Retracing the Evolutionary Pathways of Human Immunodeficiency Virus Type 1 Resistance to Protease Inhibitors: Virus Fitness in the Absence and in the Presence of Drug

Mammano, Fabrizio; Trouplin, Virginie; Zennou, Véronique; Clavel, François

doi:10.1128/jvi.74.18.8524-8531.2000

Cited by 160 publications

(167 citation statements)

References 50 publications

Supporting

Mentioning

153

Contrasting

Order By: Relevance

“…Single mutations in protease produced varied effects on replication capacity. The L90M, I47V, and M46I mutants exhibited higher replication capacity than WT, consistent with a previous study (46). The protease mutants I50V and I47A had highly impaired replication capacity (<0.1) relative to WT.…”

Section: Effect Of Resistance Mutations On Replication Capacity and Ssupporting

confidence: 78%

“…Therefore, determining inhibition at clinical concentrations requires a method for extrapolating from IC 50 to higher concentrations. IC 90 is sometimes used (46,49); however, like IC 50 , it represents only a single point on the dose-response curve. However, m describes how inhibition changes with drug concentration, and is thus critical for understanding drug effects at clinical concentrations.…”

Section: Analysis Of Resistance Mutations Using Primary Cells Vs Tramentioning

confidence: 99%

See 1 more Smart Citation

Dose–response curve slope is a missing dimension in the analysis of HIV-1 drug resistance

Sampah¹,

Shen

Jilek³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

129

View full text Add to dashboard Cite

HIV-1 drug resistance is a major clinical problem. Resistance is evaluated using in vitro assays measuring the fold change in IC 50 caused by resistance mutations. Antiretroviral drugs are used at concentrations above IC 50 , however, and inhibition at clinical concentrations can only be predicted from IC 50 if the shape of the dose-response curve is also known. Curve shape is influenced by cooperative interactions and is described mathematically by the slope parameter or Hill coefficient (m). Implicit in current analysis of resistance is the assumption that mutations shift dose-response curves to the right without affecting the slope. We show here that m is altered by resistance mutations. For reverse transcriptase and fusion inhibitors, single resistance mutations affect both slope and IC 50 . For protease inhibitors, single mutations primarily affect slope. For integrase inhibitors, only IC 50 is affected. Thus, there are fundamental pharmacodynamic differences in resistance to different drug classes. Instantaneous inhibitory potential (IIP), the log inhibition of single-round infectivity at clinical concentrations, takes into account both slope and IC 50 , and thus provides a direct measure of the reduction in susceptibility produced by mutations and the residual activity of drugs against resistant viruses. The standard measure, fold change in IC 50 , does not correlate well with changes in IIP when mutations alter slope. These results challenge a fundamental assumption underlying current analysis of HIV-1 drug resistance and suggest that a more complete understanding of how resistance mutations reduce antiviral activity requires consideration of a previously ignored parameter, the dose-response curve slope.HIV/AIDS | pharmacology | virology | highly active antiretroviral therapy | evolution

show abstract

Section: Effect Of Resistance Mutations On Replication Capacity and Ssupporting

confidence: 78%

Section: Analysis Of Resistance Mutations Using Primary Cells Vs Tramentioning

confidence: 99%

Dose–response curve slope is a missing dimension in the analysis of HIV-1 drug resistance

Sampah¹,

Shen

Jilek³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

129

View full text Add to dashboard Cite

show abstract

“…A number of studies have demonstrated that a K103N mutation has little effect on viral fitness, 7,8 whereas protease inhibitor signature mutations exact a fitness cost. 9,10 Our results would arise from addition of the new mutations at failure of the second regiment to the most fit virus. Numerous in vitro studies have looked at the fitness of an HIV virus with mutations that occur after the failure for the therapies shown in Table 1.…”

