A retrovirus that causes AIDS by infecting helper T cells of the immune system. The most common serotype, HIV-1, is distributed worldwide, while HIV-2 is primarily confined to West Africa.
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HIV, the human immunodeficiency virus, is the virus that causes AIDS, a debilitating and deadly disease of the human immune system. HIV is one of the world's most serious health problems: at the end of 2001, more than 40 million people worldwide were infected with HIV and living with the virus or AIDS. The World Health Organization estimates that about 20 million people have died from AIDS since the infection was first described in 1981. Nearly 500,000 of those deaths have occurred in the United States. Although there is no cure for the disease, therapies exist that reduce the symptoms of AIDS and can extend the life spans of HIV-infected individuals. Researchers are also pursuing protective vaccines, but a reliable vaccine might still require years to develop.
Hiv and Aids
HIV infects certain cells and tissues of the human immune system and takes them out of commission, rendering a person susceptible to a variety of infections and cancers. These infections are caused by so-called opportunistic agents, pathogens that take advantage of the compromised immune system but that would be unable to cause infection in people with a healthy immune system. Rare cancers such as Kaposi's sarcoma also take hold in HIV-infected individuals. The collection of diseases that arise because of HIV infection is called acquired immune deficiency syndrome, or AIDS. HIV is classified as a lentivirus ("lenti" means "slow") because the virus takes a long time to produce symptoms in an infected individual.
Hiv Life Cycle: Entering Cells
Like a typical virus, HIV infects a cell and appropriates the host's cellular components and machinery to make many copies of itself. The new viruses then break out of the cell and infect other cells. HIV stores its genetic information on an RNA molecule rather than a DNA chromosome. This is a distinguishing characteristic of retroviruses, which are viruses that must first convert their RNA genomes into DNA before they can reproduce.
Each HIV virion (viral particle) is a small sphere composed of several layers. The external layer is a membrane coat, or envelope, obtained from the host cell in which the particle was made. Underneath this membrane lies a shell made from proteins, called a nucleocapsid. Inside the protein shell are two copies of the virion's RNA genome and three kinds of proteins, which are used by the virion to establish itself once inside the cell that it infects.
Two proteins, called gp120 and gp41, enable the virion to recognize the type of cell to enter. These proteins project from the HIV membrane coat. Gp120 binds to two specific proteins found on the target cell's surface (these target-cell proteins are called receptors). The first receptor, CD4, is found on immune system cells known as CD4 T cells, and also sometimes on two cell types known as macrophages and dendritic cells. The immune system uses CD4 T cells in the initial step in making antibodies against infectious agents. After binding to CD4, the HIV protein called gp120 binds with a second cell membrane protein, commonly referred to as the co-receptor. The co-receptor can be one of many different proteins, depending on the cell type. The two most common are CXCR4, which is normally found on CD4 T cells, and CCR5, a receptor found on CD4 T cells as well as on certain macrophages and dendritic cells. In the absence of HIV, CXCR4 and CCR5 allow these immune system cells to respond to chemical signals, but when HIV infects the cells, the HIV commandeers their usage. In some cases, individuals have a mutation in their co-receptor that prevents HIV from entering their cells.
Once gp120 has bound to both the CD4 receptor and co-receptor, the gp41 protein fuses HIV's membrane envelope with the cellular membrane, injecting the virus into the target cell. Once in the cytoplasm, the viral protein shell opens up and releases the viral proteins—a reverse transcriptase, a viral integrase, and a protease—along with the viral RNA strands. The reverse transcriptase copies the RNA strands into DNA. The viral integrase then helps insert the DNA copies into the cell's chromosome. At this point, the virus is called a provirus, and the life cycle halts. The provirus may remain dormant in the cell's chromosome for months or years, waiting for the T cell to become activated by the immune system.
Hiv Life Cycle: Reproduction
When the immune system recruits T cells to fight an infection, the T cells start producing many proteins. Along with the normal cellular protein products, a T cell carrying an HIV provirus also produces HIV proteins. The first HIV proteins made are called Tat and Rev. Tat encourages the cellular machinery to copy HIV's proviral DNA into RNA molecules. These RNA molecules are then processed in the nucleus to become templates for several of the HIV proteins, some of whose functions are not well understood.
