HIV
From Wikipedia, the free encyclopedia
| Human immunodeficiency virus | ||||||||||
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| Image:Aids virus.jpg Stylized rendering of a cross section of the human immunodeficiency virus | ||||||||||
| Virus classification | ||||||||||
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| ICD-10 | B20-B24 |
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| ICD-9 | 042-044 |
Human immunodeficiency virus or HIV is a retrovirus that causes acquired immune deficiency 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) and lymphadenopathy-associated virus (LAV).<ref>Rick Sowadsky (1999). What is HTLV-III?. Retrieved on 2006-08-24.</ref><ref name=Coffin>Coffin, J., Haase, A., Levy, J. A., Montagnier, L., Oroszlan, S., Teich, N., Temin, H., Toyoshima, K., Varmus, H., Vogt, P. and Weiss, R. A. (1986). "What to call the AIDS virus?". Nature 321 (6065): 10. PubMed.</ref>
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.<ref name=UNAIDS2006>Joint United Nations Programme on HIV/AIDS (2006). “Overview of the global AIDS epidemic”, 2006 Report on the global AIDS epidemic (PDF format). Retrieved on 2006-06-08.</ref> A third of these deaths are occurring in sub-Saharan Africa, retarding economic growth and increasing poverty.<ref name=Greener>Greener, R. (2002). “AIDS and macroeconomic impact”, S, Forsyth (ed.): State of The Art: AIDS and Economics (PDF), IAEN, 49-55.</ref> According to current estimates, HIV is set to infect 90 million people in Africa, resulting in a minimum estimate of 18 million orphans.<ref name=UNAIDS>Joint United Nations Programme on HIV/AIDS. AIDS epidemic update, 2005 (PDF format). Retrieved on 2006-02-28.</ref> Antiretroviral treatment reduces both the mortality and the morbidity of HIV infection, but routine access to antiretroviral medication is not available in all countries.<ref name=Palella>Palella, F. J. Jr, Delaney, K. M., Moorman, A. C., Loveless, M. O., Fuhrer, J., Satten, G. A., Aschman and D. J., Holmberg, S. D. (1998). "Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators". N. Engl. J. Med 338 (13): 853-860. PubMed.</ref>
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.<ref name=Buchbinder>Buchbinder SP, Katz MH, Hessol NA, O'Malley PM, Holmberg SD. (1994). "Long-term HIV-1 infection without immunologic progression.". AIDS 8 (8): 1123-1128. PubMed.</ref> 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).
Contents |
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.<ref name=MMWR2>CDC (1981). Pneumocystis Pneumonia --- Los Angeles. CDC. Retrieved on 2006-01-17.</ref> 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.<ref name=Barre>Barré-Sinoussi, F., Chermann, J. C., Rey, F., Nugeyre, M. T., Chamaret, S., Gruest, J., Dauguet, C., Axler-Blin, C., Vezinet-Brun, F., Rouzioux, C., Rozenbaum, W. and Montagnier, L. (1983). "Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS)". Science 220 (4599): 868-871. PubMed.</ref> 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).<ref name=Popovic>Popovic, M., Sarngadharan, M. G., Read, E. and Gallo, R. C. (1984). "Detection, isolation, and continuous production of cytopathic retroviruses (HTLV-III) from patients with AIDS and pre-AIDS". Science 224 (4648): 497-500. PubMed.</ref> 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).<ref name=Coffin/>
HIV was classified as a member of the genus lentivirus,<ref name=ICTV61.0.6>International Committee on Taxonomy of Viruses. 61.0.6. Lentivirus. National Institutes of Health. Retrieved on 2006-02-28.</ref> part of the family of retroviridae.<ref name=ICTV61.>International Committee on Taxonomy of Viruses. 61. Retroviridae. National Institutes of Health. Retrieved on 2006-02-28.</ref> 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.<ref name=Levy>Lévy, J. A. (1993). "HIV pathogenesis and long-term survival". AIDS 7 (11): 1401-1410. PubMed.</ref> 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.