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

Abstract

The initial virus strains from as many as 12% of individuals with primary human immunodeficiency virus (HIV) infection have a 50% inhibitory concentration <0.4-fold that of HIV type 1 NL4-3 (HIV-1 NL4-3 ) to ritonavir (hypersusceptibility [HS]). There is also substantial variation in replicative capacity (RC) or an in vitro assay of the contributions of protease (PR) and reverse transcriptase to viral fitness. In chronically infected antiretrovirally treated patients, amprenavir HS has been associated with the mutation N88S in PR, but this mutation is not seen in untreated patients. In this study, virus strains from 182 cases of primary HIV infection were analyzed, and a highly significant association between HS and low RC (<10% that of HIV-1 NL4-3 ) was observed (P < 10 ؊6 ). Multivariate analysis was used to determine the genotypic basis of ritonavir HS, analyzing all polymorphic amino acid sites and insertions from p7gag through PR. Decision tree models developed on the entire Gag-plus-PR data set and on PR alone gave overall correct classifications of 73 and 72%, respectively, on cross-validation. They were also able to predict low RC, with sensitivities of 69 and 62% and specificities of 84 and 70%, respectively. The analysis shows that ritonavir HS in untreated primary HIV infection is not associated with single mutations but with combinations of amino acids at polymorphic sites and that the same genotypes which confer HS to PR inhibitors confer low RC. This supports the view that variation in PR function is directly responsible for variation in fitness among strains in primary infection.

Drug-associated changes in amino acid residues in Gag p2, p7NC, and p6Gag/p6Pol in human immunodeficiency virus type 1 (HIV-1) display a dominant effect on replicative fitness and drug response

“…For example, drug resistance by a wild type PR is increased by substitutions that map exclusively in the p7 NC /p1 cleavage site (Nijhuis et al, 2007), while wild type PR among viruses from therapy naïve individuals display hypersusceptibility to PI (Leigh Brown et al, 2004; Martinez-Picado et al, 2005) The Gag mutations identified in our study accumulated concomitantly with PR mutations in the presence of PI and persisted over time, similar to characteristics of amino acid residues in PR that confer drug resistance. Indeed, the predominant effect for most of the drug-associated amino acid substitutions in Gag-Pol in our study was to enhance resistance to inhibitors, as any reversions to pretherapy residues increased drug sensitivity.…”

“…Resistance to PI can be attributed to multiple mechanisms. For example, polymorphisms in PR known to reduce or increase sensitivity to PI can occur in therapy-naïve patients (Brown et al, 1999; Lech et al, 1996; Leigh Brown et al, 2004; Martinez-Picado et al, 2005; Perez et al, 2001; Rose et al, 1996). In addition, as a result of suboptimal drug therapy, viruses begin to accumulate mutations in PR in a stepwise fashion (Condra et al, 1996; Erickson et al, 1999; Molla et al, 1996).…”

HIV protease cleaves the antiviral m6A reader protein YTHDF3 in the viral particle

“…It is attractive to speculate that the extended antiviral activities of protease inhibitors are, in part, derived from the restoration of the antiviral activity of m 6 A reader proteins such as YTHDF3. Viral hypersusceptibility to protease inhibitors as well as mutations in Gag that modulate the amount of mature protease produced have been described [32,33]. Future studies are needed to determine the true antiviral potency and breadth of the YTHDF3 protein when combined with protease inhibitors.…”

Employing phylogenetic tree shape statistics to resolve the underlying host population structure

“…We then obtained the means for the measures that we used for evaluation of classifiers. Cross validation gives realistic evaluation of model performance as done in some studies [ 58 , 59 ]. Parameter tuning of model parameters and cross validation was done with help of ‘caret’ R package [ 60 ].…”