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Pancera M.,National Institute of Allergy and Infectious Diseases | Yang Y.,National Institute of Allergy and Infectious Diseases | Louder M.K.,National Institute of Allergy and Infectious Diseases | Gorman J.,National Institute of Allergy and Infectious Diseases | And 8 more authors.
PLoS ONE | Year: 2013

Dozens of broadly neutralizing HIV-1 antibodies have been isolated in the last few years from the sera of HIV-1-infected individuals. Only a limited number of regions on the HIV-1 spike, however, are recognized by these antibodies. One of these regions (N332) is characterized by an N-linked glycan at residue 332 on HIV-1 gp120 and is recognized by antibody 2G12 and by the recently reported antibodies PGT121-137, the latter isolated from three donors. To investigate the diversity in mode of antibody recognition at the N332 site, we used functional complementation between antibody heavy and light chains as a means of assessing similarity in mode of recognition. We examined a matrix of 12 PGT-heavy chains with each of 12 PGT-light chains. Expression in 96-well format for the 144 antibodies (132 chimeric and 12 wild-type) was generally consistent (58±10 μg/ml). In contrast, recognition of HIV-1 gp120 was bimodal: when the source of heavy and light chains was from the same donor, recognition was good; when sources of heavy and light chains were from different donors, recognition was poor. Moreover, neutralization of HIV-1 strains SF162.LS and TRO.11 generally followed patterns of gp120 recognition. These results are consistent with published sequence, mutational, and structural findings, all of which indicate that N332-directed neutralizing antibodies from different donors utilize different modes of recognition, and provide support for a correlation between functional complementation of antibody heavy and light chains and similarity in antibody mode of recognition. Overall, our results add to the growing body of evidence that the human immune system is capable of recognizing the N332-region of HIV-1 gp120 in diverse ways. Source


Okuku H.S.,Kenya Medical Research Institute | Sanders E.J.,Kenya Medical Research Institute | Sanders E.J.,University of Oxford | Nyiro J.,Kenya Medical Research Institute | And 6 more authors.
Sexually Transmitted Diseases | Year: 2011

Background: Herpes simplex virus type 2 (HSV-2) is an important cause of genital ulcers and can increase the risk for human immunodeficiency virus type 1 (HIV-1) transmission. Our objective was to determine the incidence and correlates of HSV-2 infection in HIV-1-seronegative Kenyan men reporting high-risk sexual behavior, compared with high-risk HIV-1-seronegative women in the same community. Methods: Cohort participants were screened for prevalent HIV-1 infection. HIV-1-uninfected participants had regularly scheduled follow-up visits, with HIV counseling and testing and collection of demographic and behavioral data. Archived blood samples were tested for HSV-2. Results: HSV-2 prevalence was 22.0% in men and 50.8% in women (P < 0.001). HSV-2 incidence in men was 9.0 per 100 person-years, and was associated with incident HIV-1 infection (adjusted incidence rate ratio [aIRR], 3.9; 95% confidence interval [CI], 1.3-12.4). Use of soap for genital washing was protective (aIRR, 0.3; 95% CI, 0.1-0.8). Receptive anal intercourse had a borderline association with HSV-2 acquisition in men (aIRR, 2.0; 95% CI, 1.0-4.1; P = 0.057), and weakened the association with incident HIV-1. Among women, HSV-2 incidence was 22.1 per 100 person-years (P < 0.001 compared with incidence in men), and was associated with incident HIV-1 infection (aIRR, 8.9; 95% CI, 3.6-21.8) and vaginal washing with soap (aIRR, 1.9; 95% CI, 1.0-3.4). Conclusions: HSV-2 incidence in these men and women is among the highest reported, and is associated with HIV-1 acquisition. Although vaginal washing with soap may increase HSV-2 risk in women, genital hygiene may be protective in men. Copyright © 2011 American Sexually Transmitted Diseases Association. All rights reserved. Source


Ruzagira E.,Uganda Virus Research Institute UVRI | Wandiembe S.,Uganda Virus Research Institute UVRI | Abaasa A.,Uganda Virus Research Institute UVRI | Levin J.,Uganda Virus Research Institute UVRI | And 4 more authors.
PLoS ONE | Year: 2011

