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Amornkul P.N.,International AIDS Vaccine Initiative | Karita E.,Project San Francisco | Kamali A.,Medical Research Council Uganda Virus Research Unit | Rida W.N.,Biostatistics Consultant | And 14 more authors.
AIDS | Year: 2013

Objective: To describe immunologic, virologic, and clinical HIV disease progression by HIV-1 subtype among Africans with well documented estimated dates of HIV infection (EDIs). Design: Prospective cohort. Methods: Adults and youth with documented HIV-1 infection in the past 12 months were recruited from seroincidence cohorts in East and Southern Africa and followed at 3-6 month intervals. Blood for lymphocyte subset and viral load determination was collected at each visit. Pol was sequenced from the first positive specimen to ascertain subtype. Preantiretroviral therapy disease progression was measured by three time-toevent endpoints: CD4+ cell count 350 cells/ml or less, viral load measurement at least 1*105 copies/ml, and clinical AIDS. Results: From 2006 to 2011, 615 participants were enrolled at nine research centers in Kenya, Rwanda, South Africa, Uganda, and Zambia; 579 (94.1%) had viral subtyping completed. Predominant subtypes were C (256, 44.2%), A (209, 36.1%), and D (84, 14.5%). After adjustment for age, sex, and human leukocyte antigen alleles in Cox regression analyses, subtype C-infected participants progressed faster than subtype A to all three endpoints [CD4+ hazard ratio 1.60, 95% (confidence interval) CI 1.16, 2.20; viral load hazard ratio 1.59, 95% CI 1.12, 2.25; and AIDS hazard ratio 1.60, 95% CI 1.11, 2.31). Subtype D-infected participants reached high viral load more rapidly (hazard ratio 1.61, 95% CI 1.01, 2.57) and progressed nearly twice as fast to AIDS compared to subtype A (hazard ratio 1.93, 95% CI 1.21, 3.09). Conclusion: Subtype-specific differences in HIV disease progression suggest that the local subtype distribution be considered when planning HIV programs and designing and defining clinical endpoints for HIV prevention trials. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Deymier M.J.,Emory University | Ende Z.,Emory University | Fenton-May A.E.,University of Oxford | Dilernia D.A.,Emory University | And 4 more authors.
PLoS Pathogens | Year: 2015

Heterosexual transmission of HIV-1 is characterized by a genetic bottleneck that selects a single viral variant, the transmitted/founder (TF), during most transmission events. To assess viral characteristics influencing HIV-1 transmission, we sequenced 167 near full-length viral genomes and generated 40 infectious molecular clones (IMC) including TF variants and multiple non-transmitted (NT) HIV-1 subtype C variants from six linked heterosexual transmission pairs near the time of transmission. Consensus-like genomes sensitive to donor antibodies were selected for during transmission in these six transmission pairs. However, TF variants did not demonstrate increased viral fitness in terms of particle infectivity or viral replicative capacity in activated peripheral blood mononuclear cells (PBMC) and monocyte-derived dendritic cells (MDDC). In addition, resistance of the TF variant to the antiviral effects of interferon-α (IFN-α) was not significantly different from that of non-transmitted variants from the same transmission pair. Thus neither in vitro viral replicative capacity nor IFN-α resistance discriminated the transmission potential of viruses in the quasispecies of these chronically infected individuals. However, our findings support the hypothesis that within-host evolution of HIV-1 in response to adaptive immune responses reduces viral transmission potential. © 2015 Deymier et al.

Prince J.L.,Emory University | Claiborne D.T.,Emory University | Carlson J.M.,Microsoft | Schaefer M.,Emory University | And 19 more authors.
PLoS Pathogens | Year: 2012

