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Interrelationship between HIV-1 fitness and mutation rate.

ABSTRACT: Differences in replication fidelity, as well as mutator and antimutator strains, suggest that virus mutation rates are heritable and prone to natural selection. Human immunodeficiency virus type 1 (HIV-1) has many distinct advantages for the study of mutation rate optimization given the wealth of structural and biochemical data on HIV-1 reverse transcriptase (RT) and mutants. In this study, we conducted parallel analyses of mutation rate and viral fitness. In particular, a panel of 10 RT mutants-most having drug resistance phenotypes-was analyzed for their effects on viral fidelity and fitness. Fidelity differences were measured using single-cycle vector assays, while fitness differences were identified using ex vivo head-to-head competition assays. As anticipated, virus mutants possessing either higher or lower fidelity had a corresponding loss in fitness. While the virus panel was not chosen randomly, it is interesting that it included more viruses possessing a mutator phenotype rather than viruses possessing an antimutator phenotype. These observations provide the first description of an interrelationship between HIV-1 fitness and mutation rate and support the conclusion that mutator and antimutator phenotypes correlate with reduced viral fitness. In addition, the findings here help support a model in which fidelity comes at a cost of replication kinetics and may help explain why retroviruses like HIV-1 and RNA viruses maintain replication fidelity near the extinction threshold.

SUBMITTER: Dapp MJ

PROVIDER: S-EPMC3534800 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Interrelationship between HIV-1 fitness and mutation rate.

Dapp Michael J MJ Heineman Richard H RH Mansky Louis M LM

Journal of molecular biology 20121016 1

Differences in replication fidelity, as well as mutator and antimutator strains, suggest that virus mutation rates are heritable and prone to natural selection. Human immunodeficiency virus type 1 (HIV-1) has many distinct advantages for the study of mutation rate optimization given the wealth of structural and biochemical data on HIV-1 reverse transcriptase (RT) and mutants. In this study, we conducted parallel analyses of mutation rate and viral fitness. In particular, a panel of 10 RT mutants ...[more]

PMID: 23084856

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Project description:BackgroundEmergency department (ED) patients comprise a high-risk population for alcohol misuse and sexual risk for HIV. In order to design future interventions to increase HIV screening uptake, we examined the interrelationship among alcohol misuse, sexual risk for HIV and HIV screening uptake among these patients.MethodsA random sample of 18-64-year-old English- or Spanish-speaking patients at two EDs during July-August 2009 completed a self-administered questionnaire about their alcohol use using the Alcohol Use Questionnaire, the Alcohol Use Disorders Identification Test (AUDIT), and the HIV Sexual Risk Questionnaire. Study participants were offered a rapid HIV test after completing the questionnaires. Binging (? five drinks/occasion for men, ? four drinks for women) was assessed and sex-specific alcohol misuse severity levels (low-risk, harmful, hazardous, dependence) were calculated using AUDIT scores. Analyses were limited to participants who had sexual intercourse in the past 12 months. Multivariable logistic regression was used to assess the associations between HIV screening uptake and (1) alcohol misuse, (2) sexual risk for HIV, and (3) the intersection of HIV sexual risk and alcohol misuse. Adjusted odds ratios (AORs) with 95% confidence intervals (CIs) were estimated. All models were adjusted for patient demographic characteristics and separate models for men and women were constructed.ResultsOf 524 participants (55.0% female), 58.4% identified as white, non-Hispanic, and 72% reported previous HIV testing. Approximately 75% of participants reported drinking alcohol within the past 30 days and 74.5% of men and 59.6% of women reported binge drinking. A relationship was found between reported sexual risk for HIV and alcohol use among men (AOR 3.31 [CI 1.51-7.24]) and women (AOR 2.78 [CI 1.48-5.23]). Women who reported binge drinking were more likely to have higher reported sexual risk for HIV (AOR 2.55 [CI 1.40-4.64]) compared to women who do not report binge drinking. HIV screening uptake was not higher among those with greater alcohol misuse and sexual risk among men or women.ConclusionsThe apparent disconnection between HIV screening uptake and alcohol misuse and sexual risk for HIV among ED patients in this study is concerning. Brief interventions emphasizing these associations should be evaluated to reduce alcohol misuse and sexual risk and increase the uptake of ED HIV screening.

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Interrelationship between HIV-1 fitness and mutation rate.

Publications

Interrelationship between HIV-1 fitness and mutation rate.

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