpr,
   and vpu (or vpx in the case of HIV-2), are regulatory genes for
   proteins that control the ability of HIV to infect cells, produce new
   copies of virus (replicate), or cause disease. The protein encoded by
   nef, for instance, appears necessary for the virus to replicate
   efficiently, and the vpu-encoded protein influences the release of new
   virus particles from infected cells. The ends of each strand of HIV RNA
   contain an RNA sequence called the long terminal repeat (LTR). Regions
   in the LTR act as switches to control production of new viruses and can
   be triggered by proteins from either HIV or the host cell.

Tropism

   The term viral tropism refers to which cell types HIV infects. HIV can
   infect a variety of immune cells such as CD4^+ T cells, macrophages,
   and microglial cells. HIV-1 entry to macrophages and CD4^+ T cells is
   mediated through interaction of the virion envelope glycoproteins
   (gp120) with the CD4 molecule on the target cells and also with
   chemokine coreceptors.

   Macrophage (M-tropic) strains of HIV-1, or non- syncitia-inducing
   strains (NSI) use the β-chemokine receptor CCR5 for entry and are thus
   able to replicate in macrophages and CD4^+ T cells. This CCR5
   coreceptor is used by almost all primary HIV-1 isolates regardless of
   viral genetic subtype. Indeed, macrophages play a key role in several
   critical aspects of HIV infection. They appear to be the first cells
   infected by HIV and perhaps the source of HIV production when CD4^+
   cells become depleted in the patient. Macrophages and microglial cells
   are the cells infected by HIV in the central nervous system. In tonsils
   and adenoids of HIV-infected patients, macrophages fuse into
   multinucleated giant cells that produce huge amounts of virus.

   T-tropic isolates, or syncitia-inducing (SI) strains replicate in
   primary CD4^+ T cells as well as in macrophages and use the α-chemokine
   receptor, CXCR4, for entry. The α-chemokine, SDF-1, a ligand for CXCR4,
   suppresses replication of T-tropic HIV-1 isolates. It does this by
   down-regulating the expression of CXCR4 on the surface of these cells.
   HIV that use only the CCR5 receptor are termed R5, those that only use
   CXCR4 are termed X4, and those that use both, X4R5. However, the use of
   coreceptor alone does not explain viral tropism, as not all R5 viruses
   are able to use CCR5 on macrophages for a productive infection and HIV
   can also infect a subtype of myeloid dendritic cells, which probably
   constitute a reservoir that maintains infection when CD4^+ T cell
   numbers have declined to extremely low levels.

   Some people are resistant to certain strains of HIV. One example of how
   this occurs is people with the CCR5-Δ32 mutation; these people are
   resistant to infection with R5 virus as the mutation stops HIV from
   binding to this coreceptor, reducing its ability to infect target
   cells.

   Heterosexual intercourse is the major mode of HIV transmission. Both X4
   and R5 HIV are present in the seminal fluid which is passed from
   partner to partner. The virions can then infect numerous cellular
   targets and disseminate into the whole organism. However, a selection
   process leads to a predominant transmission of the R5 virus through
   this pathway. How this selective process works is still under
   investigation, but one model is that spermatozoa may selectively carry
   R5 HIV as they possess both CCR3 and CCR5 but not CXCR4 on their
   surface and that genital epithelial cells preferentially sequester X4
   virus. In patients infected with subtype B HIV-1, there is often a
   co-receptor switch in late-stage disease and T-tropic variants appear
   that can infect a variety of T cells through CXCR4. These variants then
   replicate more aggressively with heightened virulence that causes rapid
   T cell depletion, immune system collapse, and opportunistic infections
   that mark the advent of AIDS. Thus, during the course of infection,
   viral adaptation to the use of CXCR4 instead of CCR5 may be a key step
   in the progression to AIDS. A number of studies with subtype B-infected
   individuals have determined that between 40 and 50% of AIDS patients
   can harbour viruses of the SI, and presumably the X4, phenotype.

Replication cycle

                                                 The HIV replication cycle
                                                                   Enlarge
                                                 The HIV replication cycle

                                      The immature and mature forms of HIV
                                                                   Enlarge
                                      The immature and mature forms of HIV

Entry to the cell

   HIV enters macrophages and CD4^+ T cells by the adsorption of
   glycoproteins on its surface to receptors on the target cell followed
   by fusion of the viral envelope with the cell membrane and the release
   of the HIV capsid into the cell.

