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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.


Koff W.C.,International AIDS Vaccine Initiative IAVI | Burton D.R.,Scripps Research Institute | Burton D.R.,Massachusetts General Hospital | Johnson P.R.,Children's Hospital of Philadelphia | And 9 more authors.
Science | Year: 2013

Vaccines are among the greatest successes in the history of public health. However, past strategies for vaccine development are unlikely to succeed in the future against major global diseases such as AIDS, tuberculosis, and malaria. For such diseases, the correlates of protection are poorly defined and the pathogens evade immune detection and/or exhibit extensive genetic variability. Recent advances have heralded in a new era of vaccine discovery. However, translation of these advances into vaccines remains impeded by lack of understanding of key vaccinology principles in humans. We review these advances toward vaccine discovery and suggest that for accelerating successful vaccine development, new human immunology-based clinical research initiatives be implemented with the goal of elucidating and more effectively generating vaccine-induced protective immune responses.


He L.,Scripps Research Institute | Sok D.,Scripps Research Institute | Azadnia P.,Scripps Research Institute | Hsueh J.,Scripps Research Institute | And 7 more authors.
Scientific Reports | Year: 2014

B-cell repertoire analysis using next-generation sequencing has become a valuable tool for interrogating the genetic record of humoral response to infection. However, key obstacles such as low throughput, short read length, high error rate, and undetermined bias of multiplex PCR method have hindered broader application of this technology. In this study, we report several technical advances in antibody repertoire sequencing. We first demonstrated the ability to sequence antibody variable domains using the Ion Torrent PGM platform. As a test case, we analyzed the PGT121 class of antibodies from IAVI donor 17, an HIV-1-infected individual. We then obtained "unbiased" antibody repertoires by sequencing the 5′-RACE PCR products of B-cell transcripts from IAVI donor 17 and two HIV-1-uninfected individuals. We also quantified the bias of previously published gene-specific primers by comparing the repertoires generated by 5′-RACE PCR and multiplex PCR. We further developed a single-molecule barcoding strategy to reduce PCR-based amplification noise. Lastly, we evaluated several new PGM technologies in the context of antibody sequencing. We expect that, based upon long-read and high-fidelity next-generation sequencing technologies, the unbiased analysis will provide a more accurate view of the overall antibody repertoire while the barcoding strategy will facilitate high-resolution analysis of individual antibody families.


Anderson S.-J.,Imperial College London | Cherutich P.,National AIDS and STI Control Programme NASCOP | Kilonzo N.,Liverpool VCT Care and Treatment | Cremin I.,Imperial College London | And 8 more authors.
The Lancet | Year: 2014

Background Epidemiological data show substantial variation in the risk of HIV infection between communities within African countries. We hypothesised that focusing appropriate interventions on geographies and key populations at high risk of HIV infection could improve the effect of investments in the HIV response. Methods With use of Kenya as a case study, we developed a mathematical model that described the spatiotemporal evolution of the HIV epidemic and that incorporated the demographic, behavioural, and programmatic differences across subnational units. Modelled interventions (male circumcision, behaviour change communication, early antiretoviral therapy, and pre-exposure prophylaxis) could be provided to different population groups according to their risk behaviours or their location. For a given national budget, we compared the effect of a uniform intervention strategy, in which the same complement of interventions is provided across the country, with a focused strategy that tailors the set of interventions and amount of resources allocated to the local epidemiological conditions. Findings A uniformly distributed combination of HIV prevention interventions could reduce the total number of new HIV infections by 40% during a 15-year period. With no additional spending, this effect could be increased by 14% during the 15 years-almost 100 000 extra infections, and result in 33% fewer new HIV infections occurring every year by the end of the period if the focused approach is used to tailor resource allocation to reflect patterns in local epidemiology. The cumulative difference in new infections during the 15-year projection period depends on total budget and costs of interventions, and could be as great as 150 000 (a cumulative difference as great as 22%) under different assumptions about the unit costs of intervention. Interpretation The focused approach achieves greater effect than the uniform approach despite exactly the same investment. Through prioritisation of the people and locations at greatest risk of infection, and adaption of the interventions to reflect the local epidemiological context, the focused approach could substantially increase the efficiency and effectiveness of investments in HIV prevention. Funding The Bill &Melinda Gates Foundation and UNAIDS.