Rev, on the other hand, ushers the HIV's RNA molecules from the nucleus, where they are being reproduced, into the host cell's cytoplasm. Early in HIV reproduction, with only a few RNA molecules from which to make protein, a small quantity of Rev is made. Therefore, most of the RNA molecules remain in the nucleus long enough to get processed. As time passes, however, and Tat continues to instigate RNA production, more Rev is made. A higher amount of Rev protein increases the speed with which RNA molecules are ejected from the nucleus. These RNA molecules, which have undergone little or no processing, become templates to make different HIV proteins. The newer proteins are made in long chains that require trimming before they become functional. One of the proteins in the chain is the protease, the protein that trims. Other proteins include those that make up the protein shell, the reverse transcriptase, and integrase.
After the newly created proteins are processed to the right size, they form new virions by first assembling into a shell, then drawing in two unprocessed RNA molecules and filling up the remaining space with integrase, protease, and replicase. The new virions bud from the host-cell membrane, appropriating some of that membrane to form an outer coat in the process. The mature virus particles are now ready to infect other cells.
Hiv's Immune-System Impairment Mechanism
One of the most disastrous effects of HIV infection is the loss of the immune system's CD4 T cells. These cells are responsible for recognizing foreign invaders to a person's body and initiating antibody production to ward off the infection. Without them, people are susceptible to a variety of diseases. HIV destroys the T cells slowly, sometimes taking a decade to destroy a person's immunity. However, in all the time before an HIV-infected individual shows any symptoms, the virus has been reproducing rapidly. The lymph tissue, the resting place for CD4 T cells, macrophages, and dendritic cells, becomes increasingly full of HIV, and viral particles are also released into the bloodstream.
HIV's main target is the population of CD4 T cells within a host's body. HIV kills them in one of three ways. It kills them directly by reproducing within them, then breaking them upon exit; it kills them indirectly by causing the cells to "commit suicide" by inducing apoptosis; or it kills them indirectly by triggering other immune cells to recognize the infected T cell and kill it as part of the immune system's normal function.
As infected T cells die, the immune system generates more to take their place. As new T cells become infected, they are either actively killed or induced to commit suicide. Meanwhile, the HIV virus is not completely hidden from the immune system. As with any infectious agent, HIV presents its proteins to the immune system, which develops antibodies against it. This antibody production, however, is hampered by the fact that HIV mutates rapidly, changing the proteins it displays to the immune system. With each new protein, the immune system must generate new antibodies to fight the infection. Thus, an HIV infection is a dramatic balance between a replicating, ever changing virus and the replenishing stores of T cells that are fighting it. Unfortunately, the immune system, without therapeutic intervention, eventually loses the battle.
Once the CD4 T cells are depleted, the immune system can no longer ward off the daily bombardment of pathogens that all human organisms experience. Common infectious agents thus overwhelm the system, and HIV patients become susceptible to a variety of "opportunistic" diseases that take advantage of the body's reduced ability to fight them off. AIDS doctors report at least twenty-six different opportunistic diseases specific to HIV infection. These include unusual fungal infections such as thrush. The chickenpox virus may come out of dormancy, manifesting itself as the painful disease known as shingles. An obscure form of pneumonia, called pneumocystis pneumonia, is also common in AIDS patients. In addition, patients can acquire cancers such as B-cell lymphoma, which is a cancer of the immune system. Doctors generally consider patients with fewer than 200 CD4 T cells per cubic milliliter of blood as having AIDS. (In contrast, a healthy person counts more than 1,000.)
Anti-Hiv Drug Therapy
Drugs that interfere with viral replication can slow down HIV disease. Early trials relied on the administration of one drug at a time. While patients' health improved and their T cell count rose, in time HIV mutated enough to render the drugs ineffective. Since 1995, however, doctors have found that rotating patients through three different drugs in very high doses significantly improves the health of AIDS patients. Known as "highly active antiretroviral therapy" (HAART), this therapeutic approach also reduces the amount of HIV circulating in the bloodstream to nearly undetectable levels. People infected with HIV who are treated by HAART are now living longer, healthier lives than ever before.