   The interactions of the trimeric envelope complex (gp160 spike,
   discussed above) and both CD4 and a chemokine receptor (generally
   either CCR5 or CXCR4 but others are known to interact) on the cell
   surface. The gp160 spike contains binding domains for both CD4 and
   chemokine receptors. The first step in fusion involves the
   high-affinity attachment of the CD4 binding domains of gp120 to CD4.
   Once gp120 is bound with the CD4 protein, the envelope complex
   undergoes a structural change, exposing the chemokine binding domains
   of gp120 and allowing them to interact with the target chemokine
   receptor. This allows for a more stable two-pronged attachment, which
   allows the N-terminal fusion peptide gp41 to penetrate the cell
   membrane. Repeat sequences in gp41, HR1 and HR2 then interact, causing
   the collapse of the extracellular portion of gp41 into a hairpin. This
   loop structure brings the virus and cell membranes close together,
   allowing fusion of the membranes and subsequent entry of the viral
   capsid.

   Once HIV has bound to the target cell, the HIV RNA and various enzymes,
   including reverse transcriptase, integrase and protease, are injected
   into the cell.

   HIV can infect dendritic cells (DCs) by this CD4-CCR5 route, but
   another route using mannose-specific C-type lectin receptors such as
   DC-SIGN can also be used. DCs are one of the first cells encountered by
   the virus during sexual transmission. They are currently thought to
   play an important role by transmitting HIV to T cells once the virus
   has been captured in the mucosa by DCs.

Replication and transcription

   Once the viral capsid enters the cell, an enzyme called reverse
   transcriptase liberates the single-stranded (+) RNA from the attached
   viral proteins and copies it into a complementary DNA of 9 kb size.
   This process of reverse transcription is extremely error-prone and it
   is during this step that mutations may occur. Such mutations may cause
   drug resistance. The reverse transcriptase then makes a complementary
   DNA strand to form a double-stranded viral DNA intermediate (vDNA).
   This vDNA is then transported into the cell nucleus. The integration of
   the viral DNA into the host cell's genome is carried out by another
   viral enzyme called integrase.

   This integrated viral DNA may then lie dormant, in the latent stage of
   HIV infection. To actively produce the virus, certain cellular
   transcription factors need to be present, the most important of which
   is NF-κB (NF kappa B), which is upregulated when T cells become
   activated. This means that those cells most likely to be killed by HIV
   are in fact those currently fighting infection.

   In this replication process, the integrated provirus is copied to mRNA
   which is then spliced into smaller pieces. These small pieces produce
   the regulatory proteins Tat (which encourages new virus production) and
   Rev. As Rev accumulates it gradually starts to inhibit mRNA splicing.
   At this stage, the structural proteins Gag and Env are produced from
   the full-length mRNA. The full-length RNA is actually the virus genome;
   it binds to the Gag protein and is packaged into new virus particles.

   HIV-1 and HIV-2 appear to package their RNA differently; HIV-1 will
   bind to any appropriate RNA whereas HIV-2 will preferentially bind to
   the mRNA which was used to create the Gag protein itself. This may mean
   that HIV-1 is better able to mutate (HIV-1 infection progresses to AIDS
   faster than HIV-2 infection and is responsible for the majority of
   global infections).

Assembly and release

   The final step of the viral cycle, assembly of new HIV-1 virons, begins
   at the plasma membrane of the host cell. The Env polyprotein (gp160)
   goes through the endoplasmic reticulum and is transported to the Golgi
   complex where it is cleaved by protease and processed into the two HIV
   envelope glycoproteins gp41 and gp120. These are transported to the
   plasma membrane of the host cell where gp41 anchors the gp120 to the
   membrane of the infected cell. The Gag (p55) and Gag-Pol (p160)
   polyproteins also associate with the inner surface of the plasma
   membrane along with the HIV genomic RNA as the forming virion begins to
   bud from the host cell. Maturation either occurs in the forming bud or
   in the immature virion after it buds from the host cell. During
   maturation, HIV proteases cleave the polyproteins into individual
   functional HIV proteins and enzymes. The various structural components
   then assemble to produce a mature HIV virion. This cleavage step can be
   inhibited by protease inhibitors. The mature virus is then able to
   infect another cell.

