Browsing by Author "Morgan, Dilys"

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    Effect of Human Immunodeficiency Virus (HIV) Type 1 Envelope Subtypes A and D on Disease Progression in a Large Cohort of HIV-1–Positive Persons in Uganda
    (The Journal of Infectious Diseases, 2002) Kaleebu, Pontiano; French, Neil; Mahe, Cedric; Yirrell, David; Watera, Christine; Lyagoba, Fred; Nakiyingi, Jessica; Rutebemberwa, Alleluiah; Morgan, Dilys; Weber, Jonathan; Gilks, Charles; Whitworth, Jimmy
    The effect of human immunodeficiency virus (HIV) type 1 envelope subtypes A and D on disease progression was investigated in 1045 adults in Uganda. At enrollment and every 6 months, a clinical history, examination, and laboratory investigations that included CD4 cell counts were done. HIV-1 envelope subtype was assessed mainly by peptide serology supplemented by heteroduplex mobility assay and DNA sequencing. A multivariate analysis of survival was performed to assess the prognostic value of HIV-1 subtype on death. A marginal general linear model also determined the effect of subtype on CD4 cell count during follow-up. Subtype D was associated with faster progression to death (relative risk, 1.29; 95% confidence interval, 1.07–1.56; P ¼ .009) and with a lower CD4 cell count during follow-up (P ¼ .001), compared with subtype A, after adjusting for CD4 cell count at enrollment. In Africa, envelope subtype D is associated with faster disease progression, compared with subtype A
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    Molecular Epidemiology of HIV Type 1 in a Rural Community in Southwest Uganda
    (AIDS Research and Human Retroviruses, 2000) Kaleebu, Pontiano; Whitworth, James; Hamilton, Laura; Rutebemberwa, Alleluiah; Lyagoba, Fred; Morgan, Dilys; Duffield, Melanie; Biryahwaho, Benon; Magambo, Brian; Oram, Jon
    The molecular epidemiology of a population-based cohort in a cluster of 15 villages in southwestern Uganda was investigated by sequencing part of the p24 gag gene and performing heteroduplex mobility assays (HMAs) of the V3 region of the env gene. Sequence and HM A data, obtained for 69 and 88 proviruses, respectively, showed that the clade A and D viruses were present at a ratio of about 0.67:1. No other clades were detected. Thirteen (22%) of 59 proviruses for which both gag and env data were obtained appeared to be recombinants. Although both clade A and D viruses were present in 13 of the villages, their distribution was unequal: for example, from env data 59% of clade A viruses were found in the eastern villages, compared with only 27% of clade D viruses. Phylogenetic (maximum likelihood) analysis of the p24 gag sequences showed a total of five clusters supported by bootstrap resampling values above or close to 75%. Four clusters were sexual partners, but there was no known sexual contact between the persons in the other cluster. The DNA sequences showed between 0.5 and 8.3% divergence from the cohort clade A or D consensus sequences. The sequences were not closely related to those published for other clade A or D proviruses.
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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
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    The Relationship between HIV Type 1 Disease Progression and V3 Serotype in a Rural Ugandan Cohort
    (AIDS Research & Human Retroviruses, 2004) Senkaali, David; Muwonge, Richard; Morgan, Dilys; Yirrell, David; Whitworth, James; Kaleebu, Pontiano
    Antigenic properties of the V3 region are reflected by HIV-1 serotypes. These may represent biological properties of the virus. We serotyped HIV-1 in 142 serum samples from participants in a rural Uganda cohort who seroconverted between August 1991 and December 2001. Clinical progression was assessed using Cox proportional hazards and Kaplan–Meier methods. Of 112 (79%) samples successfully serotyped, 36% were serotype A, 17% serotype B, 18% serotype C, and 29% serotype D. Median follow-up time, age at enrollment, and first CD4 count were similar in each serotype group. Clinical progression was faster for serotype D than other serotypes to AIDS or death, death, and CD4 count <200 cells/mm3 (all p < 0.05). HIV-1 V3 serotypes are associated with variations in the pathogenicity of HIV-1 and should be taken into account when studying the biological relevance of HIV-1 diversity.
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    Relationship between HIV-1 Env subtypes A and D and disease progression in a rural Ugandan cohort
    (AIDS, 2001) Kaleebu, Pontiano; Ross, Amanda; Morgan, Dilys; Yirrell, Davida; Oram, Jonb; Rutebemberwa, Alleluiah; Lyagoba, Fred; Hamilton, Laura; Biryahwaho, Benon; Whitworth, James
    To investigate the role of HIV-1 envelope subtypes on disease progression in a rural cohort of Ugandan adults where two major HIV-1 subtypes (A and D) exist. Participants of a clinical cohort seen between December 1995 and December 1998 had blood collected for HIV-1 subtyping. These included prevalent cases (people already infected with HIV at the start of the study in 1990) and incident cases (those who seroconverted between 1990 and December 1998). HIV-1 subtyping was carried out by heteroduplex mobility assay and DNA sequencing in the V3 env region. Disease progression was measured by the rate of CD4 lymphocyte count decline, clinical progression for the incident cases as time from seroconversion to AIDS or death, to ®rst CD4 lymphocyte count , 200 3 106/l and to the World Health Organization clinical stage 3. All analyses were adjusted for age and sex. One hundred and sixty-four individuals, including 47 prevalent and 117 incident cases, had V3 env subtype data of which 65 (40%) were subtyped as A and 99 as D. In the incident cases, 44 (38%) were subtyped as A and 73 as D. There was a suggestion that for most end-points A had a slower progression than D. The cumulative probability of remaining free from AIDS or death at 6 years post-seroconversion was 0.72 [95% con®dence interval (CI), 0.50 to 0.85] for A and 0.58 (95% CI, 0.42 to 0.71) for D, and the adjusted hazard ratio of subtype D compared to A was estimated to be 1.39 (95% CI, 0.66 to 2.94; P 0.39). The estimated difference in rates of decline in square root CD4 lymphocyte counts was ÿ0.41 per year (95% CI, ÿ0.98 to 0.15; P 0.15). This study suggests that although subtype A may have a slower progression than D, HIV-1 envelope subtype is not a major factor in determining the progression of HIV-1 disease in a rural population in Uganda.