Nursing Pharmacology: Antiviral Drugs
Antiviral Drugs
Anti-viral drugs with activity against HIV (Human Immunodeficiency Virus)
HIV-1 Pathophysiology/Pathogenesis
The immunodeficiency at the heart of HIV-1 viral disease occurs as a result of targeting by the virus of a subset of T-cell lymphocytes described as helper T cells.2
These helper T cells are described by CD4+ molecules present on its surface and it is these molecules which serve as the principal HIV-1 cellular receptor.2
As described earlier, a coreceptor must also be present along with CD4+ in support of binding, fusion and HIV-1 entry into target cells.
Two major co-receptors, CCR5 and CXCR4, are utilized by HIV.
Furthermore these co-receptors act as primary receptors for some chemoattractant cytokines (chemokines).
These co-receptors are classified as belonging to the family of seven-transmembrane domain G protein-coupled receptors.2
Destructive effects of HIV-1 are mediated both by direct interaction as well as by indirect effects, including, immunological clearance of infected cells and activation-induced cell death, such as pyroptosis.
Associated with declining CD4+ T cells is the development of a category of diseases manifested as opportunistic infections and neoplasms.2
These are "AIDS-defining" illnesses.
However, some manifestation of AIDS, including Kaposi's sarcoma and some neurological effects may be incompletely explained by HIV-1-mediated immunodeficiency, given that these complications appear to occur prior to severe immunological impairment.
The timeframe depicting the relationship between declining CD4+ T cell count, clinical latency, and opportunistic disease is described below.2
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Initial Events in HIV-1 Infection:
Entry of HIV-1 through the intact or degraded mucosal barrier or by dendritic cell transport is followed by viral association with target cells.2
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The major HIV target is typically CD4+ T cells.2
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"Partially" resting CD4+ T cells as well as activated CD4+ T cells amplify early infection.
Although resting CD4+ T cells are greater in number compared to activated CD4+ T cells, the latter subset is able to produce more virus.
During the initial days to weeks following infection, HIV-1 virus is found initially in draining lymph nodes before proceeding to other lymphoid compartments, there gaining access to elevated concentration of CD4+ T cell targets.
Access to this enriched CD4+ T cell environment accounts for an early burst of high-level viremia.2
Gut-associated lymphoid tissue (GALT) is an important HIV-1 viral target and development of HIV-1 infection in GALT infection depletes memory-cell enriched CD4+ T cell subpopulations.
Depletion of these cells occurs both by direct virus infection and virus-induced apoptosis.2
At this point, with the infection established, continued HIV replication and dissemination appear irreversible.2
Some characteristics of initial target cell infection may be dependent on the route of infection.
For example, virus entering the bloodstream directly (e.g. via blood/blood products) may be cleared by normal physiological processes to the spleen and other lymphoid organs.
At these sites primary focal infections begin and wider spread to other lymphoid tissues follow.2
HIV-1 Resistance to Antibody Neutralization:
HIV sexual transmission has been described as a single infectious event.2
Features of the HIV envelope glycoprotein appear to influence significantly HIV transmission (for subtype A and C viruses, at least).2
The viral isolate most active in transmission has been designated "founder viruses," and are less common in the viral population of the transmitting partner and also appear less divergent with respect to certain specific sequences.
The HIV-1 viral spike represents the sole viral target for neutralizing antibodies and has evolved to counteract antibody-mediated neutralization.11
As replication proceeds in the newly infected individual, the founder virus diverges, variation in glycosylation sites results in increasing resistance to antibody neutralization.2,13
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