Substitutions in the Reverse Transcriptase and Protease Genes of HIV‐1 Subtype B in Untreated Individuals and Patients Treated With Antiretroviral Drugs

Turner, Dan; Brenner, Bluma G.; Moïsi, Daniela; Liang, Chen; Wainberg, Mark A.

doi:10.1186/1758-2652-7-1-69

Cited by 4 publications

(4 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The greater conservation of resistance sites probably reflects a stronger selective disadvantage of any mutation and hence, the lower frequency of polymorphism, most likely relating to their location near structurally and functionally constrained regions of PR and RT. This finding supports the results presented in earlier reports of conservation of resistance sites relative to nonresistance sites using bulk sequencing techniques or cloning [8][9][10][11].…”

Section: Discussionsupporting

confidence: 92%

Frequent polymorphism at drug resistance sites in HIV-1 protease and reverse transcriptase

Kearney

Palmer

Maldarelli

et al. 2008

Aids

View full text Add to dashboard Cite

Background-Failure of antiretroviral therapy may result from the selection of pre-existing, drug-resistant HIV-1 variants, but the frequency and type of such variants have not been defined. Objective-We used single genome sequencing (SGS) to characterize the frequency of polymorphism at drug resistance sites in protease (PR) and reverse transcriptase (RT) in plasma samples from antiretroviral naive individuals. Methods-A total of 2229 pro-pol sequences in 79 plasma samples from 30 patients were analyzed by SGS. A mean of 28 single genome sequences was obtained from each sample. The frequency of mutations at all PR and RT sites was compared to those associated with drug resistance. Results-We detected polymorphism at one or more drug resistance sites in 27 of 30 (90%) patients. Polymorphism at positions 179 and 215 of RT was most common, both occurring in 23% of patients. Most (68%) of other drug resistance sites were polymorphic with an average of 3.2% of genomes per sample containing at least one variant from wild type. Seven drug resistance sites were polymorphic in more than 1% of genomes: PR position 33; RT positions 69, 98, 118, 179, 210, and 215. Although frequencies of synonymous polymorphism were similar at resistance and nonresistance sites, nonsynonymous polymorphism were significantly less common at drug resistance sites, implying stronger purifying selection at these positions. Conclusions-HIV-1 variants that are polymorphic at drug resistance sites pre-exist frequently as minor species in antiretroviral naive individuals. Standard genotype techniques have grossly underestimated their frequency.

show abstract

Section: Discussionsupporting

confidence: 92%

Frequent polymorphism at drug resistance sites in HIV-1 protease and reverse transcriptase

Kearney

Palmer

Maldarelli

et al. 2008

Aids

View full text Add to dashboard Cite

show abstract

“…The frequencies of transition and transversion substitutions differed considerably in the two lacZ␣ orientations (P ϭ 0.0074). Consistent with genomic analyses of HIV-1 from infected patients (38,71,72), we detected twice as many G-to-A as C-to-T substitutions (Table 3A) For both lacZ␣ orientations, there was a strong preference for mutations at specific sites (Fig. 2).…”

Section: Resultssupporting

confidence: 70%

Nature, Position, and Frequency of Mutations Made in a Single Cycle of HIV-1 Replication

Abram

Ferris

Shao

et al. 2010

J Virol

227

291

View full text Add to dashboard Cite

There is considerable HIV-1 variation in patients. The extent of the variation is due to the high rate of viral replication, the high viral load, and the errors made during viral replication. Mutations can arise from errors made either by host DNA-dependent RNA polymerase II or by HIV-1 reverse transcriptase (RT), but the relative contributions of these two enzymes to the mutation rate are unknown. In addition, mutations in RT can affect its fidelity, but the effect of mutations in RT on the nature of the mutations that arise in vivo is poorly understood. We have developed an efficient system, based on existing technology, to analyze the mutations that arise in an HIV-1 vector in a single cycle of replication. A lacZ␣ reporter gene is used to identify viral DNAs that contain mutations which are analyzed by DNA sequencing. The forward mutation rate in this system is 1.4 ؋ 10 ؊5 mutations/bp/cycle, equivalent to the retroviral average. This rate is about 3-fold lower than previously reported for HIV-1 in vivo and is much lower than what has been reported for purified HIV-1 RT in vitro. Although the mutation rate was not affected by the orientation of lacZ␣, the sites favored for mutations (hot spots) in lacZ␣ depended on which strand of lacZ␣ was present in the viral RNA. The pattern of hot spots seen in lacZ␣ in vivo did not match any of the published data obtained when purified RT was used to copy lacZ␣ in vitro.

show abstract

“…No database or algorithm exists for the interpretation of mutations selected during treatment of HIV-2 disease. In contrast, a wealth of information is available on drug resistance to PIs in HIV-1 (5,17,30,38,43,44).…”

mentioning

confidence: 99%

Natural Polymorphisms in the Human Immunodeficiency Virus Type 2 Protease Can Accelerate Time to Development of Resistance to Protease Inhibitors

Ntemgwa

Brenner

Oliveira

et al. 2007

Antimicrob Agents Chemother

Self Cite

View full text Add to dashboard Cite

Human immunodeficiency virus type 2 (HIV-2) contains numerous natural polymorphisms in its protease (PR) gene that are implicated in drug resistance in the case of HIV-1. This study evaluated emergent PR resistance in HIV-2. Three HIV-2 isolates were selected for resistance to amprenavir (APV), nelfinavir (NFV), indinavir (IDV), and tipranavir (TPV) in cell culture. Genotypic analysis determined the time to the appearance of protease inhibitor (PI)-associated mutations compared to HIV-1. Phenotypic drug susceptibility assays were used to determine the levels of drug resistance. Within 10 to 15 weeks of serial passage, three major mutations-I54M, I82F, and L90M-arose in HIV-2 viral cultures exposed to APV, NFV, and IDV, whereas I82L was selected with TPV. After 25 weeks, other cultures had developed I50V and I84V mutations. In contrast, no major PI mutations were selected in HIV-1 over this period except for D30N in the context of NFV selective pressure. The baseline phenotypes of wild-type HIV-2 isolates were in the range observed for HIV-1, except for APV and NFV for which a lower degree of sensitivity was seen. The acquisition of the I54M, I84V, L90M, and L99F mutations resulted in multi-PI-resistant viruses, conferring 10-fold to more than 100-fold resistance. Of note, we observed a 62A/99F mutational motif that conferred high-level resistance to PIs, as well as novel secondary mutations, including 6F, 12A, and 21K. Thus, natural polymorphisms in HIV-2 may facilitate the selection of PI resistance. The increasing incidence of such polymorphisms in drug-naive HIV-1-and HIV-2-infected persons is of concern.

show abstract

Substitutions in the Reverse Transcriptase and Protease Genes of HIV‐1 Subtype B in Untreated Individuals and Patients Treated With Antiretroviral Drugs

Cited by 4 publications

References 24 publications

Frequent polymorphism at drug resistance sites in HIV-1 protease and reverse transcriptase

Frequent polymorphism at drug resistance sites in HIV-1 protease and reverse transcriptase

Nature, Position, and Frequency of Mutations Made in a Single Cycle of HIV-1 Replication

Natural Polymorphisms in the Human Immunodeficiency Virus Type 2 Protease Can Accelerate Time to Development of Resistance to Protease Inhibitors

Contact Info

Product

Resources

About