NONNUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NNRTIs)
NNRTIs are structurally distinct from NRTIs, and rather than inducing DNA-chain termination through the substitution of natural nucleotides, NNRTIs bind to a nonsubstrate-specific site on the HIV reverse transcriptase enzyme.
These binding sites, situated physically close to the enzyme active site, and induce on ligation an approximately 2 A shift in the position of the active site of the enzyme that results in a dramatic reduction in the catalytic activity.49-52 There is a wide variety of chemical structures and classes that display activity against HIV-1 reverse transcriptase, and because NNRTIs do not necessarily resemble nucleosides in structure, they do not generally present the same issues of toxicity resulting from interactions with human DNA polymerases as do NRTIs. Although there are more than 30 structurally distinct classes of RT inhibitors, they all seem to function through the same mechanism. This remains a disadvantage during treatment with NNRTIs, because only a minor resistance mutation needs to emerge to effectively neutralize all NNRTIs as a treatment option (until treatment substitution or interruption can allow for reversion to wild type). There are currently three FDA-approved NNRTIs: delavirdine, efavirenz, and nevirapine, and although there is an abundance of data from clinical trials of these and other NNRTIs, there is unfortunately a paucity of published literature specifically examining the apoptotic effects of this anti-HIV drug class.53One of the few studies to address this indicated that at least one of the NNRTIs, efavirenz, possesses the ability to modulate apoptosis.54 Jurkat T cells cultured with physiologically relevant micromolar concentrations of efavirenz (EFV) showed dramatic (70%) inhibition of growth rates compared with control cultures as well as a large increase in cell death. Additionally, by several parameters, EFV-treated cells appeared apoptotic in contrast to control cells (mitochondrial membrane potential changes, Annexin-V staining, histone-DNA complex changes, high caspase-3 activity, and inhibition of the observed cell death by administration of caspase inhibitors).
The EFV-induced cell death also was found to be enhanced by coadministration of AZT, and these findings were extended to include PBMCs from HIV-negative donors upon investigation.54 We reason that such in vitro results may simply be masked in vivo by the overall rise in CD4 counts after HAART initiation, when viral suppression alleviates the major cause of CD4 apoptosis, and, in fact, some studies have begun to suggest that NNRTIs may induce measurable apoptosis in vivo. For example, replacement of the protease inhibitor with an NNRTI in stable individuals on HAART regimens consisting initially of two NRTIs and a protease inhibitor was demonstrated to lead to a decline in CD4 lymphocyte numbers.55,56The available evidence suggests that at least one member of this class possesses apoptotic modulatory activity; however, because this class of therapeutics is so diverse in its molecular structure, generalizations between members of this class are premature. The secondary targets of EFV are unclear, as is whether the other NNRTIs likewise impact apoptosis. Additional studies ideally will address this lack of understanding as well as strive to elucidate the target for this proapoptotic effect of EFV.