Targeting Life-Cycle Points
Drugs meant to knock out HIV target the activities of two HIV proteins, the reverse transcriptase and the protease. HAART requires drugs of both types. Drugs called protease inhibitors prevent the viral protease from trimming down the large proteins made late during infection. Without those proteins, the viral shell cannot be assembled. In addition, the proteins that reproduce HIV's genetic information, the reverse transcriptase and the integrase, are not functional.
Drugs that inhibit the reverse transcriptase prevent it from copying the RNA into DNA. These drugs work early in the life cycle of HIV. Reverse transcriptase inhibitors include azidothymidine (AZT), whose structure resembles the DNA nucleotide thymine. When reverse transcriptase builds DNA with AZT instead of thymine, the AZT caps the growing DNA molecule and halts DNA production, due to AZT's slight difference in structure from the thymine that DNA production requires.
Bibliography
Janeway, Charles A., et al. "Failures of Host Defense Mechanisms." In Immunobiology: The Immune System in Health and Disease, 4th ed. New York: Current Biology Publications, 1999.
———. HIV Infection and AIDS: An Overview. Washington DC: National Institute of Allergy and Infectious Diseases and U.S. Department of Health and Human Services, 2001.
Shilts, Randy. And the Band Played On: Politics, People, and the AIDS Epidemic. New York: St. Martin's Press, 2000. Stine, Gerald. Acquired Immune Deficiency Syndrome: Biological, Medical, Social and Legal Issues, 3rd ed. New York: Prentice-Hall, 1997.
—Mary Beckman
For more information on HIV, visit Britannica.com.
(Human Immunodeficiency Virus), either of two closely related retroviruses that invade T-helper lymphocytes and are responsible for AIDS. There are two types of HIV: HIV-1 and HIV-2. HIV-1 is responsible for the vast majority of AIDS in the United States. HIV-2, seen more often in western Africa, has a slower course than HIV-1. There are many strains of both types and the virus mutates rapidly, a trait that has made it especially difficult for researchers to find an effective treatment or vaccine. In many cases, a person's immune system will fight off the invasion of HIV for many years, producing billions of CD4 cells daily, always trying to keep up with the HIV's mutations, before it succumbs and permits the well-known signs of AIDS to develop.
HIV is especially lethal because it attacks the very immune system cells (variously called T4, CD4, or T-helper lymphocytes) that would ordinarily fight off such a viral infection. Receptors on these cells appear to enable the viral RNA to enter the cell. As with all retroviruses, once the RNA is inside the cell, an enzyme called reverse transcriptase allows it to act as the template for its own RNA to DNA transcription. The resultant viral DNA inserts itself into a cell's DNA and is reproduced along with the cell and its daughters.
The exact origin of the virus in humans is unclear. Scientists surmise that it jumped from an animal population, probably African monkeys or chimpanzees, to humans via a bite or meat. The first case documented in humans dates from 1959. The virus was isolated by Luc Montagnier of France's Pasteur Institute in 1983. It went through several name changes before the official name, human immunodeficiency virus, was agreed upon.
(aych-eye-vee)
An abbreviation for human immunodeficiency virus, the virus that causes AIDS.
Wikipedia:
HIV
| Human immunodeficiency virus | ||||||
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 Stylized rendering of a cross section
of the human immunodeficiency virus |
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| ICD-10 | B20-B24 |
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| ICD-9 | 042-044 |
Human immunodeficiency virus (HIV) is a retrovirus that can lead to acquired immunodeficiency syndrome (AIDS), a condition in humans 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), lymphadenopathy-associated virus (LAV), or AIDS-associated retrovirus (ARV).[1][2]
Infection with HIV occurs by the transfer of blood, semen, vaginal fluid, pre-ejaculate, or breast milk. Within these bodily fluids, HIV is present as both free virus particles and virus within infected immune cells. The four 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. It is estimated that about 0.6% of the world's living population is infected with HIV.[3] A third of these deaths are occurring in sub-Saharan Africa, retarding economic growth and increasing poverty.[4] According to current estimates, HIV is set to infect 90 million people in Africa, resulting in a minimum estimate of 18 million orphans.[5] Antiretroviral treatment reduces both the mortality and the morbidity of HIV infection, but routine access to antiretroviral medication is not available in all countries.[6]
HIV primarily infects vital cells in the human immune
system such as
Origin and discovery
- See AIDS origin.
