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1.  Differential Specificity of HIV Incidence Assays in HIV Subtypes A and D-Infected Individuals from Rakai, Uganda 
AIDS Research and Human Retroviruses  2013;29(8):1146-1150.
Abstract
Assays to determine HIV incidence from cross-sectional surveys have exhibited a high rate of false-recent misclassification in Kenya and Uganda where HIV subtypes A and D predominate. Samples from individuals infected with HIV for at least 2 years with known infecting subtype (133 subtype A, 373 subtype D) were tested using the BED-CEIA and an avidity assay. Both assays had a higher rate of false-recent misclassification for subtype D compared to subtype A (13.7% vs. 6.0%, p=0.02 for BED-CEIA; 11.0% vs. 1.5%, p<0.001 for avidity). For subtype D samples, false-recent misclassification by the BED-CEIA was also more frequent in women than men (15.0% vs. 5.6%, p=0.002), and for samples where that had an amino acid other than lysine at position 12 in the BED-CEIA peptide coding region (p=0.002). Furthermore in subtype D-infected individuals, samples misclassified by one assay were 3.5 times more likely to be misclassified by the other assay. Differential misclassification by infecting subtype of long-term infected individuals as recently infected makes it difficult to use these assays individually to estimate population level incidence without precise knowledge of the distribution of these subtypes within populations where subtype A and D cocirculate. The association of misclassification of the BED-CEIA with the avidity assay in subtype D-infected individuals limits the utility of using these assays in combination within this population.
doi:10.1089/aid.2012.0105
PMCID: PMC3715796  PMID: 23641870
2.  Liver Stiffness Is Associated With Monocyte Activation in HIV-Infected Ugandans Without Viral Hepatitis 
AIDS Research and Human Retroviruses  2013;29(7):1026-1030.
Abstract
A high prevalence of liver stiffness, as determined by elevated transient elastography liver stiffness measurement, was previously found in a cohort of HIV-infected Ugandans in the absence of chronic viral hepatitis. Given the role of immune activation and microbial translocation in models of liver disease, a shared immune mechanism was hypothesized in the same cohort without other overt causes of liver disease. This study examined whether HIV-related liver stiffness was associated with markers of immune activation or microbial translocation (MT). A retrospective case-control study of subjects with evidence of liver stiffness as defined by a transient elastography stiffness measurement ≥9.3 kPa (cases=133) and normal controls (n=133) from Rakai, Uganda was performed. Cases were matched to controls by age, gender, HIV, hepatitis B virus (HBV), and highly active antiretroviral therapy (HAART) status. Lipopolysaccharide (LPS), endotoxin IgM antibody, soluble CD14 (sCD14), C-reactive protein (CRP), and D-dimer levels were measured. Conditional logistic regression was used to estimate adjusted matched odds ratios (adjMOR) and 95% confidence intervals. Higher sCD14 levels were associated with a 19% increased odds of liver stiffness (adjMOR=1.19, p=0.002). In HIV-infected individuals, higher sCD14 levels were associated with a 54% increased odds of having liver stiffness (adjMOR=1.54, p<0.001); however, the opposite was observed in HIV-negative individuals (adjMOR=0.57, p=0.001). No other biomarker was significantly associated with liver stiffness, and only one subject was found to have detectable LPS. Liver stiffness in HIV-infected Ugandans is associated with increased sCD14 indicative of monocyte activation in the absence of viral hepatitis or microbial translocation, and suggests that HIV may be directly involved in liver disease.
doi:10.1089/aid.2013.0004
PMCID: PMC3685686  PMID: 23548102
3.  Antiretroviral Drug Susceptibility Among HIV-Infected Adults Failing Antiretroviral Therapy in Rakai, Uganda 
AIDS Research and Human Retroviruses  2012;28(12):1739-1744.
Abstract
We analyzed antiretroviral drug susceptibility in HIV-infected adults failing first- and second-line antiretroviral treatment (ART) in Rakai, Uganda. Samples obtained from participants at baseline (pretreatment) and at the time of failure on first-line ART and second-line ART were analyzed using genotypic and phenotypic assays for antiretroviral drug resistance. Test results were obtained from 73 samples from 38 individuals (31 baseline samples, 36 first-line failure samples, and six second-line failure samples). Four (13%) of the 31 baseline samples had mutations associated with resistance to nucleoside or nonnucleoside reverse transcriptase inhibitors (NRTIs and NNRTIs, respectively). Among the 36 first-line failure samples, 31 (86%) had NNRTI resistance mutations and 29 (81%) had lamivudine resistance mutations; only eight (22%) had other NRTI resistance mutations. None of the six individuals failing a second-line protease inhibitor (PI)-based regimen had PI resistance mutations. Six (16%) of the participants had discordant genotypic and phenotypic test results. Genotypic resistance to drugs included in first-line ART regimens was detected prior to treatment and among participants failing first-line ART. PI resistance was not detected in individuals failing second-line ART. Surveillance for transmitted and acquired drug resistance remains a priority for scale-up of ART.