Background: Local HIV epidemiology data are critical in determining the suitability of a population for HIV vaccine efficacy trials. The objective of this study was to estimate the prevalence and incidence of, and determine risk factors for HIV transmission in a rural community-based HIV vaccine preparedness cohort in Masaka, Uganda. Methods: Between February and July 2004, we conducted a house-to-house HIV sero-prevalence survey among consenting individuals aged 18-60 years. Participants were interviewed, counseled and asked to provide blood for HIV testing. We then enrolled the HIV uninfected participants in a 2-year HIV sero-incidence study. Medical evaluations, HIV counseling and testing, and sample collection for laboratory analysis were done quarterly. Sexual risk behaviour data was collected every 6 months. Results: The HIV point prevalence was 11.2%, and was higher among women than men (12.9% vs. 8.6%, P = 0.007). Risk factors associated with prevalent HIV infection for men were age <25 years (aOR = 0.05, 95% CI 0.01-0.35) and reported genital ulcer disease in the past year (aOR = 2.17, 95% CI 1.23-3.83). Among women, being unmarried (aOR = 2.59, 95% CI 1.75-3.83) and reported genital ulcer disease in the past year (aOR = 2.40, 95% CI 1.64-3.51) were associated with prevalent HIV infection. Twenty-one seroconversions were recorded over 2025.8 person-years, an annual HIV incidence of 1.04% (95% CI: 0.68-1.59). The only significant risk factor for incident HIV infection was being unmarried (aRR = 3.44, 95% CI 1.43-8.28). Cohort retention after 2 years was 87%. Conclusions: We found a high prevalence but low incidence of HIV in this cohort. HIV vaccine efficacy trials in this population may not be feasible due to the large sample sizes that would be required. HIV vaccine preparatory efforts in this setting should include identification of higher risk populations. © 2011 Ruzagira et al. Source


Kiwanuka N.,Makerere University | Ssetaala A.,UVRI IAVI HIV Vaccine Program | Mpendo J.,UVRI IAVI HIV Vaccine Program | Wambuzi M.,UVRI IAVI HIV Vaccine Program | And 8 more authors.
Journal of the International AIDS Society | Year: 2013

Introduction: HIV epidemics in sub-Saharan Africa are generalized, but high-risk subgroups exist within these epidemics. A recent study among fisher-folk communities (FFC) in Uganda showed high HIV prevalence (28.8%) and incidence (4.9/100 person-years). However, those findings may not reflect population-wide HIV rates in FFC since the study population was selected for high-risk behaviour. Methods: Between September 2011 and March 2013, we conducted a community-based cohort study to determine the population representative HIV rates and willingness to participate (WTP) in hypothetical vaccine trials among FFC, Uganda. At baseline (September 2011-January 2012), a household enumeration census was done in eight fishing communities (one lakeshore and seven islands), after which a random sample of 2200 participants aged 18-49 years was selected from 5360 individuals. Interviewer-administered questionnaire data were collected on HIV risk behaviours and WTP, and venous blood was collected for HIV testing using rapid HIV tests with enzyme-linked immunosorbent assay (EIA) confirmation. Adjusted prevalence proportion ratios (adj.PPRs) of HIV prevalence were determined using log-binomial regression models. Results: Overall baseline HIV prevalence was 26.7% and was higher in women than men (32.6% vs. 20.8%, p < 0.0001). Prevalence was lower among fishermen (22.4%) than housewives (32.1%), farmers (33.1%) and bar/lodge/restaurant workers (37%). The adj.PPR of HIV was higher among women than men (adj.PPR = 1.50, 95%; 1.20, 1.87) and participants aged 30-39 years (adj.PPR = 1.40, 95%; 1.10, 1.79) and 40-49 years (adj.PPR = 1.41, 95%; 1.04, 1.92) compared to those aged 18-24 years. Other factors associated with HIV prevalence included low education, previous marriage, polygamous marriage, alcohol and marijuana use before sex. WTP in hypothetical vaccine trials was 89.3% and was higher in men than women (91.2% vs. 87.3%, p =0.004) and among island communities compared to lakeshore ones (90.4% vs. 85.8%, p =0.004). Conclusions: The HIV prevalence in the general fisher-folk population in Uganda is similar to that observed in the "high-risk" fisher folk. FFC have very high levels of willingness to participate in future HIV vaccine trials. © 2013 Kiwanuka N et al; licensee International AIDS Society. Source


Munro J.B.,Yale University | Munro J.B.,Tufts University | Gorman J.,National Institute of Allergy and Infectious Diseases | Ma X.,Yale University | And 11 more authors.
Science | Year: 2014

The HIV-1 envelope (Env) mediates viral entry into host cells. To enable the direct imaging of conformational dynamics within Env, we introduced fluorophores into variable regions of the glycoprotein gp120 subunit and measured single-molecule fluorescence resonance energy transfer within the context of native trimers on the surface of HIV-1 virions. Our observations revealed unliganded HIV-1 Env to be intrinsically dynamic, transitioning between three distinct prefusion conformations, whose relative occupancies were remodeled by receptor CD4 and antibody binding. The distinct properties of neutralization-sensitive and neutralization-resistant HIV-1 isolates support a dynamics-basedmechanismof immune evasion and ligand recognition. © 2014, American Association for the Advancement of Science. All rights reserved. Source

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