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| {{CMG}}
| | #REDIRECT [[HIV structure and genome]] |
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| The [[genome]] and [[proteins]] of [[HIV]] have been the subject of extensive research since the discovery of the virus in 1983.<ref name="pmid6189183">{{cite journal |author=Barré-Sinoussi F, Chermann JC, Rey F, ''et al'' |title=Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS) |journal=Science (journal) |volume=220 |issue=4599 |pages=868–71 |year=1983 |month=May |pmid=6189183 |doi= |url=http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=6189183}}</ref><ref name="pmid6601823">{{cite journal |author=Gallo RC, Sarin PS, Gelmann EP, ''et al'' |title=Isolation of human T-cell leukemia virus in acquired immune deficiency syndrome (AIDS) |journal=Science (journal) |volume=220 |issue=4599 |pages=865–7 |year=1983 |month=May |pmid=6601823 |doi= |url=http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=6601823}}</ref> The discovery of the virus itself was not until two years after the first major cases of AIDS associated illnesses were reported in 1981.<ref name='Pneumocycstis Pneumonia - Los Angeles'> {{cite journal|title=Pneumocycstis Pneumonia - Los Angeles|journal=Morbidity and Mortality Weekly Report|date=1981-06-05|first=|last=Centers for Disease Control and Prevention |coauthors=|volume=30|issue=|pages=250-2|id= |url=http://www.cdc.gov/hiv/resources/reports/mmwr/pdf/mmwr05jun81.pdf|format=PDF|accessdate=2008-05-10 }}</ref><ref name='MMWR 1981-07'> {{cite journal|title=Kaposi's Sarcoma and Pneumocycstis Pneumonia Among Homosexual Men - New York City and California|journal=Morbidity and Mortality Weekly Report|date=1981-07-04|first=|last=Centers for Disease Control and Prevention |coauthors=|volume=30|issue=|pages=305-8|id= |url=http://www.cdc.gov/hiv/resources/reports/mmwr/pdf/mmwr04jul81.pdf|format=PDF|accessdate=2008-05-10 }}</ref>
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| ==Structure==
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| [[Image:HIV Viron.png|thumb|200px|Figure 1. Diagram of HIV]]
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| HIV is different in structure from other [[retrovirus]]es. It is around 120 [[nanometer|nm]] in diameter (120 billionths of a meter; around 60 times smaller than a red blood cell) and roughly spherical.
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| HIV-1 is composed of two copies of single-stranded [[RNA]] enclosed by a conical [[capsid]] comprising the viral protein [[#p24, p6, p7, p21|p24]], typical of [[lentivirus]]es (Figure 1). The RNA component is 9749 nucleotides long<ref>{{cite journal |author=Ratner L, Haseltine W, Patarca R, ''et al'' |title=Complete nucleotide sequence of the AIDS virus, HTLV-III |journal=Nature |volume=313 |issue=6000 |pages=277–84 |year=1985 |pmid=2578615 |doi=}}</ref>. This is in turn surrounded by a [[cell membrane|plasma membrane]] of host-cell origin. The single-strand RNA is tightly bound to the nucleocapsid proteins, [[#p24, p6, p7, p21|p7]] and [[enzymes]] that are indispensable for the development of the virion, such as [[reverse transcriptase]] and [[integrase]]. The nucleocapsid (p7 and p6) associates with the genomic RNA (one molecule per hexamer) and protects the RNA from digestion by [[nuclease]]s. A matrix composed of an association of the viral protein p17 surrounds the capsid, ensuring the integrity of the virion particle. Also enclosed within the virion particle are [[#Vif|Vif]], [[#Vpr|Vpr]], [[#Nef|Nef]], p7 and viral [[#protease|protease]] (Figure 1). The envelope is formed when the capsid buds from the host cell, taking some of the host-cell membrane with it. The envelope includes the glycoproteins [[#gp120|gp120]] and [[#gp41|gp41]].
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| In 2006, an Anglo-German team compiled a 3D structure of HIV by combining multiple images. It is hoped that this new information would contribute to scientific understanding of the virus, and help in the creation of a cure. [[Oxford University]]'s Professor [[Stephen D. Fuller]] said the 3D map would assist in understanding how the virus grows. <ref>BBC News: [http://news.bbc.co.uk/1/hi/health/4642940.stm 3D Structure of HIV Revealed]</ref> The validity of this work remains a matter of debate <ref>The SIV Surface Spike Imaged by Electron Tomography: One Leg or Three? Subramaniam S PLoS Pathogens Vol. 2, No. 8, e91 doi:10.1371/journal.ppat.0020091</ref>, with a conflicting model produced by another team led by Florida State University Professor [[Kenneth Roux]] in the US <ref>Distribution and three-dimensional structure of AIDS virus envelope spikes Ping Zhu, Jun Liu, Julian Bess, Jr, Elena Chertova, Jeffrey D. Lifson, Henry Grisé, Gilad A. Ofek, Kenneth A. Taylor and Kenneth H. Roux, Nature 441, 847-852 (15 June 2006) | doi:10.1038/nature04817; Received 8 March 2006; Accepted 24 April 2006; Published online 24 May 2006</ref>.
