Browsing by Author "Martin, Eric."

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Intersubtype differences in the effect of a rare p24 Gag mutation on HIV-1 replicative fitness.
(American Society for Microbiology., 2012) Chopera, Denis Rutendo.; Cotton, Laura A.; Zawaira, Alexander.; Mann, Jaclyn Kelly.; Ngandu, Nobubelo K.; Ntale, Roman.; Carlson, Jonathan M.; Mlisana, Koleka Patience.; Woodman, Zenda.; de Assis Rosa, Debra.; Martin, Eric.; Miura, Toshiyuki.; Pereyra, Florencia.; Walker, Bruce D.; Gray, Clive M.; Martin, Darren Patrick.; Ndung'u, Peter Thumbi.; Brockman, Mark A.; Abdool Karim, Salim Safurdeen.; Brumme, Zabrina L.; Williamson, Carolyn.
Certain immune-driven mutations in HIV-1, such as those arising in p24Gag, decrease viral replicative capacity. However, the intersubtype differences in the replicative consequences of such mutations have not been explored. In HIV-1 subtype B, the p24Gag M250I mutation is a rare variant (0.6%) that is enriched among elite controllers (7.2%) (P 0.0005) and appears to be a rare escape variant selected by HLA-B58 supertype alleles (P<0.01). In contrast, in subtype C, it is a relatively common minor polymorphic variant (10 to 15%) whose appearance is not associated with a particular HLA allele. Using site-directed mutant viruses, we demonstrate that M250I reduces in vitro viral replicative capacity in both subtype B and subtype C sequences. However, whereas in subtype C downstream compensatory mutations at p24Gag codons 252 and 260 reduce the adverse effects of M250I, fitness costs in subtype B appear difficult to restore. Indeed, patient-derived subtype B sequences harboring M250I exhibited in vitro replicative defects, while those from subtype C did not. The structural implications of M250I were predicted by protein modeling to be greater in subtype B versus C, providing a potential explanation for its lower frequency and enhanced replicative defects in subtype B. In addition to accounting for genetic differences between HIV-1 subtypes, the design of cytotoxic-T-lymphocyte-based vaccines may need to account for differential effects of host-driven viral evolution on viral fitness.
No evidence for selection of HIV-1 with enhanced gag-protease or nef function among breakthrough infections in the CAPRISA 004 tenofovir microbicide trial.
(2013) Chopera, Denis Rutendo.; Mann, Jaclyn Kelly.; Mwimanzi, Philip.; Omarjee, Saleha.; Kuang, Xiaomei T.; Ndabambi, Nonkululeko.; Goodier, Sarah A.; Martin, Eric.; Naranbhai, Vivek.; Abdool Karim, Salim Safurdeen.; Abdool Karim, Quarraisha.; Brumme, Zabrina L.; Ndung'u, Peter Thumbi.; Williamson, Carolyn.; Brockman, Mark A.
Background: Use of antiretroviral-based microbicides for HIV-1 prophylaxis could introduce a transmission barrier that inadvertently facilitates the selection of fitter viral variants among incident infections. To investigate this, we assessed the in vitro function of gag-protease and nef sequences from participants who acquired HIV-1 during the CAPRISA 004 1% tenofovir microbicide gel trial. Methods and Results: We isolated the earliest available gag-protease and nef gene sequences from 83 individuals and examined their in vitro function using recombinant viral replication capacity assays and surface protein down regulation assays, respectively. No major phylogenetic clustering and no significant differences in gag-protease or nef function were observed in participants who received tenofovir gel versus placebo gel prophylaxis. Conclusion: Results indicate that the partial protective effects of 1% tenofovir gel use in the CAPRISA 004 trial were not offset by selection of transmitted/early HIV-1 variants with enhanced Gag-Protease or Nef fitness.