<ref name=Gao>Gao, F., Bailes, E., Robertson, D. L., Chen, Y., Rodenburg, C. M., Michael, S. F., Cummins, L. B., Arthur, L. O., Peeters, M., Shaw, G. M., Sharp, P. M., and Hahn, B. H. (1999). "Origin of HIV-1 in the Chimpanzee Pan troglodytes troglodytes". Nature 397 (6718): 436-441. PubMed DOI:10.1038/17130.</ref><ref name=Keele>Keele, B. F., van Heuverswyn, F., Li, Y. Y., Bailes, E., Takehisa, J., Santiago, M. L., Bibollet-Ruche, F., Chen, Y., Wain, L. V., Liegois, F., Loul, S., Mpoudi Ngole, E., Bienvenue, Y., Delaporte, E., Brookfield, J. F. Y., Sharp, P. M., Shaw, G. M., Peeters, M., and Hahn, B. H. (2006). "Chimpanzee Reservoirs of Pandemic and Nonpandemic HIV-1". Science Online 2006-05-25. DOI:10.1126/science.1126531.</ref> HIV-2 may have originated from the Sooty Mangabey (Cercocebus atys), an Old World monkey of Guinea-Bissau, Gabon, and Cameroon.<ref name=Reeves>Reeves, J. D. and Doms, R. W (2002). "Human Immunodeficiency Virus Type 2". J. Gen. Virol. 83 (Pt 6): 1253-1265. PubMed.</ref> 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.<ref name=Reeves>Reeves, J. D. and Doms, R. W (2002). "Human Immunodeficiency Virus Type 2". J. Gen. Virol. 83 (Pt 6): 1253-1265. PubMed.</ref> 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:
- A plasma sample taken in 1959 from an adult male living in what is now the Democratic Republic of Congo.<ref name=Zhu>Zhu, T., Korber, B. T., Nahmias, A. J., Hooper, E., Sharp, P. M. and Ho, D. D. (1998). "An African HIV-1 Sequence from 1959 and Implications for the Origin of the Epidemic". Nature 391 (6667): 594-597. PubMed DOI:10.1038/35400.</ref>
- HIV found in tissue samples from a 15 year old African-American teenager who died in St. Louis in 1969.<ref name=Kolata>
Kolata, G.. "Boy's 1969 death suggests AIDS invaded U.S. several times", The New York Times, 1987-10-28. Retrieved on 2006-06-19. </ref>
- HIV found in tissue samples from a Norwegian sailor who died around 1976.<ref name=HooperBMJ>Hooper, E. (1997). "Sailors and star-bursts, and the arrival of HIV". BMJ 315 (7123): 1689-1691. PubMed.</ref>
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.<ref name=Curtis>Curtis, T. (1992). "The origin of AIDS". Rolling Stone (626): 54-59, 61, 106, 108.</ref> 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.<ref name=Hooper>Hooper, E. (1999). The River : A Journey to the Source of HIV and AIDS, 1st, Boston, MA: Little Brown & Co, 1-1070. ISBN 0-316-37261-7.</ref> 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.<ref name=Korber> Korber B, Muldoon M, Theiler J, et al (January 30-February 2, 2000). "Timing the origin of the HIV-1 pandemic". Programs and abstracts of the 7th Conference on Retroviruses and Opportunistic Infections Abstract L5.</ref>
Transmission
- For more details on this topic, see AIDS transmission and prevention
| Estimated per act risk for acquisition of HIV-1 by exposure route<ref name=MMWR>Smith, D. K., Grohskopf, L. A., Black, R. J., Auerbach, J. D., Veronese, F., Struble, K. A., Cheever, L., Johnson, M., Paxton, L. A., Onorato, I. A. and Greenberg, A. E. (2005). "Antiretroviral Postexposure Prophylaxis After Sexual, Injection-Drug Use, or Other Nonoccupational Exposure to HIV in the United States". MMWR 54 (RR02): 1-20.</ref> | ||||
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| Exposure Route | Estimated infections per 10,000 exposures to an infected source | |||
| Blood Transfusion | 9,000<ref name=Donegan>Donegan, E., Stuart, M., Niland, J. C., Sacks, H. S., Azen, S. P., Dietrich, S. L., Faucett, C., Fletcher, M. A., Kleinman, S. H., Operskalski, E. A., et al. (1990). "Infection with human immunodeficiency virus type 1 (HIV-1) among recipients of antibody-positive blood donations". Ann. Intern. Med. 113 (10): 733-739. PubMed.</ref> | |||
| Childbirth | 2,500<ref name=Coovadia>Coovadia, H. (2004). "Antiretroviral agents—how best to protect infants from HIV and save their mothers from AIDS". N. Engl. J. Med. 351 (3): 289-292. PubMed.</ref> | |||
| Needle-sharing injection drug use- | author=Kaplan, E. H. and Heimer, R. | title=HIV incidence among New Haven needle exchange participants: updated estimates from syringe tracking and testing data | journal=J. Acquir. Immune Defic. Syndr. Hum. Retrovirol. | year=1995 | pages=175-176 | volume=10 | issue=2 | id=PubMed</ref> | ||