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| ==Genome organization==
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| [[Image:HIV genome.png|right|thumb|300px|Figure 2. Diagram of the HIV genome]]
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| HIV has several major genes coding for structural proteins that are found in all retroviruses, and several nonstructural ("accessory") genes that are unique to HIV. The ''gag'' gene provides the basic physical infrastructure of the virus, and ''pol'' provides the basic mechanism by which retroviruses reproduce, while the others help HIV to enter the host cell and enhance its reproduction. Though they may be altered by mutation, all of these genes except ''tev'' exist in all known variants of HIV; see [[HIV#Genetic variability|Genetic variability of HIV]].
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| * ''gag'' (Group-specific Antigen): codes for [[#p24|p24]], the viral capsid; [[#p6 and p7|p6 and p7]], the nucleocapsid proteins; and [[#p17|p17]], a matrix protein.
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| * ''pol'': Codes for viral [[enzyme]]s, the most important of which are [[#reverse transcriptase|reverse transcriptase]], [[#integrase|integrase]], and [[#protease|protease]] which cleaves the proteins derived from ''gag'' and ''pol'' into functional proteins.
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| * ''env'' (for "envelope"): Codes for the precursor to [[#gp120|gp120]] and [[#gp41|gp41]], proteins embedded in the viral envelope which enable the virus to attach to and fuse with target cells.
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| * ''tat'', ''rev'', ''nef'', ''vif'', ''vpr'', ''vpu'': Each of these genes codes for a single protein with the same names; see [[#Tat|Tat]], [[#Rev|Rev]], [[#Nef|Nef]], [[#Vif|Vif]], [[#Vpr|Vpr]], [[#Vpu|Vpu]].
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| * ''tev'': This gene is only present in a few HIV-1 isolates. It is a fusion of parts of the ''tat'', ''env'', and ''rev'' genes, and codes for a protein with some of the properties of [[#Tat|Tat]], but little or none of the properties of [[#Rev|Rev]].
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| ==Protein function==
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| ===Gag===
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| These proteins are encoded by the ''gag'' gene, and provide structural elements of the virus.
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| ====p24====
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| p24 makes up the viral capsid.
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| When a [[Western blot]] test is used to detect HIV infection, p24 is one of the three major proteins tested for, along with [[#gp120|gp120]]/gp160 and [[#gp41|gp41]].
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| ====p6, p7, and p17====
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| p6 and p7 provide the nucleocapsid.
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| p17 provides a protective matrix.
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| ===Pol===
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| ====Reverse transcriptase====
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| {{main|Reverse transcriptase}}
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| Common to all retroviruses, this enzyme transcribes the viral [[RNA]] into double-stranded [[DNA]].
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| ====Integrase====
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| {{main|Integrase}}
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| This enzyme [[retroviral integration|integrates]] the DNA produced by reverse transcriptase into the host's genome.
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| ====Protease====
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| {{main|HIV-1 protease}}
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| A [[protease]] is any enzyme that cuts proteins into segments. HIV's ''gag'' and ''pol'' genes do not produce their proteins in their final form, but as larger combination proteins; the specific protease used by HIV cleaves these into separate functional units. [[Antiretroviral drug#Protease inhibitors (PIs)|Protease inhibitor]] drugs block this step.
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| ===Env===
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| The ''env'' gene does not actually code for gp120 and gp41, but for a precursor to both, gp160. During HIV reproduction, the host cell's own enzymes cleave gp160 into gp120 and gp41. See [[HIV#Replication cycle|Replication cycle of HIV]].
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| ====gp120====
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| {{main|gp120}}
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| Exposed on the surface of the viral envelope, the [[glycoprotein]] gp120 binds to the [[CD4]] [[receptor (biochemistry)|receptor]] on any target cell that has such a receptor, particularly the [[helper T-cell]]. See [[HIV#HIV tropism|HIV tropism]] and [[HIV#Replication cycle|Replication cycle of HIV]].
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| Since CD4 receptor binding is the most obvious step in HIV infection, gp120 was among the first targets of [[HIV vaccine]] research. These efforts have been hampered by its chemical properties, which make it difficult for antibodies to bind to gp120; also, it can easily be shed from the virus due to its loose binding with gp41.
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| ====gp41====
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| The glycoprotein gp41 is non-[[covalent bond|covalently]] bound to gp120, and provides the second step by which [[viral entry|HIV enters]] the cell. It is originally buried within the viral envelope, but when gp120 binds to a CD4 receptor, gp120 changes its [[chemical conformation|conformation]] causing gp41 to become exposed, where it can assist in fusion with the host cell.