Monath T.P.,Kleiner Perkins Caufield & Byers | Monath T.P.,Paxvax, Inc. | Monath T.P.,Hookipa Biotech | Seligman S.J.,New York Medical College | And 9 more authors.
Vaccine | Year: 2015

The Brighton Collaboration Viral Vector Vaccines Safety Working Group (V3SWG) was formed to evaluate the safety of live, recombinant viral vaccines incorporating genes from heterologous viruses inserted into the backbone of another virus (so-called "chimeric virus vaccines"). Many viral vector vaccines are in advanced clinical trials. The first such vaccine to be approved for marketing (to date in Australia, Thailand, Malaysia, and the Philippines) is a vaccine against the flavivirus, Japanese encephalitis (JE), which employs a licensed vaccine (yellow fever 17D) as a vector. In this vaccine, two envelope proteins (prM-E) of YF 17D virus were exchanged for the corresponding genes of JE virus, with additional attenuating mutations incorporated into the JE gene inserts. Similar vaccines have been constructed by inserting prM-E genes of dengue and West Nile into YF 17D virus and are in late stage clinical studies. The dengue vaccine is, however, more complex in that it requires a mixture of four live vectors each expressing one of the four dengue serotypes. This vaccine has been evaluated in multiple clinical trials. No significant safety concerns have been found. The Phase 3 trials met their endpoints in terms of overall reduction of confirmed dengue fever, and, most importantly a significant reduction in severe dengue and hospitalization due to dengue. However, based on results that have been published so far, efficacy in preventing serotype 2 infection is less than that for the other three serotypes. In the development of these chimeric vaccines, an important series of comparative studies of safety and efficacy were made using the parental YF 17D vaccine virus as a benchmark. In this paper, we use a standardized template describing the key characteristics of the novel flavivirus vaccine vectors, in comparison to the parental YF 17D vaccine. The template facilitates scientific discourse among key stakeholders by increasing the transparency and comparability of information. The Brighton Collaboration V3SWG template may also be useful as a guide to the evaluation of other recombinant viral vector vaccines. © 2014.


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.


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.


Zhou T.,U.S. National Institutes of Health | Zhu J.,U.S. National Institutes of Health | Wu X.,U.S. National Institutes of Health | Moquin S.,U.S. National Institutes of Health | And 33 more authors.
Immunity | Year: 2013

Antibodies of the VRC01 class neutralize HIV-1, arise in diverse HIV-1-infected donors, and are potential templates for an effective HIV-1 vaccine. However, the stochastic processes that generate repertoires in each individual of 1012 antibodies make elicitation of specific antibodies uncertain. Here we determine the ontogeny of the VRC01 class by crystallography and next-generation sequencing. Despite antibody-sequence differences exceeding 50%, antibody-gp120 cocrystal structures reveal VRC01-class recognition to be remarkably similar. B cell transcripts indicate that VRC01-class antibodies require few specific genetic elements, suggesting that naive-B cells with VRC01-class features are generated regularly by recombination. Virtually all of these fail to mature, however, with only a few-likely one-ancestor B cell expanding to form a VRC01-class lineage in each donor. Developmental similarities in multiple donors thus reveal the generation of VRC01-class antibodies to be reproducible in principle, thereby providing a framework for attempts to elicit similar antibodies in the general population. © 2013 Elsevier Inc.


PubMed | University of Leicester, Emory University, Public Health Agency of Canada, International AIDS Vaccine Initiative IAVI and Columbia University
Type: Journal Article | Journal: Annals of human genetics | Year: 2017

Common single-nucleotide variation in the host accounts for 25% of the variability in the plasma levels of HIV during the clinical latency stage (viral load set point). However, the role of rare variants and copy number variants remains relatively unexplored. Previous work has suggested copy number variation of a cluster of -defensin genes affects HIV load in treatment-nave sub-Saharan Africans and rate of response to antiretroviral treatment. Here we analyse a total of 1827 individuals from two cohorts of HIV-infected individuals from Europe and sub-Saharan Africa to investigate the role of -defensin copy number variation on HIV load at set point. We find no evidence for association of copy number with viral load. We also compare distribution of -defensin copy number between European cases and controls and find no differences, arguing against a role of -defensin copy number in HIV acquisition. Taken together, our data argue against an effect of copy number variation of the -defensin region in the spontaneous control of HIV infection.


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.

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