Initial studies of 88 transmission pairs in the Zambia Emory HIV Research Project cohort demonstrated that the number of transmitted HLA-B associated polymorphisms in Gag, but not Nef, was negatively correlated to set point viral load (VL) in the newly infected partners. These results suggested that accumulation of CTL escape mutations in Gag might attenuate viral replication and provide a clinical benefit during early stages of infection. Using a novel approach, we have cloned gag sequences isolated from the earliest seroconversion plasma sample from the acutely infected recipient of 149 epidemiologically linked Zambian transmission pairs into a primary isolate, subtype C proviral vector, MJ4. We determined the replicative capacity (RC) of these Gag-MJ4 chimeras by infecting the GXR25 cell line and quantifying virion production in supernatants via a radiolabeled reverse transcriptase assay. We observed a statistically significant positive correlation between RC conferred by the transmitted Gag sequence and set point VL in newly infected individuals (p = 0.02). Furthermore, the RC of Gag-MJ4 chimeras also correlated with the VL of chronically infected donors near the estimated date of infection (p = 0.01), demonstrating that virus replication contributes to VL in both acute and chronic infection. These studies also allowed for the elucidation of novel sites in Gag associated with changes in RC, where rare mutations had the greatest effect on fitness. Although we observed both advantageous and deleterious rare mutations, the latter could point to vulnerable targets in the HIV-1 genome. Importantly, RC correlated significantly (p = 0.029) with the rate of CD4+ T cell decline over the first 3 years of infection in a manner that is partially independent of VL, suggesting that the replication capacity of HIV-1 during the earliest stages of infection is a determinant of pathogenesis beyond what might be expected based on set point VL alone. © 2012 Prince et al.

Kelley A.L.,Rwanda Zambia HIV Research Group | Karita E.,Rwanda Zambia HIV Research Group | Sullivan P.S.,Emory University | Katangulia F.,Scientific Monitoring, Inc. | And 8 more authors.
PLoS ONE | Year: 2011

Background: Most incident HIV infections in sub-Saharan Africa occur between cohabiting, discordant, heterosexual couples. Though couples' voluntary HIV counseling and testing (CVCT) is an effective, well-studied intervention in Africa, <1% of couples have been jointly tested. Methods: We conducted cross-sectional household surveys in Kigali, Rwanda (n = 600) and Lusaka, Zambia (n = 603) to ascertain knowledge, perceptions, and barriers to use of CVCT. Results: Compared to Lusaka, Kigali respondents were significantly more aware of HIV testing sites (79% vs. 56%); had greater knowledge of HIV serodiscordance between couples (83% vs. 43%); believed CVCT is good (96% vs. 72%); and were willing to test jointly (91% vs. 47%). Stigma, fear of partner reaction, and distance/cost/logistics were CVCT barriers. Conclusions: Though most respondents had positive attitudes toward CVCT, the majority were unaware that serodiscordance between cohabiting couples is possible. Future messages should target gaps in knowledge about serodiscordance, provide logistical information about CVCT services, and aim to reduce stigma and fear. © 2011 Kelley et al.

Sullivan P.S.,Emory University | Fideli U.,U.S. National Institutes of Health | Wall K.M.,Emory University | Chomba E.,Zambia Emory HIV Research Project | And 9 more authors.
AIDS | Year: 2012

OBJECTIVE:: To describe symptoms, physical examination findings, and set-point viral load associated with acute HIV seroconversion in a heterosexual cohort of HIV-discordant couples in Zambia. DESIGN:: We followed HIV serodiscordant couples in Lusaka, Zambia from 1995 to 2009 with HIV testing of negative partners and symptom inventories 3 monthly, and physical examinations annually. METHODS:: We compared prevalence of self-reported or treated symptoms (malaria syndrome, chronic diarrhea, asthenia, night sweats, and oral candidiasis) and annual physical examination findings (unilateral or bilateral neck, axillary, or inguinal adenopathy; and dermatosis) in seroconverting vs. HIV-negative or HIV-positive intervals, controlling for repeated observations, age, and sex. A composite score comprised of significant symptoms and physical examination findings predictive of seroconversion vs. HIV-negative intervals was constructed. We modeled the relationship between number of symptoms and physical examination findings at seroconversion and log set-point viral load using linear regression. RESULTS:: Two thousand, three hundred and eighty-eight HIV-negative partners were followed for a median of 18 months; 429 seroconversions occurred. Neither symptoms nor physical examination findings were reported for most seroconverters. Seroconversion was significantly associated with malaria syndrome among nondiarrheic patients [adjusted odds ratio (aOR)=4.0], night sweats (aOR=1.4), and bilateral axillary (aOR=1.6), inguinal (aOR=2.2), and neck (aOR=2.2) adenopathy relative to HIV-negative intervals. Median number of symptoms and findings was positively associated with set-point viral load (P<0.001). CONCLUSION:: Although most acute and early infections were asymptomatic, malaria syndrome was more common and more severe during seroconversion. When present, symptoms and physical examination findings were nonspecific and associated with higher set-point viremia. © 2012 Lippincott Williams & Wilkins, Inc.

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