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| [[Fusion inhibitor]] drugs such as [[enfuvirtide]] block the fusion process by binding to gp41.
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| ===Transactivators===
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| ====Tat====
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| [[Image:Tat Structure.jpg|thumb|right|180px|Molecular model of Tat]]
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| Stands for "Trans-Activator of Transcription". Tat consists of between 86 and 101 amino acids depending on the subtype.<ref>Jeang, K. T. (1996) In: Human Retroviruses and AIDS: [http://hiv.lanl.gov/content/hiv-db/COMPENDIUM/1996/PART-III/1.pdf A Compilation and Analysis of Nucleic Acid and Amino Acid Sequences.] Los Alamos National Laboratory (Ed.) pp. III-3–III-18</ref>
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| Tat vastly increases the level of transcription from the HIV DNA. Before Tat is present, a small number of RNA transcripts will be made, which allow the Tat protein to be produced. Tat then binds to and phosphorylates cellular factors, resulting in increased transcription of all HIV genes<ref>Kim JB, Sharp PA. (2001) [http://www.jbc.org/cgi/content/full/276/15/12317 Positive transcription elongation factor B phosphorylates hSPT5 and RNA polymerase II carboxyl-terminal domain independently of cyclin-dependent kinase-activating kinase]. ''J. Biol. Chem.'' '''276''', 12317-12323 PMID 11145967</ref>, providing a [[positive feedback]] cycle. This in turn allows HIV to have an explosive response once a threshold amount of Tat is produced, a useful tool for defeating the body's response.
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| Tat also appears to play a more direct role in the HIV disease process. The protein is released by infected cells in culture, and is found in the blood of HIV-1 infected patients.<ref name="Xiao">Xiao, H., Neuveut, C., Tiffany, H. L., Benkirane, M., Rich, E. A., Murphy, P. M. and Jeang, K. T. (2000) [http://www.ncbi.nlm.nih.gov/entrez/utils/lofref.fcgi?PrId=3494&uid=11027346&db=pubmed&url=http://www.pubmedcentral.gov/articlerender.fcgi?tool=pubmed&pubmedid=11027346 Selective CXCR4 antagonism by Tat: implications for in vivo expansion of coreceptor use by HIV-1]. ''Proc. Natl. Acad. Sci. U.S.A.'' '''97''', 11466-11471 PMID 11027346</ref>
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| It can be absorbed by cells that are not infected with HIV, and can act directly as a [[toxin]] producing cell death via [[apoptosis]] in uninfected "bystander" [[T cell]]s, assisting in progression toward [[AIDS]].<ref>Campbell GR, Pasquier E, Watkins J, Bourgarel-Rey V, Peyrot V, Esquieu D, Barbier P, de Mareuil J, Braguer D, Kaleebu P, Yirrell DL, Loret EP. (2004) [http://www.ncbi.nlm.nih.gov/entrez/utils/lofref.fcgi?PrId=3051&uid=15331610&db=pubmed&url=http://www.jbc.org/cgi/pmidlookup?view=long&pmid=15331610 The glutamine-rich region of the HIV-1 Tat protein is involved in T-cell apoptosis]. ''J. Biol. Chem.'' '''279''', 48197-48204 PMID 15331610</ref>
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| By interacting with the [[CXCR4]] receptor, Tat also appears to encourage the reproduction of less virulent M-tropic strains of HIV early in the course of infection, allowing the more rapidly pathogenic T-tropic strains to emerge later.<ref name="Xiao" />
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| ====Rev====
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| [[Image:Rev-mediated HIV mRNA transport.png|thumb|none|400px|'''Rev-mediated HIV mRNA transport.''' Rev (red) binds the Rev response element (RRE, blue) to mediate export of unspliced and singly spliced mRNA from the nucleus to the cytoplasm.]]
