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Chapter: Modern Pharmacology with Clinical Applications: Therapy of Human Immunodeficiency Virus

Human Immunodeficiency Virus

Human Immunodeficiency Virus
Production of Immunodeficiency by HIV

HUMAN IMMUNODEFICIENCY VIRUS

 

Human immunodeficiency virus (HIV) is a single-stranded RNA retrovirus that causes acquired immun-odeficiency syndrome (AIDS), a condition in which in-dividuals are at increased risk for developing certain infections and malignancies. The virus is found in two major forms: HIV-1, the most prevalent worldwide, and HIV-2, the most common in western Africa. More than 22 million people have died of HIV infection, and 40 million are believed to be infected worldwide. AIDS epidemics threaten populations in sub-Saharan Africa, Southeast Asia, Central and South America, and Russia. In the United States about 450,000 deaths have occurred and another 900,000 people are estimated to carry the virus. Although the development of new drugs, complex multidrug regimens, and behavioral modifica-tion have done much to combat the spread of HIV infection, AIDS remains a serious threat because of the expense and inaccessibility of antiretroviral agents in the developing countries in which the disease is most prevalent. In addition, the effectiveness of antiretroviral drugs has been diminished by the emergence of mul-tidrug-resistant virus.

 

 

Production of Immunodeficiency by HIV

 

HIV infects CD4+ T lymphocytes, macrophages, and dendritic cells. Viral entry is initiated when gp120 (SU), a glycoprotein on the surface of the viral envelope, at-taches itself to the CD4 surface glycoprotein of the tar-get cell (Fig. 51.1). This interaction produces a confor-mational change in gp120 that allows it to bind to a chemokine coreceptor: CXCR4 for CD-4 T (helper) cells or CCR5 for macrophages. 


Chemokine coreceptor binding is required for viral entry; individuals with ge-netic defects in these proteins are resistant to HIV in-fection. 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 re-verse 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 vi-ral genes and produces viral proteins and progeny viral RNA. New virions assemble, bud from the cell mem-brane, and undergo a maturation process in which the gag-pol polyprotein is cleaved by the viral enzyme pro-tease. The resultant mature virus particles spread to in-fect 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 popula-tions 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 reser-voirs 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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