Reduced Susceptibility of Human Immunodeficiency Virus Type 1 (HIV-1) from Patients with Primary HIV Infection to Nonnucleoside Reverse Transcriptase Inhibitors Is Associated with Variation at Novel Amino Acid Sites

Abstract

Recently, significant numbers of individuals with primary human immunodeficiency virus (HIV) infectionhave been found to harbor viral strains with reduced susceptibility to antiretroviral drugs. In one study, HIV from 16% of such antiretroviral-naive individuals was shown to have a susceptibility to nonnucleoside reverse transcriptase (RT) inhibitors (NNRTIs) between 2.5-and 10-fold lower than that of a wild-type control. Mutations in the RT domain that had previously been associated with antiretroviral resistance were not shared by these strains. We have analyzed by logistic regression 46 variable amino acid sites in RT for their effect on susceptibility and have identified two novel sites influencing susceptibility to NNRTIs: amino acids 135 and 283 in RT. Eight different combinations of amino acids at these sites were observed among these patients. These combinations showed a 14-fold range in mean susceptibility to both nevirapine and delavirdine. In vitro mutagenesis of the control strain combined with a phenotypic assay confirmed the significance of amino acid variation at these sites for susceptibility to NNRTIs.

Genetic Basis of Hypersusceptibility to Protease Inhibitors and Low Replicative Capacity of Human Immunodeficiency Virus Type 1 Strains in Primary Infection

“…In previous work, it was shown that such mutations can be associated with variation in susceptibility to nonnucleoside reverse transcriptase inhibitors which is observed in primary HIV infection (6). This conclusion was tested in that study by in vitro mutagenesis, which confirmed the in vivo observations.…”

“…The presence at several polymorphic amino acid sites of multiple mutant amino acids raises two possible approaches. Either all nonwild-type amino acids are pooled as "mutant," as in previous studies (6,14), or in order to distinguish their individual contributions (in case different mutant amino acids have effects in different directions), it is possible to consider each amino acid mutation at a site as a separate variable. However, the additional variables that this introduces can result in overfitting of the model so that the results are not generalizable to other data sets.…”

Characterization of a Subtype D Human Immunodeficiency Virus Type 1 Isolate That Was Obtained from an Untreated Individual and That Is Highly Resistant to Nonnucleoside Reverse Transcriptase Inhibitors

“…Sequence alignments with RT sequences of NNRTIsensitive subtype D isolates identified three putative amino acid residues associated with this high-level resistance: 135L, 139V, and 245T. Only substitutions at position 135 (I135T and I135L) have been associated with NNRTI resistance in subtype B isolates (14).…”

“…Recent studies showed that ARV drug treatment of nonsubtype B HIV-1 infections can select for novel drug resistance mutations or substitutions considered "rare" in drug-resistant HIV-1 subtype B isolates (13,14). For example, a V106M substitution in the subtype C HIV-1 RT coding region was selected both during in vitro selection experiments with efavirenz and in subtype C-infected patients treated with efavirenz (13).…”

The Future of HIV Prevention: Prospects for an Effective Anti-HIV Microbicide

“…One issue is the potential for transmission of drug-resistant strains that may overcome an ARV-based microbicide [41]. It is important to remember, however, that resistance represents a reduced susceptibility of HIV rather than a total invulnerability to a drug [80], so a resistant strain will only overcome a microbicide if it is unsusceptible to the concentration of drug to which it is exposed in the vaginal lumen or target tissues.…”