Overview Of Hiv Infection

In 2004, an estimated 42 million people were living with HIV infection worldwide, mostly in resource-poor countries. Of those who would benefit, fewer than 5% were receiving combination antiretroviral therapy, even though such treatment reduces the complications of infection and has the capacity to produce near normal Life expectancies for some patients with a previously lethal disease.

Pathogenesis of HIV-Related Disease

Human immunodeficiency viruses (HIVs) are lentiviruses, retroviruses evolved to establish chronic persistent infection with gradual onset of clinical symptoms. Replication is constant following infection; while some infected cells may harbor nonreplicating but infectious virus for years, there generally is no true period of viral latency following infection. Humans and chimpanzees are the only hosts for these viruses.

There are two major families of HIV. Most of the epidemic involves HIV-1; HIV-2 is a close relative whose distribution is concentrated in western Africa. HIV-1 is genetically diverse, with at least five distinct subfamilies or clades. HIV-1 and HIV-2 have similar sensitivities to most antiretroviral drugs, although the nonnucleoside reverse transcriptase inhibitors have no activity against HIV-2.

virus structure HIV has a small RNA genome of 9300 base pairs. Two copies of the genome are contained in a nucleocapsid core surrounded by a lipid bilayer, or envelope, that is derived from the host cell plasma membrane (Figure 50-1). The viral genome includes three major open reading frames: gag encodes a polyprotein that is processed to release the major structural proteins; pol overlaps gag and encodes three important enzymatic activities—an RNA-dependent DNA polymerase or reverse transcriptase, HIV protease, and the viral integrase; and env encodes the large transmembrane envelop protein responsible for cell binding and entry. Several small genes encode regulatory proteins that enhance virus production or combat host defenses, including tat, rev, nef, and vpr.

virus life cycle HIV tropism is controlled by the envelope (env) protein gp160 (Figure 50-1). The major target for env binding is the CD4 receptor present on lymphocytes and macrophages; cell entry also requires binding to a coreceptor, generally the chemokine receptor CCR5 (present on macrophage lineage cells) or CXCR4. Most infected individuals harbor predominantly the CCR5-tropic virus; it is believed that this virus is responsible for sexual transmission of HIV and that the first cells infected in sexual transmission express this coreceptor. A shift from CCR5 to CXCR4 is associated with advancing disease and heralds accelerated loss of CD4 helper T cells and increased risk of immunosuppression. The doligatory role of coreceptors in HIV entry provides a novel target for phar-macotherapy, and the FDA has recently approved a new drug that targets CCR5 to inhibit viral entry.

The gp41 domain of env controls the fusion of the virus lipid bilayer with that of the host cell. Thereafter, full-length viral RNA enters the cytoplasm and is replicated by reverse transcriptase to a short-lived RNA-DNA duplex; the original RNA is degraded by RNase H to allow creation of a full-length double-stranded DNA copy of the virus (Figure 50-1). Because the HIV reverse transcriptase is error-prone and lacks a proofreading function, mutation is quite frequent (~3 bases/9300 base-pair replication). Viral DNA is transported into the nucleus, where it is integrated into a host chromosome by the viral integrase in a random or quasi-random location.

Following integration, the virus may remain quiescent, not producing RNA or protein but replicating as the cell divides. When a cell that harbors the virus is activated, viral RNA and proteins are produced. Structural proteins assemble around full-length genomic RNA to form a nucleocap-sid (Figure 50-1). The transmembrane envelope and other structural proteins assemble at the cell surface, concentrated in lipid rafts. The nucleocapsid cores are directed to these sites and bud through the cell membrane, creating a new enveloped HIV particle containing two complete single-stranded RNA genomes. Reverse transcriptase is incorporated into this particle; thus, replication can begin immediately after the virus enters a new cell.

how the virus causes disease Sexual acquisition of HIV infection is thought to be mediated by one or, at most, a handful of infectious virus particles. Soon after infection, there is a rapid burst of replication peaking at 2-4 weeks, with 109 or more cells becoming infected. This peak is associated with a transient dip in the number of peripheral CD4 (helper) T lymphocytes. As

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

Get My Free Ebook


Post a comment