Browsing by Author "Yirrell, David L."

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    Genotypic Variation in the pol Gene of HIV Type 1 in an Antiretroviral Treatment-Naive Population in Rural Southwestern Uganda
    (AIDS Research & Human Retroviruses, 2006) Gale, Catherine V.; Yirrell, David L.; Campbell, Eileen; Kaleebu, Pontiano
    The majority of studies of HIV-1 drug resistance have involved subtype B viruses. Here we have characterized subtype distribution and determined the levels of polymorphism at protease (PR) and reverse transcriptase (RT) drug resistance positions, in antiretroviral treatment-naive HIV-positive Ugandan patients. We have also investigated codon usage variability at these positions and assessed intersubtype recombination within the polgene. The study population consisted of 187 patients, from a cohort established by the UK Medical Research Council Programme on AIDS in Uganda in 1990. Results indicate that 28.3% of patients were infected with subtype A (n 53), 64.2% subtype D (n 120), 6.4% A/D recombinant (n 12), and 1.1% subtype C (n 2). Variation in amino acid usage at drug resistance-associated positions was minimal between the two main subtypes (A and D) in RT, but there was appreciable variation in PR. Codon usage, however, was considerably more variable between subtypes A and D in both PR and RT. Thus, while no natural high-level resistance to antiretroviral therapy was detected in this cohort, subtypes A and D may possess different genetic barriers to be overcome in order to achieve resistance. With the increasing introduction of antiretroviral therapy into Africa, such information will be vital in our understanding and evaluation of the development of drug resistance as it occurs, and how to interpret resistance data the type of which has rarely previously been seen. This analysis also significantly increases the number of Ugandan PR and RT sequences characterized to date.
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    Relation Between Chemokine Receptor Use, Disease Stage, and HIV-1 Subtypes A and D Results From a Rural Ugandan Cohort
    (JAIDS Journal of Acquired Immune Deficiency Syndromes, 2007) Kaleebu, Pontiano; Nankya, Immaculate L.; Yirrell, David L.; Shafer, Leigh Anne; Kyosiimire-Lugemwa, Jacqueline; Lule, Daniel B.; Morgan, Dilys; Beddows, Simon; Weber, Jonathan; Whitworth, James A. G.
    To determine whether there are differences in coreceptor use in subjects infected with HIV-1 envelope subtypes A and D that could explain the differences in progression rates between these subtypes in a rural Ugandan cohort. HIV-1 was subtyped in env by V3 sequencing or heteroduplex mobility assay. Coreceptor use was determined by the ability of the isolates to replicate in U87 CD4+ cells expressing different coreceptors. The Fisher exact test was used to examine the relation between coreceptor use and subtype, clinical stage, and V3 charge. The Kruskall-Wallis nonparametric test was used to examine the association between median CD4 cell counts, coreceptor use, and subtype. Logistic regression was used to examine predicted coreceptor use at different CD4 groupings. Isolates from 66 participants were analyzed. Thirty-one were infected with subtype A, and 35 were infected with subtype D. Although this work was based on a small sample size, we found statistically significant differences. The probability of having an X4 virus was higher in subtype D infections than in subtype A infections among those with a non-AIDS clinical status (Fisher exact test, P = 0.040). Logistic regression analysis, in which we predicted X4 use by subtype and stratified by CD4 group, confirmed these findings among those with a CD4 count .200 cells/mL (likelihood ratio test, P = 0.003). R5 viruses were associated with higher median CD4 cell counts than X4 or X4/R5 (Kruskall-Wallis test, P = 0.0045). AV3 charge of +5 and greater was highly associated with X4 virus (Fisher exact test, P = 0.006). These subtype differences in coreceptor use may partially explain the faster progression rates we have previously