Insertions in the Human Immunodeficiency Virus Type 1 Protease and Reverse Transcriptase Genes: Clinical Impact and Molecular Mechanisms

Abstract

Treatment of human immunodeficiency virus (HIV) type 1 (HIV-1)-infected individuals with antiretroviral (ARV) drugs is highly effective in inhibiting viral replication, increasing both the duration and the quality of life (71). Regimens consisting of combinations of protease (PR), reverse transcriptase (RT), and fusion inhibitors are the current standard of care and typically reduce the circulating virus levels in previously untreated patients to below current limits of detection. Treatment failure, however, is not uncommon and is typically defined as a return to detectable levels of circulating virus, eventually resulting in decreases of CD4-cell counts and immune function and progression to AIDS. The development of viral resistance to ARV drugs is a primary cause of treatment failure (24). Extensive genetic diversity is inherent in HIV because the highly error-prone RT enzyme creates a population of variants from which drug-resistant strains can be selected during treatment (49). Many individual point mutations (single amino acid changes) or groups of point mutations in the PR, RT, or gp41 gene have been associated in clinical studies with the failure of treatment with protease inhibitors (PIs), nucleoside reverse transcriptase inhibitors (NRTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs), and fusion inhibitors, respectively (17, 24, 50, 52). HIV-1 strains isolated both from patients who have failed treatment and from laboratory strains modified by site-directed mutagenesis to possess specific mutations show reduced susceptibilities in vitro to one or more ARV drugs. Some point mutations are specific to individual drugs, while others confer cross-resistance to one or more drugs of the same class. Over the past several years, strains with insertions of nucleotides in the PR and the RT genes (and that thus have extra amino acids in those proteins) have been found in patients who have failed ARV drug therapy. Numerous publications have examined the origins, prevalences, in vitro susceptibilities, and replication capacities of insert-containing strains, as well as the mechanisms by which the insertions affect drug resistance. This minireview focuses on the clinically related information regarding PR and RT insert-containing strains of HIV and briefly addresses the topics of mechanism and structure.