Understanding HIV resistance, fitness, replication capacity and compensation: targeting viral fitness as a therapeutic strategy

Abstract

The increasingly prevalent emergence of drug-resistant virus strains in patients being treated with highly active antiretroviral regimens and the increasing rates of transmission of drug-resistant virus strains have focused attention on the critical need for additional antiretroviral agents with novel mechanisms of action and enhanced potency. Furthermore, novel means of employing highly active antiretroviral therapy are needed to reduce or eliminate the virological treatment failures that currently occur. Over the past several years, evidence has mounted supporting the fact that the emergence of resistant strains is associated with reductions in viral fitness, yielding decreases in plasma virus load in treated patients harbouring resistant populations of the virus. Additional mutations that serve to modify fitness (compensatory mutations) and mutations that impact the viral replication capacity also emerge under the selective pressure of drug treatment, and have both negative and positive effects on virus growth. Fitness is generally accepted to refer to the ability of HIV to replicate in a defined environment and thus is used to describe the viral replication potential in the absence of the drug. Although viral fitness and replication capacity are related in some ways, it is important to recognise that viral fitness is not the same as viral replication capacity. This review will assess the recent literature on antiviral drug resistance, viral fitness and viral replication capacity, and discuss means by which the adaptability of HIV to respond rapidly to antiviral treatment through mutation may be used against it. This would be done by treating patients with an aim to lock the deleterious mutations into the resistant virus genome, resulting in a positive therapeutic outcome despite the presence of resistance to the selecting agents. The review will specifically discuss the literature on nucleoside and non-nucleoside reverse transcriptase inhibitors, protease inhibitors, integrase inhibitors, fusion inhibitors, as well as other biological factors involved in viral fitness.

Effects of the W153L Substitution in HIV Reverse Transcriptase on Viral Replication and Drug Resistance to Multiple Categories of Reverse Transcriptase Inhibitors

“…The emergence of HIV-1 drug resistance is often associated with reductions in viral fitness, but the subsequent selection of additional compensatory substitutions can often restore fitness while increasing levels of resistance (62). Here, we have demonstrated that W153L-harboring viruses display diminished replicative fitness compared to that of WT virus.…”

Impact of Drug Resistance-Associated Amino Acid Changes in HIV-1 Subtype C on Susceptibility to Newer Nonnucleoside Reverse Transcriptase Inhibitors

“…In the current study, only a single subtype C reference isolate was used, and the phenotypic responses observed could be isolate specific. Third, the variation in responses could be subtype specific, and several studies have shown differences between subtypes regarding both replication capacity and phenotypic susceptibility (44)(45)(46). The screening of additional subtype C isolates could validate the phenotypic differences that were observed between our subtype C mutants and the published subtype B mutants.…”

Getting to Know Viral Evolutionary Strategies: Towards the Next Generation of Quasispecies Models

“…Fitness changes monitored in several clones of FMDV transmitted through successive population bottlenecks, where the fixation of mutations proceeded independently of their selective value, were interpreted on the basis of a higher availability of compensatory mutations in low-fitness genomes . Compensatory mutations also balance the fitness cost of drug-resistant mutants, causing the permanence of the resistant phenotype in the absence of the drug (Buckheit 2004). The dynamics of adaptation to new selective pressures, showing the largest fitness gains at the beginning of the process, has been ascribed, at least partially, to a diminished effect of beneficial mutations as fitness increases, which is also a form of epistasis (Bull et al 2000;Rokyta et al 2011).…”