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Mapping protease inhibitor resistance to human immunodeficiency virus type 1 sequence polymorphisms within patients.

ABSTRACT: Resistance genotyping provides an important resource for the clinical management of patients infected with human immunodeficiency virus type 1 (HIV-1). However, resistance to protease (PR) inhibitors (PIs) is a complex phenotype shaped by interactions among nearly half of the residues in HIV-1 PR. Previous studies of the genetic basis of PI resistance focused on fixed substitutions among populations of HIV-1, i.e., host-specific adaptations. Consequently, they are susceptible to a high false discovery rate due to founder effects. Here, we employ sequencing "mixtures" (i.e., ambiguous base calls) as a site-specific marker of genetic variation within patients that is independent of the phylogeny. We demonstrate that the transient response to selection by PIs is manifested as an excess of nonsynonymous mixtures. Using a sample of 5,651 PR sequences isolated from both PI-naive and -treated patients, we analyze the joint distribution of mixtures and eight PIs as a Bayesian network, which distinguishes residue-residue interactions from direct associations with PIs. We find that selection for resistance is associated with the emergence of nonsynonymous mixtures in two distinct groups of codon sites clustered along the substrate cleft and distal regions of PR, respectively. Within-patient evolution at several positions is independent of PIs, including those formerly postulated to be involved in resistance. These positions are under strong positive selection in the PI-naive patient population, implying that other factors can produce spurious associations with resistance, e.g., mutational escape from the immune response.

SUBMITTER: Poon AF

PROVIDER: S-EPMC2168824 | biostudies-literature | 2007 Dec

REPOSITORIES: biostudies-literature

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Mapping protease inhibitor resistance to human immunodeficiency virus type 1 sequence polymorphisms within patients.

Poon Art F Y AF Kosakovsky Pond Sergei L SL Richman Douglas D DD Frost Simon D W SD

Journal of virology 20071003 24

Resistance genotyping provides an important resource for the clinical management of patients infected with human immunodeficiency virus type 1 (HIV-1). However, resistance to protease (PR) inhibitors (PIs) is a complex phenotype shaped by interactions among nearly half of the residues in HIV-1 PR. Previous studies of the genetic basis of PI resistance focused on fixed substitutions among populations of HIV-1, i.e., host-specific adaptations. Consequently, they are susceptible to a high false dis ...[more]

PMID: 17913806

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Project description:Plasma-derived sequences of human immunodeficiency virus type 1 (HIV-1) protease from 1,162 patients (457 drug-naive patients and 705 patients receiving protease inhibitor [PI]-containing antiretroviral regimens) led to the identification and characterization of 17 novel protease mutations potentially associated with resistance to PIs. Fourteen mutations were positively associated with PIs and significantly correlated in pairs and/or clusters with known PI resistance mutations, suggesting their contribution to PI resistance. In particular, E34Q, K43T, and K55R, which were associated with lopinavir treatment, correlated with mutations associated with lopinavir resistance (E34Q with either L33F or F53L, or K43T with I54A) or clustered with multi-PI resistance mutations (K43T with V82A and I54V or V82A, V32I, and I47V, or K55R with V82A, I54V, and M46I). On the other hand, C95F, which was associated with treatment with saquinavir and indinavir, was highly expressed in clusters with either L90M and I93L or V82A and G48V. K45R and K20T, which were associated with nelfinavir treatment, were specifically associated with D30N and N88D and with L90M, respectively. Structural analysis showed that several correlated positions were within 8 A of each other, confirming the role of the local environment for interactions among mutations. We also identified three protease mutations (T12A, L63Q, and H69N) whose frequencies significantly decreased in PI-treated patients compared with that in drug-naive patients. They never showed positive correlations with PI resistance mutations; if anything, H69N showed a negative correlation with the compensatory mutations M36I and L10I. These mutations may prevent the appearance of PI resistance mutations, thus increasing the genetic barrier to PI resistance. Overall, our study contributes to a better definition of protease mutational patterns that regulate PI resistance and strongly suggests that other (novel) mutations beyond those currently known to confer resistance should be taken into account to better predict resistance to antiretroviral drugs.

Project description:The maturation inhibitor bevirimat [3-O-(3',3'dimethysuccinyl)betulinic acid; BVM; also known as PA-457 or DSB] potently inhibits human immunodeficiency virus type 1 (HIV-1) replication by blocking protease (PR)-mediated cleavage at the junction between capsid (CA) and spacer peptide 1 (SP1) in Gag. We previously isolated a panel of single-amino-acid substitutions that confer resistance to BVM in vitro (C. S. Adamson, S. D. Ablan, I. Boeras, R. Goila-Gaur, F. Soheilian, K. Nagashima, F. Li, K. Salzwedel, M. Sakalian, C. T. Wild, and E. O. Freed, J. Virol. 80:10957-10971, 2006). The BVM resistance mutations cluster at or near the CA-SP1 cleavage site. Because BVM likely will be used clinically in patients harboring viruses resistant to PR inhibitors (PIs), in this study we evaluated the interplay between a PI-resistant (PIR) PR and the BVM resistance mutations in Gag. As expected, the PIR mutations had no effect on inhibition by BVM; however, we observed general processing defects and a slight delay in viral replication in Jurkat T cells associated with the PIR mutations, even in the absence of compound. When combined, most BVM resistance and PIR mutations acted additively to impair viral replication, particularly in the presence of BVM. The BVM-resistant mutant SP1-A1V was an exception, as it supported robust replication in the context of either wild-type (WT) or PIR PR, even at high BVM concentrations. Significantly, the emergence of BVM resistance was delayed in the context of the PIR PR, and the SP1-A1V mutation was acquired most frequently with either WT or PIR PR. These results suggest that resistance to BVM is less likely to emerge in patients who have failed PIs than in patients who are PI naive. We predict that the SP1-A1V substitution is the most likely to emerge in vivo, as this mutant replicates robustly independently of PR mutations or BVM. These findings offer insights into the effect of PIR mutations on the evolution of BVM resistance in PI-experienced patients.

Dataset Information

Mapping protease inhibitor resistance to human immunodeficiency virus type 1 sequence polymorphisms within patients.

Publications

Mapping protease inhibitor resistance to human immunodeficiency virus type 1 sequence polymorphisms within patients.

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