| Receptive anal intercourse* | 50<ref name=ESG>European Study Group on Heterosexual Transmission of HIV (1992). "Comparison of female to male and male to female transmission of HIV in 563 stable couples". BMJ. 304 (6830): 809-813. PubMed.</ref><ref name=Varghese>Varghese, B., Maher, J. E., Peterman, T. A., Branson, B. M. and Steketee, R. W. (2002). "Reducing the risk of sexual HIV transmission: quantifying the per-act risk for HIV on the basis of choice of partner, sex act, and condom use". Sex. Transm. Dis. 29 (1): 38-43. PubMed.</ref> | |||
| Percutaneous needle stick | 30<ref name=Bell>Bell, D. M. (1997). "Occupational risk of human immunodeficiency virus infection in healthcare workers: an overview.". Am. J. Med. 102 (5B): 9-15. PubMed.</ref> | |||
| Receptive penile-vaginal intercourse* | 10<ref name=ESG /><ref name=Varghese /><ref name=Leynaert>Leynaert, B., Downs, A. M. and de Vincenzi, I. (1998). "Heterosexual transmission of human immunodeficiency virus: variability of infectivity throughout the course of infection. European Study Group on Heterosexual Transmission of HIV". Am. J. Epidemiol. 148 (1): 88-96. PubMed.</ref> | |||
| Insertive anal intercourse* | 6.5<ref name=ESG /><ref name=Varghese /> | |||
| Insertive penile-vaginal intercourse* | 5<ref name=ESG /><ref name=Varghese /> | |||
| Receptive fellatio* | 1<ref name=Varghese /> | |||
| Insertive fellatio* | 0.5<ref name=Varghese /> | |||
| * assuming no condom use </br> | ||||
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%.<ref name=Coovadia /> However, where drug treatment and Cesarian section are available, this can be reduced to 1%.<ref name=Coovadia /> 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.<ref name="spermicide">Should spermicides be used with condoms?. Condom Brochure, FDA OSHI HIV STDs. Retrieved on 2006-10-23.</ref> Current research is clarifying the relationship between male circumcision and HIV in differing social and cultural contexts.<ref name=Siegfred>
Siegfried, N., Muller, M., Deeks, J., Volmink, J., Egger, M., Low, N., Walker, S. and Williamson, P. (2005). "HIV and male circumcision--a systematic review with assessment of the quality of studies". Lancet Infect. Dis. 5 (3): 165-173. PubMed.</ref> Even though male circumcision may lead to a reduction of infection risk in heterosexual men by up to 60%,<ref name=Williams>Williams BG, Lloyd-Smith JO, Gouws E, Hankins C, Getz WM, Hargrove J, de Zoysa I, Dye C, Auvert B. (2006). "The Potential Impact of Male Circumcision on HIV in Sub-Saharan Africa.". PLoS Med 3 (7): e262. PubMed.</ref> UNAIDS believes that it is premature to recommend male circumcision as part of HIV prevention programs.<ref name=WHOcircumcision>WHO (2005). UNAIDS statement on South African trial findings regarding male circumcision and HIV. Retrieved on 2006-03-28.</ref> South African medical experts are concerned that the repeated use of unsterilized blades in the ritual circumcision of adolescent boys may be spreading HIV.<ref name=Kaisercircum>Various (2005). Repeated Use of Unsterilized Blades in Ritual Circumcision Might Contribute to HIV Spread in S. Africa, Doctors Say. Kaisernetwork.org. Retrieved on 2006-03-28.</ref>
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.<ref name=McGovern>McGovern SL, Caselli E, Grigorieff N, Shoichet BK (2002). "A common mechanism underlying promiscuous inhibitors from virtual and high-throughput screening". J Med Chem 45 (8): 1712-22. PubMed.</ref>
