Estimation of the HIV-1 backward mutation rate from transmitted drug-resistant strains

Kitayimbwa, John M; Mugisha, Johnny; Saenz, Roberto A.

doi:10.1016/j.tpb.2016.08.001

Cited by 9 publications

(5 citation statements)

References 28 publications

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“…We tested the hypothesis that positive epistasis prevented resistance associated genotypes from reverting to wild-type [ 41 , 95 , 96 ]. Although RAMs incurred significant fitness cost, some drug resistant mutants would not revert to wild-type after transmitting to a drug naïve patient.…”

Section: Resultsmentioning

confidence: 99%

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Predominance of positive epistasis among drug resistance-associated mutations in HIV-1 protease

et al. 2020

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Drug-resistant mutations often have deleterious impacts on replication fitness, posing a fitness cost that can only be overcome by compensatory mutations. However, the role of fitness cost in the evolution of drug resistance has often been overlooked in clinical studies or in vitro selection experiments, as these observations only capture the outcome of drug selection. In this study, we systematically profile the fitness landscape of resistance-associated sites in HIV-1 protease using deep mutational scanning. We construct a mutant library covering combinations of mutations at 11 sites in HIV-1 protease, all of which are associated with resistance to protease inhibitors in clinic. Using deep sequencing, we quantify the fitness of thousands of HIV-1 protease mutants after multiple cycles of replication in human T cells. Although the majority of resistance-associated mutations have deleterious effects on viral replication, we find that epistasis among resistance-associated mutations is predominantly positive. Furthermore, our fitness data are consistent with genetic interactions inferred directly from HIV sequence data of patients. Fitness valleys formed by strong positive epistasis reduce the likelihood of reversal of drug resistance mutations. Overall, our results support the view that strong compensatory effects are involved in the emergence of clinically observed resistance mutations and provide insights to understanding fitness barriers in the evolution and reversion of drug resistance.

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Section: Resultsmentioning

confidence: 99%

“…We found positive epistasis plays a critical role in HIV-1 gaining and maintaining drug resistance. Epistasis makes the fitness landscape rugged, preventing RAMs from reversion to wild-type, even when antiviral therapy is interrupted or virus transmits to a healthy individual [ 95 , 108 ].…”

Section: Discussionmentioning

confidence: 99%

Predominance of positive epistasis among drug resistance-associated mutations in HIV-1 protease

et al. 2020

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“…We tested the hypothesis that positive epistasis prevented drug resistance associated genotypes from reverting to wild-type [41,87,88]. Although DRAMs incurred significant fitness cost, some drug resistant mutants would not revert to wild-type after transmitting to a drug naïve patient.…”

Section: Resultsmentioning

confidence: 99%

“…We found positive epistasis plays a critical role in HIV-1 gaining and maintaining drug resistance. Epistasis makes the fitness landscape rugged, preventing DRAMs from reversion to wild-type, even when antiviral therapy is interrupted or virus transmits to a healthy individual [87, 99].…”

Section: Discussionmentioning

confidence: 99%

Predominance of positive epistasis among drug resistance-associated mutations in HIV-1 protease

