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Molecular targets of antiretroviral therapies

Problem

The mechanism by which HIV infects a cell—whereby it incorporates its viral DNA into the genome of the host—suggests inherent difficulties in effectively eradicating the pathogen from host material. That is, once infection has occurred, the only means of eliminating the virus is to destroy the infected cell. Though a ‘cure’ for HIV/AIDS has yet to be developed, several modalities currently exist which, if properly adhered to, are highly effective in controlling viral replication and activity.
Several intuitive sites for potential therapies are readily identified when examining the steps necessary for HIV entry and integration into the host genome (shown in Figure 1). First, the viral envelope protein gp120 binds with CD4 and CCR5 proteins on the target cell, which facilitate the attachment to and fusion of the virus with host cell membranes. In the cytosol, viral reverse transcriptase produces a genome which is compatible with that of the host cell. This then enters the nucleus and is integrated into the host’s genome, catalyzed by the enzyme ‘integrase’.
Figure 1: Mechanism of HIV infection with potential therapy targets.
(1) HIV attaches as envelope proteins bind to CD4 and CCR5 receptors on the host cell membrane. (2) Virus and host membranes fuse and the contents of the viral capsid are injected into the cell. (3) Reverse transcriptase produces a viral genome compatible with the host. (4) The viral genome enters the host nucleus and is integrated into the host genome. (5) Translation and production of viral proteins by host cell machinery. (6) Budding HIV molecules are released from the cell.
No single drug has proven to be individually effective for long-term treatment of HIV infection. Reverse transcriptase has no inherent mechanism to correct mistakes and is highly error prone, producing a high rate of mutation and fostering resistance to pharmacological therapies. An attractive target for antiretroviral therapies is reverse transcriptase itself. By inhibiting this key enzyme, the viral genetic material cannot be incorporated into the host genome, and therefore cannot proceed with replication or protein synthesis.
The first antiretroviral drugs, nucleoside/nucleotide analog reverse-transcriptase inhibitors (NRTIs), achieve this in an indirect fashion. NRTIs are composed of lab-synthesized analogs of nucleoside or nucleotide bases, commonly guanosine, albeit lacking the 3, ’-hydroxyl group on the deoxyribose moiety (demonstrated in Figure 2). As DNA is synthesized, this analog will be incorporated into the growing DNA chain in place of a naturally occurring nucleotide. The defunct 3, ’-hydroxyl group on the NRTI is not capable of forming the next bond necessary for extending the chain. The result then, is that when a NRTI is incorporated into the growing chain, DNA synthesis is interrupted and the chain terminated.
Figure 2: Structural/functional significance of nucleoside analog reverse-transcriptase inhibitors.
The NRTI Abacavir is an analog of guanosine, but lacks the 3, ’ hydroxyl group on the deoxyribose moiety (Panel A). Functional deficits due to this change arise from an inability to bond with subsequent nucleotides.
What is the function of reverse transcriptase?
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