Classification
HIV was classified as a member of the genus Lentivirus,[8] part of the family of Retroviridae.[9] 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.[10] 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.[11][12] HIV-1 is the virus that was initially discovered and termed LAV.
HIV-2 may have originated from the Sooty Mangabey (Cercocebus atys), an Old World monkey of Guinea-Bissau, Gabon, and Cameroon.[13] HIV-1 is more 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.[13]
Early history
- See AIDS origin#History of known cases and spread for early cases of HIV / AIDS.
Transmission
- For more details on this topic, see AIDS transmission and prevention
| Estimated per act risk for acquisition of HIV-1 by exposure route[14] |
||||
|---|---|---|---|---|
| Exposure Route | Estimated infections per 10,000 exposures to an infected source |
|||
| Blood Transfusion | 9,000[15] | |||
| Childbirth | 2,500[16] | |||
| Needle-sharing injection drug use | 67[17] | |||
| Receptive anal intercourse* | 50[18][19] | |||
| Percutaneous needle stick | 30[20] | |||
| Receptive penile-vaginal intercourse* | 10[18][19][21] | |||
| Insertive anal intercourse* | 6.5[18][19] | |||
| Insertive penile-vaginal intercourse* | 5[18][19] | |||
| Receptive fellatio* | 1[19] | |||
| Insertive fellatio* | 0.5[19] | |||
| * 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 genital, oral, or rectal 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. HIV can also be spread through the sharing of needles. 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%.[16] However, where drug treatment and Cesarian section are available, this can be reduced to 1%.[16] 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 there are no recorded cases of infection by these secretions and the potential risk of transmission is negligible.[22] 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; it should not be considered a barrier to infection.[23] Trials, in which uncircumcised men were randomly assigned to be medically circumcised in sterile conditions and given counseling and other men were not circumcised, have been conducted in South Africa,[24] Kenya[25] and Uganda[26] showing reductions in HIV transmission for heterosexual sex of 60%, 53%, and 48% respectively. As a result, a panel of experts convened by WHO and the UNAIDS Secretariat has "recommended that male circumcision now be recognized as an additional important intervention to reduce the risk of heterosexually acquired HIV infection in men."[27] Research is clarifying whether there is a historical relationship between rates of male circumcision and rates of HIV in differing social and cultural contexts. Critics point out that any correlation between circumcision and HIV is likely to come from cultural factors (which govern not only whether someone is circumcised, but also their sexual practices and beliefs).[28] South African medical experts are concerned that the repeated use of unsterilized blades in the ritual (not medical) circumcision of adolescent boys may be spreading HIV.[29]
Structure and genome
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.[30]
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.[31] 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, ribonuclease and integrase. A matrix composed of the viral protein p17 surrounds the capsid ensuring the integrity of the virion particle.[31] 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.[31] 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.[32] This glycoprotein complex enables the virus to attach to and fuse with target cells to initiate the infectious cycle.[32] Both these surface proteins, especially gp120, have been considered as targets of future treatments or vaccines against HIV.[33]
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.[31] 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.[31] 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.[31] 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.[31]
Tropism
The term viral tropism refers to which cell types HIV infects. HIV can infect a variety of immune cells such as
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.[34] 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.[34][35][36] Dual-tropic HIV-1 strains are thought to be transitional strains of the HIV-1 virus and thus are able to use both CCR5 and LESTR as co-receptors for viral 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[34] and HIV can also infect a subtype of myeloid dendritic cells,[37] 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.[38] 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.
