Mini MCAT passage: Molecular targets of antiretroviral therapies

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. Intuitive targets for therapy include 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. Another target is the reverse transcriptase (RT) enzyme, a highly error prone enzyme that allows for conversion and incorporation of the HIV genome into the host cell.

The first antiretroviral drugs, nucleoside/nucleotide analog reverse-transcriptase inhibitors (NRTIs) inhibit RT 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 is 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. Figure 1 shows the NRTI Abacavir, an analog of guanosine.

Figure 1 Structural of NRTI vs deoxyguanosine (Panel A) and functional implications (Panel B)