User:Hob/HIV life cycle
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The life cycle of HIV is the process by which the human immunodeficiency virus enters various cells of the body and reproduces. As with all viruses, there are three steps to this process: entry to a target cell, replication (using the cell's own genetic machinery), and release of new virus particles. However, many steps can vary depending on genetic variation in the virus and in human hosts.
The term viral tropism refers to the cell type that the virus infects and replicates in, also called the target cell.
All cells that can be infected by HIV are CD4+ (CD4 positive), meaning that they have the CD4 receptor molecule on their surface, but not every CD4+ cell is a target of HIV. The most common target cells are helper T-cells and macrophages. In the central nervous system, HIV infects macrophages and also microglial cells. It can also target dendritic cells, found mostly in the lymphatic system (Knight et al., 1990).
What determines the target cell favored by a particular strain of HIV is the presence of another receptor besides CD4, the coreceptor, without which HIV cannot enter the cell. This is always a chemokine receptor; the most common ones are CCR5 and CXCR4. HIV strains that use CCR5 have a tropism for macrophages, and are therefore called M-tropic, though they can also enter T cells; these are the most common strains in newly infected patients. Strains that use CXCR4 are T-tropic, having a greater tropism for T cells; these are usually seen later in the course of infection. T-tropic strains are thought to cause more rapidly progressing disease; see Pathogenicity of HIV. HIV strains that use only CCR5 are called R5 strains, and those that use only CXCR4 are called X4 strains; some can use both, and some use other, less common coreceptors. The use of coreceptors alone does not fully explain viral tropism, as some R5 strains are still not able to infect macrophages (Coakley et al., 2005).
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The interaction between the gp120 on the HIV virion and its receptor, CD4 on the target cell, provokes conformational changes in gp120 that exposes a previously buried portion of the transmembrane glycoprotein, gp41, and allows access of the V3 loop of gp120 to the coreceptor (a chemokine receptor on the target cell). A fusion peptide within gp41 causes the fusion of the viral envelope and the host-cell envelope, allowing the capsid to enter the target cell. The exact mechanism by which gp41 causes the fusion is still largely unknown (Chan and Kim, 1998; Wyatt and Sodroski, 1998).
Once HIV has bound to the CD4+ T-cell the HIV RNA and various enzymes including but not limited to reverse transcriptase, integrase and protease are injected into the cell.
Once the viral capsid has entered the cell, an enzyme called reverse transcriptase liberates the single-stranded (+)RNA from the attached viral proteins and copies it into a negatively sensed viral complementary DNA of 9 kb pairs (cDNA) (Figure 2). This process of reverse transcription is extremely error prone and it is during this step that mutations (such as drug resistance) are likely to arise. The reverse transcriptase then makes a complementary DNA strand to form a double-stranded viral DNA intermediate (vDNA). This new vDNA is then transported into the nucleus. The integration of the proviral DNA into the host genome is carried out by another viral enzyme called integrase. This is called the latent stage of HIV infection (Zheng et al., 2005).
To actively produce virus, certain transcription factors need to be present in the cell. The most important is called NF-kB (NF Kappa B) and is present once the T cells becomes activated. This means that those cells most likely to be killed by HIV are in fact those currently fighting infection.
The production of the virus is regulated, like that of many viruses. Initially the integrated provirus is copied to mRNA which is then spliced into smaller chunks. These small chunks produce the regulatory proteins Tat (which encourages new virus production) and Rev. As Rev accumulates it gradually starts to inhibit mRNA splicing (Pollard and Malim, 1998). At this stage the structural proteins Gag and Env are produced from the full-length mRNA. Additionally the full-length RNA is actually the virus genome, so it binds to the Gag protein and is packaged into new virus particles.
Interestingly, 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 causes AIDS faster than HIV-2 and is the majority species of the virus).
The final step of the viral cycle is the assembly of new HIV-1 virions, 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 (proteinases) cleave the polyproteins into individual functional HIV proteins and enzymes. The various structural components then assemble to produce a mature HIV virion (Gelderblom, 1997). This step can be inhibited by drugs. The virus is then able to infect another cell.
- Chan, D. C. and Kim, P. S. (1998) HIV entry and its inhibition. Cell 93, 681-684 PMID 9630213
- Coakley, E., Petropoulos, C. J. and Whitcomb, J. M. (2005) Assessing chemokine co-receptor usage in HIV. Curr Opin Infect Dis. 18, 9-15. PMID 15647694
- Gelderblom, H. R. (1997) Fine structure of HIV and SIV. In: Los Alamos National Laboratory (Ed) HIV Sequence Compendium, 31-44.
- Knight, S. C., Macatonia, S. E. and Patterson, S. (1990) HIV I infection of dendritic cells. Int Rev Immunol. 6,163-75 PMID 2152500
- Pollard, V. W. and Malim, M. H. (1998) The HIV-1 Rev protein. Annu Rev Microbiol. 52, 491-532 PMID 9891806
- Wyatt, R. and Sodroski, J. (1998) The HIV-1 envelope glycoproteins: fusogens, antigens, and immunogens. Science 280, 1884-1888 PMID 9632381
- Zheng, Y. H., Lovsin, N. and Peterlin, B. M. (2005) Newly identified host factors modulate HIV replication. Immunol Lett. 97, 225-234 PMID 15752562
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