126 Questions and challenges in HIV drug resistance: A molecular perspective

The introduction of potent combination therapies in the mid-90s had a tremendous impact on AIDS mortality. However, drug resistance has been a major factor contributing to antiretroviral therapy failure. At present, reverse transcriptase (RT) inhibitors constitute the backbone of successful antiretroviral therapies. The HIV-1 RT is a heterodimer composed of subunits of 560 and 440 amino acids. Mutations in the RT-coding region selected during treatment with nucleoside RT inhibitors (NRTIs) confer resistance by altering discrimination between NRTIs and natural substrates (dNTPs), or by conferring a phosphorolytic activity (dependent on pyrophosphate or ATP) that unblocks the chain-terminating inhibitor from the 3′ end of the DNA that is being synthesized. The most relevant mutations conferring resistance to RT inhibitors map within the DNA polymerase domain of the RT (first 260 residues), and this region is subjected to genotypic analysis in order to select the proper antiretroviral treatment. Despite the reasonable knowledge of the correlates between HIV genotype and the virological response to current therapies, our knowledge is still incomplete. The effects of antagonistic mutations and amino acid substitutions outside the DNA polymerase domain of the RT have been poorly characterized and examples will be given to illustrate the complexities of mutational patterns involved in resistance. In addition, I will provide examples of epistatic effects of HIV-1 protease and RT mutations that could affect viral fitness. Finally, an overview of mutational pathways and mechanisms of resistance to novel antiretroviral drugs (eg, raltegravir, elvitegravir, etravirine, rilpivirine and maraviroc) will be briefly presented.