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| Stands for "Regulator of Virion". This protein allows fragments of HIV mRNA that contain a Rev Response Element(RRE) to be exported from the nucleus to the cytoplasm. In the absence of the ''rev'' gene, RNA splicing machinery in the nucleus quickly splices the RNA so that only the smaller, regulatory proteins can be produced; in the presence of ''rev'', RNA is exported from the nucleus before it can be spliced, so that the structural proteins and RNA genome can be produced. Again, this mechanism allows a positive feedback loop to allow HIV to overwhelm the host's defenses, and provides time-dependent regulation of replication (a common process in viral infections)<ref name="Strebel">Strebel, K (2003) Virus-host interactions: role of HIV proteins Vif, Tat, and Rev. ''AIDS'' '''17 Suppl 4''', S25-S34 PMID 15080177</ref>
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| ====Vpr====
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| Stands for "Viral Protein R". Vpr, a 96 amino acid 14-kDa protein, plays an important role in regulating nuclear import of the [[HIV-1 pre-integration complex]], and is required for virus replication in non-dividing cells such as macrophages. Vpr also induces cell cycle arrest and apoptosis in proliferating cells, which can result in immune dysfunction.<ref>Bukrinsky M, Adzhubei A. (1999) Viral protein R of HIV-1. ''Rev Med Virol'' '''9''', 39-49 PMID 10371671</ref><ref>Muthumani K., et al (2006) The HIV-1 Vpr and glucocorticoid receptor complex: A gain of function interaction that prevents the nuclear localization of PARP-1. Nat Cell Biol. Feb;8(2):170-9.</ref>
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| Vpr is also immunosuppressive due to its ability to sequester a proinflammatory transcriptional activator in the cytoplasm. HIV-2 contains both a Vpr protein and a related (by sequence homology) Vpx protein (Viral Protein X). Two functions of Vpr in HIV-1 are split between Vpr and Vpx in HIV-2, with the HIV-2 Vpr protein inducing cell cylce arrest and the Vpx protein required for nuclear import.
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| ===Other regulatory proteins===
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| ====Nef====
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| Nef stands for "Negative Factor".<ref name="titleHIV-1 Nef Protein">{{cite web |url=http://www.callutheran.edu/Academic_Programs/Departments/BioDev/omm/hiv1nef/molmast.htm |title=HIV-1 Nef Protein |accessdate=2008-03-27 |format= |work=}}</ref> The expression of Nef early in the viral life cycle ensures T cell activation and the establishment of a persistent state of infection, two basic attributes of HIV infection. Nef also promotes the survival of infected cells by downmodulating the expression of several surface molecules important in host immune function. These include [[major histocompatibility complex]]-I (MHC I) and MHC II present on [[antigen presenting cell]]s (APCs) and target cells, [[CD4]] and [[CD28]] present on CD4+ T cells. One group of patients in Sydney were infected with a nef-deleted virus and took much longer than expected to progress to AIDS.<ref>Learmont JC, Geczy AF, Mills J, Ashton LJ, Raynes-Greenow CH, Garsia RJ, Dyer WB, McIntyre L, Oelrichs RB, Rhodes DI, Deacon NJ, Sullivan JS. (1999) [http://content.nejm.org/cgi/content/abstract/340/22/1715 Immunologic and virologic status after 14 to 18 years of infection with an attenuated strain of HIV-1]. A report from the Sydney Blood Bank Cohort. ''N Engl J Med'' '''340''', 1715-1722 PMID 10352163</ref>
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| A ''nef''-deleted virus vaccine has not been trialed in humans and has failed in nonhuman animals.{{Fact|date=February 2008}}
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| HIV-1 Nef-induced FasL induction and bystander killing requires p38 MAPK activation.[http://bloodjournal.hematologylibrary.org/cgi/content/abstract/106/6/2059]
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| ====Vif====
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| Stands for "[[Viral infectivity factor]]". Vif is a 23-[[kilodalton]] protein that is essential for viral replication.<ref name="Strebel" /> Vif inhibits the cellular protein, [[APOBEC3G]], from entering the virion during budding from a host cell by targeting it for proteasomal degradation. Vif hijacks the cellular Cullin5 E3 ubiquitin ligase in order to target APOBEC3G for degradation. In the absence of Vif, APOBEC3G causes hypermutation of the viral genome, rendering it dead-on-arrival at the next host cell. APOBEC3G is thus a host defence to retroviral infection which HIV-1 has overcome by the acquisition of Vif. Targeting vif has been suggested as a strategy for future HIV drug therapies.<ref>{{cite journal |author=Miller JH, Presnyak V, Smith HC |title=The dimerization domain of HIV-1 viral infectivity factor Vif is required to block APOBEC3G incorporation with virions |journal=Retrovirology |volume=4 |issue=1 |pages=81 |year=2007 |pmid=18036235 |doi=10.1186/1742-4690-4-81 |url=http://www.retrovirology.com/content/4/1/81}}</ref>
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| ====Vpu====
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| Stands for "Viral Protein U". Vpu is involved in viral budding, enhancing virion release from the cell. It can be found in HIV-1 but not in HIV-2.<ref>Principle of Virology: Molecular Biology, Pathrogenesis, and Control.(2000) Washington:American Society for Microbiology ISBN 1-55581-127-2</REF>
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| ==References==
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| {{Reflist}}
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| ==External links==
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| *[http://pathmicro.med.sc.edu/lecture/hiv9.htm Genome at sc.edu]
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| {{AIDS}}
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| [[Category:HIV/AIDS]]
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| {{WH}}
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| {{WS}}
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