HIV-1 reverse transcriptase inhibitor resistance mutations and fitness: A view from the clinic and ex vivo

Genetic diversity plays a key role in human immunodeficiency virus (HIV) adaptation, providing a mechanism to escape host immune responses and develop resistance to antiretroviral drugs. This process is driven by the high-mutation rate during DNA synthesis by reverse transcriptase (RT), by the large viral populations, by rapid viral turnover, and by the high-recombination rate. Drugs targeting HIV RT are included in all regimens of highly active antiretroviral therapy (HAART), which helps to reduce the morbidity and mortality of HIV-infected patients. However, the emergence of resistant viruses is a significant obstacle to effective long-term management of HIV infection and AIDS. The increasing complexity of antiretroviral regimens has favored selection of HIV variants harboring multiple drug resistance mutations. Evolution of drug resistance is characterized by severe fitness losses when the drug is not present, which can be partially overcome by compensatory mutations or other adaptive changes that restore replication capacity. Here, we review the impact of mutations conferring resistance to nucleoside and nonnucleoside RT inhibitors on in vitro and in vivo fitness, their involvement in pathogenesis, persistence upon withdrawal of treatment, and transmission. We describe the techniques used to estimate viral fitness, the molecular mechanisms that help to improve the viral fitness of drug-resistant variants, and the clinical implications of viral fitness data, by exploring the potential relationship between plasma viral load, drug resistance, and disease progression.