Section: Discussionmentioning

confidence: 99%

HIV-1 Diversity After a Class Switch Failure

Kolber

Buendia

DeGruttola

et al. 2010

AIDS Research and Human Retroviruses

View full text Add to dashboard Cite

The purpose of this study is to evaluate whether the choice of a PI-or an efavirenz (EFV)-based HAART initial regimen impacts on the viral diversity after failure from a second, class-switch salvage regimen. Sequential HAART failures after a class switch were identified for which the genotypes showed evidence of signature mutations at each failure. Each second failure was required to be from a viral burden <400 RNA c/ml. Thirteen cases of sequential failure from an initial EFV-containing to a PI-containing regimen (EP), and 19 sequential failures from an initial PI-containing to an EFV-containing regimen (PE) were identified. The persistence of signature mutations from the first failure were evaluated at second failure and compared between the EP and PE groups. Phylogenetic trees were constructed for a subgroup of cases from existing genetic sequence information and branch length analysis was used to determine evidence of viral diversity between groups. For EP sequential therapy, 10 of 12 cases carried forward a key non-nucleoside reverse transcriptase inhibitor (NNRTI) mutation in the second failure compared to 5 of 13 cases for PE sequential therapy ( p ¼ 0.041). Phylogenetic analysis demonstrated that there was more viral diversity in the PE group as compared to the EP group, consistent with the interpretation that mutations at the second failure added to an ancestral virus closer to baseline rather than to the dominant virus at first failure. The development of HIV viral diversity after multiple HAART failures is determined by the sequence in which the regimens are ordered.

show abstract

“…V82T, which is one of the substitutions at codon 82 that confer broad crossresistance, was also significantly reduced in fitness compared to that of the wild-type virus (118). V82A, which confers low-level but broad cross-resistance, did not demonstrate significantly reduced fitness in a single-cycle assay but did have a replicative advantage compared to wild-type virus in the presence of drug (109). Consistent with these results from site-directed mutants are studies of serial clinical isolates obtained from patients failing protease inhibitor therapy that have correlated the development of reduced fitness in the Monogram RC assay with the emergence of V82A, I84V, or L90M (14).…”

Section: Mutations Conferring Resistance To Protease Inhibitorsmentioning

confidence: 99%

“…G48V, which is a major mutation conferring resistance to saquinavir, was shown to have decreased fitness in a singlecycle assay (109). I50L, which confers resistance to atazanavir, also has reduced fitness in parallel infections (34).…”

Section: Mutations Conferring Resistance To Protease Inhibitorsmentioning

confidence: 99%

Clinical Significance of Human Immunodeficiency Virus Type 1 Replication Fitness

Dykes

Demeter

2007

Clin Microbiol Rev

View full text Add to dashboard Cite

SUMMARY The relative fitness of a variant, according to population genetics theory, is that variant's relative contribution to successive generations. Most drug-resistant human immunodeficiency virus type 1 (HIV-1) variants have reduced replication fitness, but at least some of these deficits can be compensated for by the accumulation of second-site mutations. HIV-1 replication fitness also appears to influence the likelihood of a drug-resistant mutant emerging during treatment failure and is postulated to influence clinical outcomes. A variety of assays are available to measure HIV-1 replication fitness in cell culture; however, there is no agreement regarding which assays best correlate with clinical outcomes. A major limitation is that there is no high-throughput assay that incorporates an internal reference strain as a control and utilizes intact virus isolates. Some retrospective studies have demonstrated statistically significant correlations between HIV-1 replication fitness and clinical outcomes in some patient populations. However, different studies disagree as to which clinical outcomes are most closely associated with fitness. This may be in part due to assay design, sample size limitations, and differences in patient populations. In addition, the strength of the correlations between fitness and clinical outcomes is modest, suggesting that, at present, it would be difficult to utilize these assays for clinical management.

show abstract

Retracing the Evolutionary Pathways of Human Immunodeficiency Virus Type 1 Resistance to Protease Inhibitors: Virus Fitness in the Absence and in the Presence of Drug

Cited by 160 publications

References 50 publications

Dose–response curve slope is a missing dimension in the analysis of HIV-1 drug resistance

Dose–response curve slope is a missing dimension in the analysis of HIV-1 drug resistance

HIV-1 Diversity After a Class Switch Failure

Clinical Significance of Human Immunodeficiency Virus Type 1 Replication Fitness

Contact Info

Product

Resources

About