Genetic variability

   The phylogenetic tree of the SIV and HIV (click on image for a detailed
                                                             description).
                                                                   Enlarge
   The phylogenetic tree of the SIV and HIV (click on image for a detailed
                                                             description).

       Map showing HIV-1 subtype prevalence. The bigger the pie chart, the
                                              more infections are present.
                                                                   Enlarge
       Map showing HIV-1 subtype prevalence. The bigger the pie chart, the
                                              more infections are present.

   HIV differs from many other viruses as it has very high genetic
   variability. This diversity is a result of its fast replication cycle,
   with the generation of 10^9 to 10^10 virions every day, coupled with a
   high mutation rate of approximately 3 x 10^-5 per nucleotide base per
   cycle of replication and recombinogenic properties of reverse
   transcriptase. This complex scenario leads to the generation of many
   variants of HIV in a single infected patient in the course of one day.
   This variability is compounded when a single cell is simultaneously
   infected by two or more different strains of HIV. When simultaneous
   infection occurs, the genome of progeny virions may be composed of RNA
   strands from two different strains. This hybrid virion then infects a
   new cell where it undergoes replication. As this happens, the reverse
   transcriptase, by jumping back and forth between the two different RNA
   templates, will generate a newly synthesized retroviral DNA sequence
   that is a recombinant between the two parental genomes. This
   recombination is most obvious when it occurs between subtypes..

   The closely related simian immunodeficiency virus (SIV) exhibits a
   somewhat different behaviour: in its natural hosts, African green
   monkeys and sooty mangabeys, the retrovirus is present in high levels
   in the blood, but evokes only a mild immune response, does not cause
   the development of simian AIDS, and does not undergo the extensive
   mutation and recombination typical of HIV. By contrast, infection of
   heterologous hosts (rhesus or cynomologus macaques) with SIV results in
   the generation of genetic diversity that is on the same order as HIV in
   infected humans; these heterologous hosts also develop simian AIDS. The
   relationship, if any, between genetic diversification, immune response,
   and disease progression is unknown.

   Three groups of HIV-1 have been identified on the basis of differences
   in env: M, N, and O. Group M is the most prevalent and is subdivided
   into eight subtypes (or clades), based on the whole genome, which are
   geographically distinct. The most prevalent are subtypes B (found
   mainly in North America and Europe), A and D (found mainly in Africa),
   and C (found mainly in Africa and Asia); these subtypes form branches
   in the phylogenetic tree representing the lineage of the M group of
   HIV-1. Coinfection with distinct subtypes gives rise to circulating
   recombinant forms (CRFs). In 2000, the last year in which an analysis
   of global subtype prevalence was made, 47.2% of infections worldwide
   were of subtype C, 26.7% were of subtype A/CRF02_AG, 12.3% were of
   subtype B, 5.3% were of subtype D, 3.2% were of CRF_AE, and the
   remaining 5.3% were composed of other subtypes and CRFs. Most HIV-1
   research is focused on subtype B; few laboratories focus on the other
   subtypes.

   The genetic sequence of HIV-2 is only partially homologous to HIV-1 and
   more closely resembles that of SIV than HIV-1.

The clinical course of infection

   A generalized graph of the relationship between HIV copies (viral load)
   and CD4 counts over the average course of untreated HIV infection; any
   particular individual's disease course may vary considerably.  CD4+ T
   cell count (cells per µL)  HIV RNA copies per mL of plasma
   Enlarge
   A generalized graph of the relationship between HIV copies (viral load)
   and CD4 counts over the average course of untreated HIV infection; any
   particular individual's disease course may vary considerably.

   CD4^+ T cell count (cells per µL)

   HIV RNA copies per mL of plasma

   Infection with HIV-1 is associated with a progressive decrease of the
   CD4^+ T cell count and an increase in viral load. The stage of
   infection can be determined by measuring the patient's CD4^+ T cell
   count, and the level of HIV in the blood.

