Showing papers by "Bluma G. Brenner published in 2012"
TL;DR: These findings suggest that naturally occurring polymorphisms can affect both the magnitude of resistance conferred by some major mutations as well as the propensity to acquire certain resistance mutations, even though such differences are sometimes difficult to demonstrate in phenotypic assays.
Abstract: The vast majority of reports on drug resistance deal with subtype B infections in developed countries, and this is largely due to historical delays in access to antiretroviral therapy (ART) on a worldwide basis. This notwithstanding the concept that naturally occurring polymorphisms among different non-B subtypes can affect HIV-1 susceptibility to antiretroviral drugs (ARVs) is supported by both enzymatic and virological data. These findings suggest that such polymorphisms can affect both the magnitude of resistance conferred by some major mutations as well as the propensity to acquire certain resistance mutations, even though such differences are sometimes difficult to demonstrate in phenotypic assays. It is mandatory that tools are optimized to assure accurate measurements of drug susceptibility in non-B subtypes and to recognize that each subtype may have a distinct resistance profile and that differences in resistance pathways may also impact on cross-resistance and the choice of regimens to be used in second-line therapy. Although responsiveness to first-line therapy should not theoretically be affected by considerations of viral subtype and drug resistance, well-designed long-term longitudinal studies involving patients infected by viruses of different subtypes should be carried out.
60 citations
TL;DR: The M/L89 natural polymorphism present in non-B subtypes may lead to the M89T mutational pathway conferring resistance to atazanavir, lopinavir and nelfinavir.
Abstract: Objectives: Relatively little is known about the development of resistance to protease inhibitors (PIs) in non-B subtypes. In subtype B viruses, L89 is commonly found at position 89 in the HIV protease (PR) gene, whereas M89 is commonly observed as a polymorphism in other subtypes. We compared the frequencies of substitutions at position 89 in PR in tissue culture selections and in clinical databases of PI-naive and PI-experienced populations. Methods: Representative subtype A/CRF01_AE (n¼2 and 3) and subtype C (n¼5) isolates were cultured in MT-2 cells and cord blood mononuclear cells (CBMCs), respectively, under increasing drug pressure with PIs, and drug resistance mutations were identified. Results: The M89 natural polymorphism in non-B subtypes commonly led to the appearance of an M89T mutation in selections with atazanavir in subtypes A/AE and C, and was accompanied by other previously recognized atazanavir mutations. The M89T mutation contributed to phenotypic resistance to atazanavir and cross-resistance to lopinavir and nelfinavir, but not to other PIs. A shift from a L89 natural polymorphism to L89I/M arose in two of five subtype C selections with PIs. M89I/V/T mutations were acquired by 10%‐11% of individuals harbouring non-B subtypes who were failing PI-based regimens, but were rarely observed in drugnaive persons and in patients failing non-PI-based regimens. Conclusions: The M/L89 natural polymorphism present in non-B subtypes may lead to the M89T mutational pathway conferring resistance to atazanavir, lopinavir and nelfinavir.
18 citations
TL;DR: It is demonstrated that ETR was able to select for the E138K mutation in viruses containing the M184I/V mutations and that the M 184I/v mutations consistently emerged when E138k viruses were selected with 3TC-FTC.
Abstract: The emergence of HIV-1 drug resistance remains a major obstacle in antiviral therapy. M184I/V and E138K are signature mutations of clinical relevance in HIV-1 reverse transcriptase (RT) for the nucleoside reverse transcriptase inhibitors (NRTIs) lamivudine (3TC) and emtricitabine (FTC) and the second-generation (new) nonnucleoside reverse transcriptase inhibitor (NNRTI) rilpivirine (RPV), respectively, and the E138K mutation has also been shown to be selected by etravirine in cell culture. The E138K mutation was recently shown to compensate for the low enzyme processivity and viral fitness associated with the M184I/V mutations through enhanced deoxynucleoside triphosphate (dNTP) usage, while the M184I/V mutations compensated for defects in polymerization rates associated with the E138K mutations under conditions of high dNTP concentrations. The M184I mutation was also shown to enhance resistance to RPV and ETR when present together with the E138K mutation. These mutual compensatory effects might also enhance transmission rates of viruses containing these two mutations. Therefore, we performed tissue culture studies to investigate the evolutionary dynamics of these viruses. Through experiments in which E138K-containing viruses were selected with 3TC-FTC and in which M184I/V viruses were selected with ETR, we demonstrated that ETR was able to select for the E138K mutation in viruses containing the M184I/V mutations and that the M184I/V mutations consistently emerged when E138K viruses were selected with 3TC-FTC. We also performed biochemical subunit-selective mutational analyses to investigate the impact of the E138K mutation on RT function and interactions with the M184I mutation. We now show that the E138K mutation decreased rates of polymerization, impaired RNase H activity, and conferred ETR resistance through the p51 subunit of RT, while an enhancement of dNTP usage as a result of the simultaneous presence of both mutations E138K and M184I occurred via both subunits.
18 citations
TL;DR: These findings underscore the opportunities and challenges in implementing new testing and tailored prevention paradigms for different MSM populations and have disturbing implications in light of the introduction of non-B subtype and drug-resistant sub-epidemics.
Abstract: While highly active antiretroviral therapy (HAART) has transformed HIV/AIDS to a chronic, treatable disease in Canada, HIV incidence continues to rise among male-sex-male (MSM) populations. Montreal, Canada, is a unique environment for a comprehensive surveillance study on HIV transmission dynamics. Phylogenetic strategies show that half of all new MSM infections in Montreal may arise through onward transmission by individuals who are in primary HIV infection (PHI) (< 6 months post-infection) and often unaware of their HIV status. Large cluster networks, wherein one infection leads to 5-31 onward transmissions, constitute the fastest-growing sub-epidemic, representing 25% and 39% of genotyped incident infections in 2005 and 2009, respectively. This has disturbing implications in light of the introduction of non-B subtype and drug-resistant sub-epidemics. Biological and behavioural correlates of cluster membership are being investigated to establish risk determinants implicated in the onward transmission of the MSM epidemic. Our findings underscore the opportunities and challenges in implementing new testing and tailored prevention paradigms for different MSM populations.
10 citations