Figure 511

Exploded view of the human immunodeficiency virus. It is an RNA (retrovirus) virus that contains surface proteins composed of a knoblike glycoprotein (gp120) linked to a transmembrane stalk (gp41). These surface proteins are the infective mechanisms that allow the virus to bind to CD4 proteins of cells, such as T4 lymphocytes and monocytes.

binding is required for viral entry; individuals with genetic defects in these proteins are resistant to HIV infection. The binding of gp120 to CXCR4 or CCR5 causes a rearrangement in the envelope glycoproteins that allows the fusion of a viral transmembrane glyco-protein (gp41) with the target cell membrane. Fusion of the viral and cellular membranes follows as the virus enters the target cell.

After entering the host cell and uncoating, viral reverse transcriptase synthesizes DNA using viral RNA as a template. This DNA circularizes, enters the nucleus, and is integrated into the host genome by another viral enzyme, integrase. The host cell then transcribes the viral genes and produces viral proteins and progeny viral RNA. New virions assemble, bud from the cell membrane, and undergo a maturation process in which the gag-pol polyprotein is cleaved by the viral enzyme protease. The resultant mature virus particles spread to infect other susceptible cells.

The majority of viral replication occurs in recently infected CD4+ lymphocytes and depletes them during the first several years of infection. Macrophage populations are depleted or cease to function properly in 3 to 10 years or more. It is during this time that an HIV-infected person becomes immunodeficient and can die of infections that under normal conditions are not life threatening. Eventually the macrophages of the brain

(microglia) may become infected and an inflammation-based dementia may occur.

Several pools of nonreplicating virus serve as reservoirs of infection and limit the effectiveness of anti-retroviral therapy. HIV can live and multiply in mono-cytes and macrophages; these cells are present in all tissues and can live for many months. Infective virus can also reside in long-lived resting CD4+ lymphocytes.

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