Sexual 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.[39][40][41] 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[42] and that genital epithelial cells preferentially sequester X4 virus.[43] 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.[44] 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.[45] 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.[46][47]
Replication cycle
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.[48][49]
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.[48][49] The gp160 spike contains binding domains for both CD4 and chemokine receptors.[48][49] 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.[48][49] This allows for a more stable two-pronged attachment, which allows the N-terminal fusion peptide gp41 to penetrate the cell membrane.[48][49] 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.[48][49]
Once HIV has bound to the target cell, the HIV RNA and various enzymes, including reverse transcriptase, integrase, ribonuclease and protease, are injected into the cell.[48]
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.[50] 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.[50]
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.[51] 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.[51]
This integrated viral DNA may then lie dormant, in the latent stage of HIV infection.[51] 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.[52] 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.[53] 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.[54] This cleavage step can be inhibited by protease inhibitors. The mature virus is then able to infect another cell.
Genetic variability
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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 109 to 1010 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.[55] This complex scenario leads to the generation of many variants of HIV in a single infected patient in the course of one day.[55] 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.[55] This recombination is most obvious when it occurs between subtypes.[55]
The closely related simian immunodeficiency virus (SIV) exhibits a somewhat different behavior: 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,[56] does not cause the development of simian AIDS,[57] and does not undergo the extensive mutation and recombination typical of HIV.[58] 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.[59] 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.[60] Group M is the most prevalent and is subdivided into eight subtypes (or clades), based on the whole genome, which are geographically distinct.[61] 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.[62] Most HIV-1 research is focused on subtype B; few laboratories focus on the other subtypes.[63]
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
- For more details on this topic, see AIDS Diagnosis, AIDS Symptoms and Complications and WHO Disease Staging System for HIV Infection and Disease
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.[64] 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
| sensitivity | specificity | |
|---|---|---|
| Fever | 88% | 50% |
| Malaise | 73% | 58% |
| Myalgia | 60% | 74% |
| Rash | 58% | 79% |
| Headache | 55% | 56% |
| Night sweats | 50% | 68% |
| Sore throat | 43% | 51% |
| Lymphadenopathy | 38% | 71% |
| Arthralgia | 28% | 87% |
| Nasal congestion | 18% | 62% |
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.[68] 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,
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), prostatitis, skin rashes, 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 susceptibility to oral candidiasis (thrush) and tuberculosis. Later, reactivation of latent herpes viruses may cause worsening recurrences of herpes simplex eruptions, shingles, Epstein-Barr virus-induced B-cell lymphomas, or 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 jirovecii 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 HIV-positive people are unaware that they are infected with the virus.[70] 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.[70] Furthermore, only 0.5% of pregnant women attending urban health facilities are counselled, tested or receive their test results.[70] Again, this proportion is even lower in rural health facilities.[70] 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.[71]
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.[72] 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.[73] Although IFA can be used to confirm infection in these ambiguous cases, this assay is not widely used. Generally, a second specimen should be collected more than a 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.[72] 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
- See also AIDS Treatment and Antiretroviral drug.
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.[74] Current treatment for HIV infection consists of highly active antiretroviral therapy, or HAART.[75] This has been highly beneficial to many HIV-infected individuals since its introduction in 1996, when the protease inhibitor-based HAART initially became available.[76] 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.[77] 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.[78]
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.[79][80] Moreover, it would take more than a lifetime for HIV infection to be cleared using HAART.[81] 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.[76][82][83] 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.[84] 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.[85] 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.[86] 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.[87][88][89] The side effects include lipodystrophy, dyslipidaemia, insulin resistance, an increase in cardiovascular risks and birth defects.[90][91]
The timing for starting HIV treatment is still debated. There is no question that treatment should be started before the patient's CD4 count falls below 200, and most national guidelines say to start treatment once the CD4 count falls below 350; but there is some evidence from cohort studies that treatment should be started before the CD4 count falls below 350.[92][82] There is also evidence to say that treatment should be started before CD4 percentage falls below 15%.[93] In those countries where CD4 counts are not available, patients with WHO stage III or IV disease[94] should be offered treatment.
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.[95] 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.[95] However, after over 20 years of research, HIV-1 remains a difficult target for a vaccine.[95]In February 2007, The National Institute of Allergy and Infectious Diseases published a report that gave details of a potential region on HIV's surface that is a potential target for a vaccine.[96]
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.[3]
Globally, between 33.4 and 46 million people currently live with HIV.[3] 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.[3] 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.[97] 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.[98]
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.[99]