Zhang¹,

Dai

Barton³

et al. 2019

Preprint

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23Drug-resistant mutations often have deleterious impacts on replication fit-24 ness, posing a fitness cost that can only be overcome by compensatory muta-25 tions. However, the role of fitness cost in the evolution of drug resistance has 26 often been overlooked in clinical studies or in vitro selection experiments, as 27 these observations only capture the outcome of drug selection. In this study, 28 we systematically profile the fitness landscape of resistance-associated sites in 29 HIV-1 protease using deep mutational scanning. We construct a mutant li-30 brary covering combinations of mutations at 11 sites in HIV-1 protease, all of 31 which are associated with resistance to protease inhibitors in clinic. Using deep 32 sequencing, we quantify the fitness of thousands of HIV-1 protease mutants 33 1 after multiple cycles of replication in human T cells. Although the majority 34 of resistance-associated mutations have deleterious effects on viral replication, 35 we find that epistasis among resistance-associated mutations is predominantly 36 positive. Furthermore, our fitness data are consistent with genetic interactions 37 inferred directly from HIV sequence data of patients. Fitness valleys formed 38 by strong positive epistasis reduce the likelihood of reversal of drug resistance 39 mutations. Overall, our results support the view that strong compensatory 40 effects are involved in the emergence of clinically observed resistance muta-41 tions and provide insights to understanding fitness barriers in the evolution 42 and reversion of drug resistance. 43 1 Introduction 44 Antibiotics and antiviral drugs have achieved great success in recent history [1]. 45However, therapeutic failure may occur due to low adherence and the emergence of 46 drug resistance [2, 3]. The increasing amount of drug resistant pathogens is a global 47 threat to public health [4][5][6][7][8][9][10][11]. The genetic barrier to drug resistance, defined as 48 the number of mutations needed to acquire resistance, is a major determining factor 49 of treatment outcomes [12][13][14]. Another important but often overlooked aspect of 50 drug resistance is the fitness barrier [15][16][17]. Drug resistance associated mutations 51 (DRAMs) in pathogen proteins may decrease enzymatic activities, interfere with 52 molecular interactions, or destabilize the protein structure [18][19][20][21][22]. Because of the 53 impaired replication capacity without drug selection, drug-resistant mutants can-54 not normally outcompete wild-type or establish in the population [23][24][25]. However, 55 drug-resistant mutants can sometimes reach substantial frequency in the population. 56 Fluctuating drug concentrations may create time windows when drug-resistant mu-57 tants replicate better than wild-type virus [26]. Moreover, compensatory mutations 58 can rescue the impaired replication capacity of mutants and stabilize drug resis-59 tance [22, 27, 27-29]. Thus, comprehensive quantification of the fitness landscape is 60 needed to predict the evolution of drug ...

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“…Moreover, along with a growing number of drug-resistant strains, ART has led to an ever-growing pool of individuals who can transmit drug-resistant strains of HIV-1 [ 43 , 44 ].…”

Section: Treatmentmentioning

confidence: 99%

HIV and Drug-Resistant Subtypes

et al. 2023

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Acquired Immunodeficiency Syndrome (AIDS) is a human viral infectious disease caused by the positive-sense single-stranded (ss) RNA Human Immunodeficiency Virus (HIV) (Retroviridae family, Ortervirales order). HIV-1 can be distinguished into various worldwide spread groups and subtypes. HIV-2 also causes human immunodeficiency, which develops slowly and tends to be less aggressive. HIV-2 only partially homologates to HIV-1 despite the similar derivation. Antiretroviral therapy (ART) is the treatment approved to control HIV infection, based on multiple antiretroviral drugs that belong to different classes: (i) NNRTIs, (ii) NRTIs, (iii) PIs, (iv) INSTIs, and (v) entry inhibitors. These drugs, acting on different stages of the HIV life cycle, decrease the patient’s total burden of HIV, maintain the function of the immune system, and prevent opportunistic infections. The appearance of several strains resistant to these drugs, however, represents a problem today that needs to be addressed as best as we can. New outbreaks of strains show a widespread geographic distribution and a highly variable mortality rate, even affecting treated patients significantly. Therefore, novel treatment approaches should be explored. The present review discusses updated information on HIV-1– and HIV-2–resistant strains, including details on different mutations responsible for drug resistance.

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Estimation of the HIV-1 backward mutation rate from transmitted drug-resistant strains

Cited by 9 publications

References 28 publications

Predominance of positive epistasis among drug resistance-associated mutations in HIV-1 protease

Predominance of positive epistasis among drug resistance-associated mutations in HIV-1 protease

Predominance of positive epistasis among drug resistance-associated mutations in HIV-1 protease

HIV and Drug-Resistant Subtypes

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