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.<ref name=compendia>Various (2005). HIV Sequence Compendium 2005 (PDF format). Retrieved on 2006-09-01.</ref> 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.<ref name=compendia/> 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.<ref name=compendia/> 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.<ref name=Chan>Chan, DC., Fass, D., Berger, JM., Kim, PS. (1997). "Core Structure of gp41 from the HIV Envelope Glycoprotein" (pdf). Cell 89: 263–273. PubMed.</ref> This glycoprotein complex enables the virus to attach to and fuse with target cells to initiate the infectious cycle.<ref name=Chan>Chan, DC., Fass, D., Berger, JM., Kim, PS. (1997). "Core Structure of gp41 from the HIV Envelope Glycoprotein" (pdf). Cell 89: 263–273. PubMed.</ref> Both these surface proteins, especially gp120, have been considered as targets of future treatments or vaccines against HIV.<ref name=nih1998>National Institute of Health. "Crystal Structure of Key HIV Protein Reveals New Prevention, Treatment Targets", June 17, 1998. Retrieved on 2006-09-14.</ref>
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.<ref name=compendia/> 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.<ref name=compendia/> 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.<ref name=compendia/> 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.<ref name=compendia/>
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.<ref name=Chan/>
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.<ref name=Coakley>Coakley, E., Petropoulos, C. J. and Whitcomb, J. M. (2005). "Assessing chemokine co-receptor usage in HIV". Curr. Opin. Infect. Dis. 18 (1): 9-15. PubMed.</ref> 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.<ref name=Coakley /><ref name=Deng>
Deng H, Liu R, Ellmeier W, Choe S, Unutmaz D, Burkhart M, Di Marzio P, Marmon S, Sutton RE, Hill CM, Davis CB, Peiper SC, Schall TJ, Littman DR, Landau NR. (1996). "Identification of a major co-receptor for primary isolates of HIV-1.". Nature 381 (6584): 661-666. PubMed.</ref><ref name=Feng>
Feng Y, Broder CC, Kennedy PE, Berger EA. (1996). "HIV-1 entry cofactor: functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor.". Science 272 (5263): 872-877. PubMed.</ref> 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<ref name=Coakley /> and HIV can also infect a subtype of myeloid dendritic cells,<ref name=Knight>
Knight, S. C., Macatonia, S. E. and Patterson, S. (1990). "HIV I infection of dendritic cells". Int. Rev. Immunol. 6 (2-3): 163-175. PubMed.</ref> 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.<ref name=Tang>Tang, J. and Kaslow, R. A. (2003). "The impact of host genetics on HIV infection and disease progression in the era of highly active antiretroviral therapy". AIDS 17 (Suppl 4): S51-S60. PubMed.</ref> 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.<ref name=Zhu1993>
Zhu T, Mo H, Wang N, Nam DS, Cao Y, Koup RA, Ho DD. (1993). "Genotypic and phenotypic characterization of HIV-1 patients with primary infection". Science 261 (5125): 1179–1181. PubMed.</ref><ref name=Wout>
van’t Wout AB, Kootstra NA, Mulder-Kampinga GA, Albrecht-van Lent N, Scherpbier HJ, Veenstra J, Boer K, Coutinho RA, Miedema F, Schuitemaker H. (1994). "Macrophage-tropic variants initiate human immunodeficiency virus type 1 infection after sexual, parenteral, and vertical transmission". J Clin Invest 94 (5): 2060–2067. PubMed.</ref><ref name=Zhu1996>
Zhu T, Wang N, Carr A, Nam DS, Moor-Jankowski R, Cooper DA, Ho DD. (1996). "Genetic characterization of human immunodeficiency virus type 1 in blood and genital secretions: evidence for viral compartmentalization and selection during sexual transmission". J Virol 70 (5): 3098-3107. PubMed.</ref> 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<ref name=Muciaccia>
Muciaccia B, Padula F, Vicini E, Gandini L, Lenzi A, Stefanini M. (2005). "Beta-chemokine receptors 5 and 3 are expressed on the head region of human spermatozoon". FASEB J 19 (14): 2048-2050. PubMed.</ref> and that genital epithelial cells preferentially sequester X4 virus.<ref name=Berlier>
Berlier W, Bourlet T, Lawrence P, Hamzeh H, Lambert C, Genin C, Verrier B, Dieu-Nosjean MC, Pozzetto B, Delezay O. (2005). "Selective sequestration of X4 isolates by human genital epithelial cells: Implication for virus tropism selection process during sexual transmission of HIV". J Med Virol. 77 (4): 465-474. PubMed.</ref> 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.<ref name=Clevestig>