   The initial infection with HIV generally occurs after transfer of body
   fluids from an infected person to an uninfected one. The first stage of
   infection, the primary, or acute infection, is a period of rapid viral
   replication that immediately follows the individual's exposure to HIV
   leading to an abundance of virus in the peripheral blood with levels of
   HIV commonly approaching several million viruses per mL. This response
   is accompanied by a marked drop in the numbers of circulating CD4^+ T
   cells. This acute viremia is associated in virtually all patients with
   the activation of CD8^+ T cells, which kill HIV-infected cells, and
   subsequently with antibody production, or seroconversion. The CD8^+ T
   cell response is thought to be important in controlling virus levels,
   which peak and then decline, as the CD4^+ T cell counts rebound to
   around 800 cells per mL (the normal value is 1200 cells per mL ). A
   good CD8^+ T cell response has been linked to slower disease
   progression and a better prognosis, though it does not eliminate the
   virus. During this period most individuals (80 to 90%) develop an
   influenza-like illness with symptoms of fever, malaise,
   lymphadenopathy, pharyngitis, headache, myalgia, and sometimes a rash.
   Because of the nonspecific nature of these illnesses, it is often not
   recognized as a sign of HIV infection. Even if patients go to their
   doctors or a hospital, they will often be misdiagnosed as having one of
   the more common infectious diseases with the same symptoms.
   Consequently, these primary symptoms are not used to diagnose HIV
   infection as they do not develop in all cases and because many are
   caused by other more common diseases. However, recognizing the syndrome
   can be important because the patient is much more infectious during
   this period.

   A strong immune defense reduces the number of viral particles in the
   blood stream, marking the start of the infection's clinical latency
   stage. Clinical latency can vary between two weeks and 20 years. During
   this early phase of infection, HIV is active within lymphoid organs,
   where large amounts of virus become trapped in the follicular dendritic
   cells (FDC) network. The surrounding tissues that are rich in CD4^+ T
   cells may also become infected, and viral particles accumulate both in
   infected cells and as free virus. Individuals who are in this phase are
   still infectious. During this time, CD4^+ CD45RO^+ T cells carry most
   of the proviral load.

   When CD4^+ T cell numbers decline below a critical level, cell-mediated
   immunity is lost, and infections with a variety of opportunistic
   microbes appear. The first symptoms often include moderate and
   unexplained weight loss, recurring respiratory tract infections (such
   as sinusitis, bronchitis, otitis media, pharyngitis), and oral
   ulcerations. Common opportunistic infections and tumors, most of which
   are normally controlled by robust CD4^+ T cell-mediated immunity then
   start to affect the patient. Typically, resistance is lost early on to
   oral Candida species and to Mycobacterium tuberculosis, which leads to
   an increased susceptibilty to oral candidiasis (thrush) and
   tuberculosis. Later, reactivation of latent herpes viruses causes
   patients to suffer from shingles from Epstein-Barr virus-induced B-cell
   lymphomas, and from Kaposi's sarcoma, a tumor of endothelial cells that
   occurs when HIV proteins such as Tat interact with Human Herpesvirus-8.
   Pneumonia caused by the fungus Pneumocystis jiroveci is common and
   often fatal. In the final stages of AIDS, infection with
   cytomegalovirus (another herpes virus) or Mycobacterium avium complex
   is more prominent. Not all patients with AIDS get all these infections
   or tumors, and there are other tumors and infections that are less
   prominent but still significant.

HIV test

   Many people are unaware that they are infected with HIV. For example,
   less than 1% of the sexually active urban population in Africa have
   been tested and this proportion is even lower in rural populations.
   Furthermore, only 0.5% of pregnant women attending urban health
   facilities are counselled, tested or receive their test results. Again,
   this proportion is even lower in rural health facilities. Since donors
   may therefore be unaware of their infection, donor blood and blood
   products used in medicine and medical research are routinely screened
   for HIV.

