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9.10D: Replicative Cycle of HIV

LEARNING OBJECTIVES

  • Compare and contrast HIV replication to other viruses

Human immunodeficiency virus (HIV) is a lentivirus (a member of the retrovirus family) that causes acquired immunodeficiency syndrome (AIDS). AIDS is a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive. HIV can infect dendritic cells (DCs). 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 when the virus is captured in the mucosa by DCs. HIV enters macrophages and T cells by the adsorption of glycoproteins on its surface to receptors on the target cell. This is followed by fusion of the viral envelope with the cell membrane and the release of the HIV capsid into the cell.

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HIV Replication: Steps in the HIV Replication Cycle: Fusion of the HIV cell to the host cell surface.Cell Entry, HIV RNA, reverse transcriptase, integrase, and other viral proteins enter the host cell.Viral DNA is formed by reverse transcription.Viral DNA is transported across the nucleus and integrates into the host DNA.New viral RNA is used as genomic RNA to make viral proteins.New viral RNA and proteins move to cell surface and a new, immature, HIV virus forms.Virus maturation and protease release of individual HIV proteins.

Shortly after the viral capsid enters the cell, an enzyme called reverse transcriptase liberates the single-stranded (+)RNA genome from the attached viral proteins and copies it into a complementary DNA (cDNA) molecule. The process of reverse transcription is extremely error-prone, and the resulting mutations may cause drug resistance or allow the virus to evade the body’s immune system. The reverse transcriptase also has ribonuclease activity that degrades the viral RNA during the synthesis of cDNA, as well as DNA-dependent DNA polymerase activity that creates a sense DNA from the antisense cDNA. Together, the cDNA and its complement form a double-stranded viral DNA that is then transported into the cell nucleus.

This integrated viral DNA may then lie dormant, in the latent stage of HIV infection. To actively produce the virus, certain cellular transcription factors need to be present. The most important of these is NF-κB (NF kappa B), which is upregulated when T-cells become activated. This means that those cells most likely to be killed by HIV are those currently fighting infection. During viral replication, the integrated DNA provirus is transcribed into mRNA, which is then spliced into smaller pieces. These small pieces are exported from the nucleus into the cytoplasm, where they are translated into the regulatory proteins Tat (which encourages new virus production) and Rev.

As the newly produced Rev protein accumulates in the nucleus, it binds to viral mRNAs and allows unspliced RNAs to leave the nucleus, where they are otherwise retained until spliced. 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. The final step of the viral cycle, assembly of new HIV-1 virions, begins at the plasma membrane of the host cell. The Env polyprotein goes through the endoplasmic reticulum and is transported to the Golgi complex. There, it is cleaved by HIV 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 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 occurs either 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. This cleavage step can be inhibited by protease inhibitors. The various structural components then assemble to produce a mature HIV virion. The mature virion is then able to infect another cell.

Key Points

  • First the HIV viron binds to host cell, after binding the virus and cell fuse, which releases the various enzymes HIV needs to reverse transcribe and integrate into the host genome.
  • The reverse transcription of HIV viral RNA to DNA is error prone, causing HIV to have a high mutation rate. This makes it difficult to design treatments against HIV.
  • The HIV provirus can stay dormant in the host genome for years. It may become active when the host T cell is itself activated by fighting an infection that the body is facing.
  • Understanding the HIV life cycle will help in providing effective treatments against HIV.

Key Terms

  • provirus: A virus genome, such as HIV, that integrates itself into the DNA of a host cell so as to be passively replicated along with the host genome.
  • reverse transcriptase: An enzyme that catalyzes the formation of DNA from RNA; found in retroviruses.

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