Clevestig P, Maljkovic I, Casper C, Carlenor E, Lindgren S, Naver L, Bohlin AB, Fenyo EM, Leitner T, Ehrnst A. (2005). "The X4 phenotype of HIV type 1 evolves from R5 in two children of mothers, carrying X4, and is not linked to transmission". AIDS Res Hum Retroviruses 5 (21): 371-378. PubMed.</ref> 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.<ref name=Moore>
Moore JP. (1997). "Coreceptors: implications for HIV pathogenesis and therapy". Science 276 (5309): 51-52. PubMed.</ref> 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.<ref name=Karlsson>
Karlsson A, Parsmyr K, Aperia K, Sandstrom E, Fenyo EM, Albert J. (1994). "MT-2 cell tropism of human immunodeficiency virus type 1 isolates as a marker for response to treatment and development of drug resistance". J Infect Dis. 170 (6): 1367-1375. PubMed.</ref><ref name=Koot>
Koot M, van 't Wout AB, Kootstra NA, de Goede RE, Tersmette M, Schuitemaker H. (1996). "Relation between changes in cellular load, evolution of viral phenotype, and the clonal composition of virus populations in the course of human immunodeficiency virus type 1 infection". J Infect Dis. 173 (2): 349-354. PubMed.</ref>
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.<ref name=Chan2>
Chan, D. C. and Kim, P. S. (1998). "HIV entry and its inhibition". Cell 93 (5): 681-684. PubMed. </ref><ref name=Wyatt>
Wyatt, R. and Sodroski, J. (1998). "The HIV-1 envelope glycoproteins: fusogens, antigens, and immunogens". Science 280 (5371): 1884-1888. PubMed DOI:10.1126/science.280.5371.1884.</ref>
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.<ref name=Chan2/><ref name=Wyatt/> The gp160 spike contains binding domains for both CD4 and chemokine receptors.<ref name=Chan2/><ref name=Wyatt/> 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.<ref name=Chan2/><ref name=Wyatt/> This allows for a more stable two-pronged attachment, which allows the N-terminal fusion peptide gp41 to penetrate the cell membrane.<ref name=Chan2/><ref name=Wyatt/> 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.<ref name=Chan2/><ref name=Wyatt/>
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.<ref name=Chan2/>
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.<ref>
Pope, M. and Haasse, A. T. (2003). "Transmission, acute HIV-1 infection and the quest for strategies to prevent infection.". Nature Medicine 9: 847-852. PubMed.</ref> 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.<ref>
Pope, M. and Haasse, A. T. (2003). "Transmission, acute HIV-1 infection and the quest for strategies to prevent infection.". Nature Medicine 9: 847-852. PubMed.</ref>
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.<ref name=Zheng>
Zheng, Y. H., Lovsin, N. and Peterlin, B. M. (2005). "Newly identified host factors modulate HIV replication". Immunol. Lett. 97 (2): 225-234. PubMed.</ref> 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.<ref name=Zheng/>
This integrated viral DNA may then lie dormant, in the latent stage of HIV infection.<ref name=Zheng/> 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.<ref name=Hiscott>
Hiscott J, Kwon H, Genin P. (2001). "Hostile takeovers: viral appropriation of the NF-kappaB pathway". J Clin Invest. 107 (2): 143-151. PubMed.</ref> 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.<ref name=Pollard>
Pollard, V. W. and Malim, M. H. (1998). "The HIV-1 Rev protein". Annu. Rev. Microbiol. 52: 491-532. PubMed.</ref> 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.<ref name=Gelderblom>Gelderblom, H. R (1997). “Fine structure of HIV and SIV”, Los Alamos National Laboratory (ed.): HIV Sequence Compendium (PDF format), Los Alamos, New Mexico: Los Alamos National Laboratory, 31-44.</ref> 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.<ref name=RobertsonDL>
Robertson DL, Hahn BH, Sharp PM. (1995). "Recombination in AIDS viruses". J Mol Evol. 40 (3): 249-259. PubMed.</ref> This complex scenario leads to the generation of many variants of HIV in a single infected patient in the course of one day.<ref name=RobertsonDL/> 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.<ref name=RobertsonDL/> This recombination is most obvious when it occurs between subtypes.<ref name=RobertsonDL/>.