   HIV-1 testing consists of initial screening with an enzyme-linked
   immunosorbent assay (ELISA) to detect antibodies to HIV-1. Specimens
   with a nonreactive result from the initial ELISA are considered
   HIV-negative unless new exposure to an infected partner or partner of
   unknown HIV status has occurred. Specimens with a reactive ELISA result
   are retested in duplicate. If the result of either duplicate test is
   reactive, the specimen is reported as repeatedly reactive and undergoes
   confirmatory testing with a more specific supplemental test (e.g.,
   Western blot or, less commonly, an immunofluorescence assay (IFA)).
   Only specimens that are repeatedly reactive by ELISA and positive by
   IFA or reactive by Western blot are considered HIV-positive and
   indicative of HIV infection. Specimens that are repeatedly
   ELISA-reactive occasionally provide an indeterminate Western blot
   result, which may be either an incomplete antibody response to HIV in
   an infected person, or nonspecific reactions in an uninfected person.
   Although IFA can be used confirm infection in these ambiguous cases,
   this assay is not widely used. Generally, a second specimen should be
   collected >1 month later and retested for persons with indeterminate
   Western blot results. Although much less commonly available, nucleic
   acid testing (e.g., viral RNA or proviral DNA amplification method) can
   also help diagnosis in certain situations. In addition, a few tested
   specimens might provide inconclusive results because of a low quantity
   specimen. In these situations, a second specimen is collected and
   tested for HIV infection.

Treatment

   Abacavir - a nucleoside analog reverse transcriptase inhibitors (NARTIs
   or NRTIs)
   Enlarge
   Abacavir - a nucleoside analog reverse transcriptase inhibitors (NARTIs
   or NRTIs)
   The chemical structure of Abacavir
   Enlarge
   The chemical structure of Abacavir

   There is currently no vaccine or cure for HIV or AIDS. The only known
   method of prevention is avoiding exposure to the virus. However, an
   antiretroviral treatment, known as post-exposure prophylaxis is
   believed to reduce the risk of infection if begun directly after
   exposure. Current treatment for HIV infection consists of highly active
   antiretroviral therapy, or HAART. This has been highly beneficial to
   many HIV-infected individuals since its introduction in 1996, when the
   protease inhibitor-based HAART initially became available. Current
   HAART options are combinations (or "cocktails") consisting of at least
   three drugs belonging to at least two types, or "classes," of
   anti-retroviral agents. Typically, these classes are two nucleoside
   analogue reverse transcriptase inhibitors (NARTIs or NRTIs) plus either
   a protease inhibitor or a non-nucleoside reverse transcriptase
   inhibitor (NNRTI). Because AIDS progression in children is more rapid
   and less predictable than in adults, particularly in young infants,
   more aggressive treatment is recommended for children than adults. In
   developed countries where HAART is available, doctors assess their
   patients thoroughly: measuring the viral load, how fast CD4 declines,
   and patient readiness. They then decide when to recommend starting
   treatment.

   HAART allows the stabilisation of the patient’s symptoms and viremia,
   but it neither cures the patient, nor alleviates the symptoms, and high
   levels of HIV-1, often HAART resistant, return once treatment is
   stopped. Moreover, it would take more than a lifetime for HIV infection
   to be cleared using HAART. Despite this, many HIV-infected individuals
   have experienced remarkable improvements in their general health and
   quality of life, which has led to a large reduction in HIV-associated
   morbidity and mortality in the developed world. A computer based study
   in 2006 projected that following the 2004 United States treatment
   guidelines gave an average life expectancy of an HIV infected
   individual to be 32.1 years from the time of infection if treatment was
   started when the CD4 count was 350/µL. This study was limited as it did
   not take into account possible future treatments and the projection has
   not been confirmed within a clinical cohort setting. In the absence of
   HAART, progression from HIV infection to AIDS has been observed to
   occur at a median of between nine to ten years and the median survival
   time after developing AIDS is only 9.2 months. However, HAART sometimes
   achieves far less than optimal results, in some circumstances being
   effective in less than fifty percent of patients. This is due to a
   variety of reasons such as medication intolerance/side effects, prior
   ineffective antiretroviral therapy and infection with a drug-resistant
   strain of HIV. However, non-adherence and non-persistence with
   antiretroviral therapy is the major reason most individuals fail to
   benefit from HAART. The reasons for non-adherence and non-persistence
   with HAART are varied and overlapping. Major psychosocial issues, such
   as poor access to medical care, inadequate social supports, psychiatric
   disease and drug abuse contribute to non-adherence. The complexity of
   these HAART regimens, whether due to pill number, dosing frequency,
   meal restrictions or other issues along with side effects that create
   intentional non-adherence also contribute to this problem. The side
   effects include lipodystrophy, dyslipidaemia, insulin resistance, an
   increase in cardiovascular risks and birth defects.