doi:10.1089/aid.2011.0352
PMCID: PMC3505045  PMID: 22443282
4.  HIV Type 1 Genetic Variation in Foreskin and Blood from Subjects in Rakai, Uganda 
Abstract
The foreskin contains a subset of dendritic cells, macrophages, and CD4+ and CD8+ T cells that may be targets for initial HIV infection in female-to-male sexual transmission of HIV-1. We present analyses comparing HIV-1 sequences isolated from foreskin DNA and serum RNA in 12 heterosexual men enrolled in an adult male circumcision trial performed in Rakai, Uganda. Phylogenetic analysis demonstrated three topologies: (1) little divergence between foreskin and serum, (2) multiple genetic bottlenecks occurring in both foreskin and serum, and (3) complete separation of foreskin and serum populations. The latter tree topology provided evidence that foreskin may serve as a reservoir for distinct HIV-1 strains. Distance and recombination analysis also demonstrated that viral genotypes in the foreskin might segregate independently from the circulating pool of viruses.
doi:10.1089/aid.2011.0176
PMCID: PMC3380386  PMID: 21902587
5.  Efficiency of CCR5 Coreceptor Utilization by the HIV Quasispecies Increases over Time, But Is Not Associated with Disease Progression 
Abstract
CCR5 is the primary coreceptor for HIV entry. Early after infection, the HIV viral population diversifies rapidly into a quasispecies. It is not known whether the initial efficiency of the viral quasispecies to utilize CCR5 is associated with HIV disease progression or if it changes in an infected individual over time. The CCR5 and CXCR4 utilization efficiencies (R5-UE and X4-UE) of the HIV quasispecies were examined using a pseudovirus, single-round infection assay for samples obtained from known seroconverters from Rakai district, Uganda (n=88). Initial and longitudinal R5-UE values were examined to assess the association of R5-UE with HIV disease progression using multivariate Cox proportional hazard models. Longitudinal samples were analyzed for 35 seroconverters who had samples available from multiple time points. There was no association between initial or longitudinal changes in R5-UE and the hazard of HIV disease progression (p=0.225 and p=0.942, respectively). In addition, R5-UE increased significantly over time after HIV seroconversion (p<0.001), regardless of HIV subtype or the emergence of CXCR4-tropic virus. These data demonstrate that the R5-UE of the viral quasispecies early in HIV infection is not associated with disease progression, and that R5-UE levels increase in HIV-infected individuals over time.
doi:10.1089/aid.2011.0006
PMCID: PMC3292754  PMID: 21663455
6.  Changes in the Distribution of HIV Type 1 Subtypes D and A in Rakai District, Uganda Between 1994 and 2002 
AIDS Research and Human Retroviruses  2010;26(10):1087-1091.
Abstract
HIV-1 subtype D (HIV-1D) progresses to disease faster and has lower transmissibility than subtype A (HIV-1A). We examined whether these differences could lead to a population level change in the distribution of these subtypes over time. HIV-1 viral RNA was extracted from stored serum samples from HIV-positive subjects participating in a population-based cohort study in Rakai, Uganda in 1994 and 2002. Portions of the viral proteins gag and gp41 were sequenced and subtyped. HIV-1 subtype assignments were generated for 773 subjects in 1994 and 812 subjects in 2002. The change in subtype distribution of the population as a whole as well as quartile age groups were examined for significant changes using a linear model. There was a significant decrease in the proportion of subjects infected with HIV-1D from 70.2% to 62.4% and a significant increase in subjects infected with HIV-1A from 16.7% to 23.3% over the 8-year period (p = 0.005). The most marked changes in proportion of HIV-1D and A were seen in the younger individuals (<25 and 25–30 years; p < 0.05). The percentages of subjects infected with HIV-1C and recombinant subtypes did not change significantly. Over this 8-year period, the overall viral population in this region evolved toward the less virulent HIV-1A strain, most likely as a consequence of the faster disease progression and lower transmissibility of HIV-1D.
doi:10.1089/aid.2010.0054
PMCID: PMC2965693  PMID: 20925575
7.  Geographic HIV Type 1 Subtype Distribution in Rakai District, Uganda 
AIDS Research and Human Retroviruses  2009;25(10):1045-1048.
Abstract
To analyze HIV-1 subtype distribution, sequence analysis was performed on serum specimens obtained in 1994 from the Rakai Health Sciences community cohort in Uganda. Portions of gag-p24 and env-gp41 were sequenced and HIV subtype was determined for 773 subjects residing in 10 community clusters in rural Uganda. Subtypes A (17%) and D (70%) were the most common strains in the population. Subtype distribution varied by geographic region with significantly more subtype A in northern community clusters compared with southern clusters (21% vs. 8%, p < 0.001) and more subtype D in southern clusters compared with northern clusters (78% vs. 65%, p < 0.008). These data illustrate the geographic complexity of subtype variation, which has important implications for HIV-1 vaccine design.
doi:10.1089/aid.2009.0127
PMCID: PMC2785855  PMID: 19803713
8.  Geographic HIV Type 1 Subtype Distribution in Rakai District, Uganda 
AIDS research and human retroviruses  2009;25(10):1045-1048.
To analyze HIV-1 subtype distribution, sequence analysis was performed on serum specimens obtained in 1994 from the Rakai Health Sciences community cohort in Uganda. Portions of gag-p24 and env-gp41 were sequenced and HIV subtype was determined for 773 subjects residing in 10 community clusters in rural Uganda. Subtypes A (17%) and D (70%) were the most common strains in the population. Subtype distribution varied by geographic region with significantly more subtype A in northern community clusters compared with southern clusters (21% vs. 8%, p < 0.001) and more subtype D in southern clusters compared with northern clusters (78% vs. 65%, p < 0.008). These data illustrate the geographic complexity of subtype variation, which has important implications for HIV-1 vaccine design.
doi:10.1089/aid.2009.0127
PMCID: PMC2785855  PMID: 19803713

Results 1-8 (8)