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<ref>Holzammer, S., Holznagel, E., Kaul, A., Kurth, R. and Norley, S. (2001) High virus loads in naturally and experimentally SIVagm-infected African green monkeys. Virology. 283, 324-31</ref>, does not cause the development of simian AIDS<ref>Kurth, R. and Norley, S. (1996) Why don't the natural hosts of SIV develop simian AIDS?, J. NIH Res. 8, 33-37.</ref>, and does not undergo the extensive mutation and recombination typical of HIV<ref>Baier, M., Dittmar, M. T., Cichutek, K. and Kurth, R. (1991) Development of vivo of genetic variability of simian immunodeficiency virus, Proc Natl Acad Sci U S A. 88, 8126-30.</ref>. 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<ref>Daniel, M. D., King, N. W., Letvin, N. L., Hunt, R. D., Sehgal, P. K. & Desrosiers, R. C. (1984) A new type D retrovirus isolated from macaques with an immunodeficiency syndrome, Science. 223, 602-5</ref>. 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.<ref name=Thomson>
Thomson, M. M., Perez-Alvarez, L. and Najera, R. (2002). "Molecular epidemiology of HIV-1 genetic forms and its significance for vaccine development and therapy". Lancet Infect. Dis. 2 (8): 461-471. PubMed.</ref> Group M is the most prevalent and is subdivided into eight subtypes (or clades), based on the whole genome, which are geographically distinct.<ref name=Carr>Carr, J. K., Foley, B. T., Leitner, T., Salminen, M., Korber, B. and McCutchan, F. (1998). “Reference Sequences Representing the Principal Genetic Diversity of HIV-1 in the Pandemic”, Los Alamos National Laboratory (ed.): HIV Sequence Compendium (PDF format), Los Alamos, New Mexico: Los Alamos National Laboratory, 10-19.</ref> 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.<ref name=Osmanov>
Osmanov S, Pattou C, Walker N, Schwardlander B, Esparza J; WHO-UNAIDS Network for HIV Isolation and Characterization. (2002). "Estimated global distribution and regional spread of HIV-1 genetic subtypes in the year 2000". Acquir. Immune. Defic. Syndr. 29 (2): 184-190. PubMed.</ref> Most HIV-1 research is focused on subtype B; few laboratories focus on the other subtypes.<ref name=Perrin>
Perrin L, Kaiser L, Yerly S. (2003). "Travel and the spread of HIV-1 genetic variants". Lancet Infect Dis. 3 (1): 22-27. PubMed.</ref>
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.<ref name=Piatak> Piatak, M., Jr, Saag, M. S., Yang, L. C., Clark, S. J., Kappes, J. C., Luk, K. C., Hahn, B. H., Shaw, G. M. and Lifson, J.D. (1993). "High levels of HIV-1 in plasma during all stages of infection determined by competitive PCR". Science 259 (5102): 1749-1754. PubMed.</ref> 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.<ref name=Pantaleo1998>
Pantaleo G, Demarest JF, Schacker T, Vaccarezza M, Cohen OJ, Daucher M, Graziosi C, Schnittman SS, Quinn TC, Shaw GM, Perrin L, Tambussi G, Lazzarin A, Sekaly RP, Soudeyns H, Corey L, Fauci AS. (1997). "The qualitative nature of the primary immune response to HIV infection is a prognosticator of disease progression independent of the initial level of plasma viremia". Proc Natl Acad Sci U S A. 94 (1): 254-258. PubMed.</ref> 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.<ref name=Kahn>
Kahn, J. O. and Walker, B. D. (1998). "Acute Human Immunodeficiency Virus type 1 infection". N. Engl. J. Med. 331 (1): 33-39. PubMed.</ref> 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.<ref name=burton>
Burton GF, Keele BF, Estes JD, Thacker TC, Gartner S. (2002). "Follicular dendritic cell contributions to HIV pathogenesis". Semin Immunol. 14 (4): 275-284. PubMed.</ref> 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.<ref name=clapham>
Clapham PR, McKnight A. (2001). "HIV-1 receptors and cell tropism". Br Med Bull. 58 (4): 43-59. PubMed.</ref>
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.<ref name=Kumaranayake>
Kumaranayake, L. and Watts, C. (2001). "Resource allocation and priority setting of HIV/AIDS interventions: addressing the generalized epidemic in sub-Saharan Africa". J. Int. Dev. 13 (4): 451-466. DOI:10.1002/jid.797.</ref> 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.<ref name=Kumaranayake>