   Anti-retroviral drugs are expensive, and the majority of the world's
   infected individuals do not have access to medications and treatments
   for HIV and AIDS. Research to improve current treatments includes
   decreasing side effects of current drugs, further simplifying drug
   regimens to improve adherence, and determining the best sequence of
   regimens to manage drug resistance. Unfortunately, only a vaccine is
   thought to be able to halt the pandemic. This is because a vaccine
   would cost less, thus being affordable for developing countries, and
   would not require daily treatment. However, after over 20 years of
   research, HIV-1 remains a difficult target for a vaccine.

Epidemiology

   UNAIDS and the WHO estimate that AIDS has killed more than 25 million
   people since it was first recognized in 1981, making it one of the most
   destructive pandemics in recorded history. Despite recent, improved
   access to antiretroviral treatment and care in many regions of the
   world, the AIDS pandemic claimed an estimated 2.8 million (between 2.4
   and 3.3 million) lives in 2005 of which more than half a million
   (570,000) were children.

   Globally, between 33.4 and 46 million people currently live with HIV.
   In 2005, between 3.4 and 6.2 million people were newly infected and
   between 2.4 and 3.3 million people with AIDS died, an increase from
   2004 and the highest number since 1981.

   Sub-Saharan Africa remains by far the worst-affected region, with an
   estimated 21.6 to 27.4 million people currently living with HIV.
   Two million [1.5–3.0 million] of them are children younger than 15
   years of age. More than 64% of all people living with HIV are in
   sub-Saharan Africa, as are more than three quarters of all women living
   with HIV. In 2005, there were 12.0 million [10.6–13.6 million] AIDS
   orphans living in sub-Saharan Africa 2005. South & South East Asia are
   second-worst affected with 15% of the total. AIDS accounts for the
   deaths of 500,000 children in this region. Two-thirds of HIV/AIDS
   infections in Asia occur in India, with an estimated 5.7 million
   infections (estimated 3.4–9.4 million) (0.9% of population), surpassing
   South Africa's estimated 5.5 million (4.9–6.1 million) (11.9% of
   population) infections, making India the country with the highest
   number of HIV infections in the world. In the 35 African nations with
   the highest prevalence, average life expectancy is 48.3 years—6.5 years
   less than it would be without the disease.

   The latest evaluation report of the World Bank's Operations Evaluation
   Department assesses the development effectiveness of the World Bank's
   country-level HIV/AIDS assistance defined as policy dialogue, analytic
   work, and lending with the explicit objective of reducing the scope or
   impact of the AIDS epidemic. This is the first comprehensive evaluation
   of the World Bank's HIV/AIDS support to countries, from the beginning
   of the epidemic through mid-2004. Because the Bank aims to assist in
   implementation of national government programmes, their experience
   provides important insights on how national AIDS programmes can be made
   more effective.

   The development of HAART as effective therapy for HIV infection and
   AIDS has substantially reduced the death rate from this disease in
   those areas where these drugs are widely available. This has created
   the misperception that the disease has gone away. In fact, as the life
   expectancy of persons with AIDS has increased in countries where HAART
   is widely used, the number of persons living with AIDS has increased
   substantially. In the United States, the number of persons with AIDS
   increased from about 35,000 in 1988 to over 220,000 in 1996.

   In Africa, the number of MTCT and the prevalence of AIDS is beginning
   to reverse decades of steady progress in child survival. Countries such
   as Uganda are attempting to curb the MTCT epidemic by offering VCT
   (voluntary counselling and testing), PMTCT (prevention of
   mother-to-child transmission) and ANC (ante-natal care) services, which
   include the distribution of antiretroviral therapy.

Alternative hypotheses

   A small minority of scientists and activists question the connection
   between HIV and AIDS, the existence of HIV itself, or the validity of
   current testing methods. These claims are considered unsupported by
   most of the scientific community, who accuse the dissenters of
   selectively ignoring evidence in favour of HIV's role in AIDS and
   irresponsibly posing a threat to public health by discouraging HIV
   testing and proven treatments.

   AIDS dissidents assert that the current mainstream approach to AIDS,
   based on HIV causation, has resulted in inaccurate diagnoses,
   psychological terror, toxic treatments, and a squandering of public
   funds. Dissident views have been widely rejected, and are considered
   pseudoscience by the mainstream scientific community.

Proteins Involved in Treatment

     * APOBEC3G

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