Current Perspectives on HIV-1 Antiretroviral Drug Resistance (original) (raw)
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Primary HIV-1 resistance: Persistence of transmitted drug resistance mutations
Archives of Biological Sciences, 2012
Transmitted drug resistance (TDR) is one of the consequences of the high variability of HIV-1. The widespread use of antiretroviral therapy for the treatment of HIV-1 infection results in a large circulating pool of resistant virus variants. It is known that TDR mutations can persist for extended periods and may pose an important problem to the overall success of antiretroviral therapy. Factors that determine the duration of continuous persistence of resistance-associated mutations are the number and type of these mutations and their impact on viral fitness. Here we describe the follow-up of a case study of prolonged persistence of resistance-associated mutations, namely RT mutations Q151M, K65KR and Y181C conferring an intermediate-to-high level resistance to multiple NRTIs and NNRTIs that lasted for seven years. The infection was caused by subtype G virus.
Evolution of resistance to drugs in HIV-1-infected patients failing antiretroviral therapy
AIDS, 2004
Background and objective-The optimal time for changing failing antiretroviral therapy (ART) is not known. It involves balancing the risk of exhausting future treatment options against the risk of developing increased drug resistance. The frequency with which new drug-resistance mutations (DRM) developed and their potential consequences in patients continuing unchanged treatment despite persistent viremia were assessed.
1996
Multidrug-resistant human immunodeficiency virus type 1 (HIV-1) strains with reverse transcriptase (RT) mutations at codons A623V, V753I, F773L, F1163Y, and Q1513M have been reported in patients receiving combination therapy with zidovudine (AZT) and didanosine (ddI). Infectious clones with each mutation alone, all five mutations together, and various combinations of mutations were created by site-directed mutagenesis. Mutation Q1513M conferred partial resistance to AZT, ddI, zalcitibine, and stavudine, whereas a combination of four mutations conferred increased resistance to AZT, ddI, zalcitibine, and stavudine. The positions of residues 75, 77, and 151 in the three-dimensional crystal structure of HIV-1 RT suggest that these residues may affect the ability of the enzyme to discriminate between deoxynucleoside triphosphates and nucleoside analog RT inhibitors. Replication experiments showed that clones with mutation F773L but without V753I (HIV-1 77 , HIV-1 77,151 , and HIV-1 77,116,151 ) had attenuated growth compared with that of the original HIV-1 NL4-3 strain and strains containing mutations at both positions 75 and 77 . Sequence analysis of viral RNA and proviral DNA from several patients indicated that RT mutations developed in a sequential and cumulative pattern over the course of a 2-to 4-year observation period. The present results suggest that drug resistance and viral replicative capacity both may play a role in selection of HIV-1 RT mutations.
Viruses, 2020
The high mutation rate of the human immunodeficiency virus type 1 (HIV-1) plays a major role in treatment resistance, from the development of vaccines to therapeutic drugs. In addressing the crux of the issue, various attempts to estimate the mutation rate of HIV-1 resulted in a large range of 10 −5-10 −3 errors/bp/cycle due to the use of different types of investigation methods. In this review, we discuss the different assay methods, their findings on the mutation rates of HIV-1 and how the locations of mutations can be further analyzed for their allosteric effects to allow for new inhibitor designs. Given that HIV is one of the fastest mutating viruses, it serves as a good model for the comprehensive study of viral mutations that can give rise to a more horizontal understanding towards overall viral drug resistance as well as emerging viral diseases.
Temporal Trends in HIV-1 Mutations Used for the Surveillance of Transmitted Drug Resistance
Viruses, 2021
In 2009, a list of nonpolymorphic HIV-1 drug resistance mutations (DRMs), called surveillance DRMs (SDRMs), was created to monitor transmitted drug resistance (TDR). Since 2009, TDR increased and antiretroviral therapy (ART) practices changed. We examined the changing prevalence of SDRMs and identified candidate SDRMs defined as nonpolymorphic DRMs present on ≥ 1 expert DRM list and in ≥0.1% of ART-experienced persons. Candidate DRMs were further characterized according to their association with antiretrovirals and changing prevalence. Among NRTI-SDRMs, tenofovir-associated mutations increased in prevalence while thymidine analog mutations decreased in prevalence. Among candidate NRTI-SDRMs, there were six tenofovir-associated mutations including three which increased in prevalence (K65N, T69deletion, K70G/N/Q/T). Among candidate NNRTI-SDRMs, six that increased in prevalence were associated with rilpivirine (E138K/Q, V179L, H221Y) or doravirine (F227C/L) resistance. With the notable...
HIV-1 fitness and antiretroviral drug resistance
AIDS Rev, 2001
During the last few years, considerable new information has been obtained regarding HIV-1 replication capacity, often referred as viral fitness, and the potential effects on population size (viral load), drug resistance, and disease progression. Although viral fitness data ...
JAIDS Journal of Acquired Immune Deficiency Syndromes, 2003
We investigated the evolution of HIV reverse transcriptase (RT)-and protease-associated antiretroviral (ARV) drug resistance mutations during the time taken to perform genotypic drug resistance testing. Thirty treatment-experienced patients who were adherent to therapy and who underwent genotypic drug resistance testing provided blood samples at randomization and when reviewing the test results (baseline). Patients remained on their existing therapy between randomization and baseline. The predominant HIV strains in 10 patients (33%) either lost and/or gained primary RT inhibitor (RTI)-or protease inhibitor (PI)-associated resistance mutations during the testing period. Of the 9 patients with RT mutations, 2 lost, 5 gained, and 2 both lost and gained RTI resistance mutations. One patient gained a significant PIassociated resistance mutation on an existing PI-resistant background. The evolution that occurred in the RT may have altered the effectiveness of subsequent ARV therapy in some patients. Neither viral load at randomization, ARV drug class used at randomization, time between collection of blood samples, duration of current therapy, nor number of ARV drugs used influenced gain or loss of resistance mutations. There was a significant association between duration of previous ARV therapy and gain of RTIassociated resistance mutations (p ס .02), however. In general, our results suggest that patients should continue current therapy until test results are available. A few patients would be expected to gain ARV drug-associated resistance mutations during this time, however.