Kumaranayake, L. and Watts, C. (2001). "Resource allocation and priority setting of HIV/AIDS interventions: addressing the generalized epidemic in sub-Saharan Africa". J. Int. Dev. 13 (4): 451-466. DOI:10.1002/jid.797.</ref> Furthermore, only 0.5% of pregnant women attending urban health facilities are counselled, tested or receive their test results.<ref name=Kumaranayake/> Again, this proportion is even lower in rural health facilities.<ref name=Kumaranayake/> 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.<ref name=Kleinman>Kleinman, S. (September 2004). Patient information: Blood donation and transfusion. Uptodate. Retrieved on 2006-09-01.</ref>
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.<ref name=CDC2001>
Centers for Disease Control and Prevention. (2001). "Revised guidelines for HIV counseling, testing, and referral". MMWR Recomm Rep. 50 (RR-19): 1-57. PubMed.</ref> 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.<ref name=celum>
Celum CL, Coombs RW, Lafferty W, Inui TS, Louie PH, Gates CA, McCreedy BJ, Egan R, Grove T, Alexander S, et al. (1991). "Indeterminate human immunodeficiency virus type 1 western blots: seroconversion risk, specificity of supplemental tests, and an algorithm for evaluation". J Infect Dis. 164 (4): 656-664. PubMed.</ref> 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.<ref name=CDC2001 /> 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
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.<ref name=Fan> (2005) Fan, H., Conner, R. F. and Villarreal, L. P. eds: AIDS : science and society, 4th edition, Boston, MA: Jones and Bartlett Publishers. ISBN 0-7637-0086-X.</ref> Current treatment for HIV infection consists of highly active antiretroviral therapy, or HAART.<ref name=DhhsHivTreatment>Department of Health and Human Services (January, 2005). A Pocket Guide to Adult HIV/AIDS Treatment January 2005 edition. Retrieved on 2006-01-17.</ref> This has been highly beneficial to many HIV-infected individuals since its introduction in 1996, when the protease inhibitor-based HAART initially became available.<ref name=Pallelal>Palella, F. J., Delaney, K. M., Moorman, A. C., Loveless, M. O., Fuhrer, J., Satten, G. A., Aschman, D. J. and Holmberg, S. D. (1998). "Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection". N. Engl. J. Med. 338 (13): 853-860. PubMed.</ref> 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.<ref name=2005dhhsHivChildren>Department of Health and Human Services Working Group on Antiretroviral Therapy and Medical Management of HIV-Infected Children (November 3, 2005). Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection (PDF). Retrieved on 2006-01-17.</ref> 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.<ref name=2005DhhsHivTreatment>Department of Health and Human Services Panel on Clinical Practices for Treatment of HIV Infection (October 6, 2005). Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents (PDF). Retrieved on 2006-01-17.</ref>
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.<ref name=martinez>Martinez-Picado, J., DePasquale, M. P., Kartsonis, N., Hanna, G. J., Wong, J., Finzi, D., Rosenberg, E., Gunthard, H. F., Sutton, L., Savara, A., Petropoulos, C. J., Hellmann, N., Walker, B. D., Richman, D. D., Siliciano, R. and D'Aquila, R. T. (2000). "Antiretroviral resistance during successful therapy of human immunodeficiency virus type 1 infection". Proc. Natl. Acad. Sci. U. S. A. 97 (20): 10948-10953. PubMed.</ref><ref name=Dybul>Dybul, M., Fauci, A. S., Bartlett, J. G., Kaplan, J. E., Pau, A. K.; Panel on Clinical Practices for Treatment of HIV. (2002). "Guidelines for using antiretroviral agents among HIV-infected adults and adolescents". Ann. Intern. Med. 137 (5 Pt 2): 381-433. PubMed.</ref> Moreover, it would take more than a lifetime for HIV infection to be cleared using HAART.<ref name=blankson>Blankson, J. N., Persaud, D., Siliciano, R. F. (2002). "The challenge of viral reservoirs in HIV-1 infection". Annu. Rev. Med. 53: 557-593. PubMed.</ref> 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.<ref name=Pallelal>Palella, F. J., Delaney, K. M., Moorman, A. C., Loveless, M. O., Fuhrer, J., Satten, G. A., Aschman, D. J. and Holmberg, S. D. (1998). "Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection". N. Engl. J. Med. 338 (13): 853-860. PubMed.</ref><ref name=Wood>Wood, E., Hogg, R. S., Yip, B., Harrigan, P. R., O'Shaughnessy, M. V. and Montaner, J. S. (2003). "Is there a baseline CD4 cell count that precludes a survival response to modern antiretroviral therapy?". AIDS 17 (5): 711-720. PubMed.</ref><ref name=Chene>Chene, G., Sterne, J. A., May, M., Costagliola, D., Ledergerber, B., Phillips, A. N., Dabis, F., Lundgren, J., D'Arminio Monforte, A., de Wolf, F., Hogg, R., Reiss, P., Justice, A., Leport, C., Staszewski, S., Gill, J., Fatkenheuer, G., Egger, M. E. and the Antiretroviral Therapy Cohort Collaboration. (2003). "Prognostic importance of initial response in HIV-1 infected patients starting potent antiretroviral therapy: analysis of prospective studies". Lancet 362 (9385): 679-686. PubMed.</ref> 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.<ref name=schack>Schackman BR, Gebo KA, Walensky RP, Losina E, Muccio T, Sax PE, Weinstein MC, Seage GR 3rd, Moore RD, Freedberg KA. (2006). "The lifetime cost of current HIV care in the United States". Med Care 44 (11): 990-997. PubMed.</ref> 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.<ref name=Morgan2>Morgan, D., Mahe, C., Mayanja, B., Okongo, J. M., Lubega, R. and Whitworth, J. A. (2002). "HIV-1 infection in rural Africa: is there a difference in median time to AIDS and survival compared with that in industrialized countries?". AIDS 16 (4): 597-632. PubMed.</ref> 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.<ref name=becker>Becker SL, Dezii CM, Burtcel B, Kawabata H, Hodder S. (2002). "Young HIV-infected adults are at greater risk for medication nonadherence". MedGenMed. 4 (3): 21. PubMed.</ref> 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.<ref name=Nieuwkerk>Nieuwkerk, P., Sprangers, M., Burger, D., Hoetelmans, R. M., Hugen, P. W., Danner, S. A., van Der Ende, M. E., Schneider, M. M., Schrey, G., Meenhorst, P. L., Sprenger, H. G., Kauffmann, R. H., Jambroes, M., Chesney, M. A., de Wolf, F., Lange, J. M. and the ATHENA Project. (2001). "Limited Patient Adherence to Highly Active Antiretroviral Therapy for HIV-1 Infection in an Observational Cohort Study". Arch. Intern. Med. 161 (16): 1962-1968. PubMed.</ref><ref name=Kleeberger>Kleeberger, C., Phair, J., Strathdee, S., Detels, R., Kingsley, L. and Jacobson, L. P. (2001). "Determinants of Heterogeneous Adherence to HIV-Antiretroviral Therapies in the Multicenter AIDS Cohort Study". J. Acquir. Immune Defic. Syndr. 26 (1): 82-92. PubMed.</ref><ref name=heath>Heath, K. V., Singer, J., O'Shaughnessy, M. V., Montaner, J. S. and Hogg, R. S. (2002). "Intentional Nonadherence Due to Adverse Symptoms Associated With Antiretroviral Therapy". J. Acquir. Immune Defic. Syndr. 31 (2): 211-217. PubMed.</ref> The side effects include lipodystrophy, dyslipidaemia, insulin resistance, an increase in cardiovascular risks and birth defects.<ref name=Montessori>Montessori, V., Press, N., Harris, M., Akagi, L., Montaner, J. S. (2004). "Adverse effects of antiretroviral therapy for HIV infection.". CMAJ 170 (2): 229-238. PubMed.</ref><ref name=Saitoh>Saitoh, A., Hull, A. D., Franklin, P. and Spector, S. A. (2005). "Myelomeningocele in an infant with intrauterine exposure to efavirenz". J. Perinatol. 25 (8): 555-556. PubMed.</ref>
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.<ref name=Ferrantelli>Ferrantelli F, Cafaro A, Ensoli B. (2004). "Nonstructural HIV proteins as targets for prophylactic or therapeutic vaccines". Curr Opin Biotechnol. 15 (6): 543-556. PubMed.</ref> Research to improve current treatments includes decreasing side effects of current drugs, further simplifying drug regimens to improve adherence, an