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Rockville, MD, United States

Manocheewa S.,University of Washington | Swain J.V.,University of Washington | Lanxon-Cookson E.,University of Washington | Rolland M.,University of Washington | And 2 more authors.

The recently available x-ray crystal structure of HIV-1 capsid hexamers has provided insight into the molecular interactions crucial for the virus's mature capsid formation. Amino acid changes at these interaction points are likely to have a strong impact on capsid functionality and, hence, viral infectivity and replication fitness. To test this hypothesis, we introduced the most frequently observed single amino acid substitution at 30 sites: 12 at the capsid hexamerization interface and 18 at non-interface sites. Mutations at the interface sites were more likely to be lethal (Fisher's exact test p = 0.027) and had greater negative impact on viral replication fitness (Wilcoxon rank sum test p = 0.040). Among the interface mutations studied, those located in the cluster of hydrophobic contacts at NTD-NTD interface and those that disrupted NTD-CTD inter-domain helix capping hydrogen bonds were the most detrimental, indicating that these interactions are particularly important for maintaining capsid structure and/or function. These functionally constrained sites provide potential targets for novel HIV drug development and vaccine immunogen design. © 2013 Manocheewa et al. Source

Crawford K.W.,Johns Hopkins University | Crawford K.W.,Us Military Hiv Research Program | Ripin D.H.B.,Clinton Health Access Initiative | Levin A.D.,Clinton Health Access Initiative | And 2 more authors.
The Lancet Infectious Diseases

It is expected that funding limitations for worldwide HIV treatment and prevention in resource-limited settings will continue, and, because the need for treatment scale-up is urgent, the emphasis on value for money has become an increasing priority. The Conference on Antiretroviral Drug Optimization-a collaborative project between the Clinton Health Access Initiative, the Johns Hopkins University School of Medicine, and the Bill & Melinda Gates Foundation-brought together process chemists, clinical pharmacologists, pharmaceutical scientists, physicians, pharmacists, and regulatory specialists to explore strategies for the reduction of antiretroviral drug costs. The antiretroviral drugs discussed were prioritised for consideration on the basis of their market impact, and the objectives of the conference were framed as discussion questions generated to guide scientific assessment of potential strategies. These strategies included modifications to the synthesis of the active pharmaceutical ingredient (API) and use of cheaper sources of raw materials in synthesis of these ingredients. Innovations in product formulation could improve bioavailability thus needing less API. For several antiretroviral drugs, studies show efficacy is maintained at doses below the approved dose (eg, efavirenz, lopinavir plus ritonavir, atazanavir, and darunavir). Optimising pharmacoenhancement and extending shelf life are additional strategies. The conference highlighted a range of interventions; optimum cost savings could be achieved through combining approaches. © 2012 Elsevier Ltd. Source

Bergmann-Leitner E.S.,U.S. Army | Chaudhury S.,U.S. Army | Steers N.J.,Us Military Hiv Research Program | Sabato M.,Vital Probes, Inc. | And 4 more authors.

Vaccine development efforts will be guided by algorithms that predict immunogenic epitopes. Such prediction methods rely on classification-based algorithms that are trained against curated data sets of known B and T cell epitopes. It is unclear whether this empirical approach can be applied prospectively to predict epitopes associated with protective immunity for novel antigens. We present a comprehensive comparison of in silico B and T cell epitope predictions with in vivo validation using an previously uncharacterized malaria antigen, CelTOS. CelTOS has no known conserved structural elements with any known proteins, and thus is not represented in any epitope databases used to train prediction algorithms. This analysis represents a blind assessment of this approach in the context of a novel, immunologically relevant antigen. The limited accuracy of the tested algorithms to predict the in vivo immune responses emphasizes the need to improve their predictive capabilities for use as tools in vaccine design. Source

Burton D.R.,Scripps Research Institute | Burton D.R.,Massachusetts General Hospital | Ahmed R.,Emory University | Ahmed R.,Scripps Research Institute | And 31 more authors.
Cell Host and Microbe

Despite numerous attempts over many years to develop an HIV vaccine based on classical strategies, none has convincingly succeeded to date. A number of approaches are being pursued in the field, including building upon possible efficacy indicated by the recent RV144 clinical trial, which combined two HIV vaccines. Here, we argue for an approach based, in part, on understanding the HIV envelope spike and its interaction with broadly neutralizing antibodies (bnAbs) at the molecular level and using this understanding to design immunogens as possible vaccines. BnAbs can protect against virus challenge in animal models, and many such antibodies have been isolated recently. We further propose that studies focused on how best to provide T cell help to B cells that produce bnAbs are crucial for optimal immunization strategies. The synthesis of rational immunogen design and immunization strategies, together with iterative improvements, offers great promise for advancing toward an HIV vaccine. © 2012 Elsevier Inc. Source

Kim J.H.,U.S. Army | Excler J.-L.,U.S. Army | Excler J.-L.,Us Military Hiv Research Program | Michael N.L.,U.S. Army
Annual Review of Medicine

RV144 remains the only HIV-1 vaccine trial to demonstrate efficacy against HIV-1 acquisition. The prespecified analysis of immune correlates of risk showed that antibodies directed against the V1V2 region of gp120, in particular the IgG1 and IgG3 subclass mediating antibody-dependent cell-mediated cytotoxicity, seem to play a predominant role in protection against HIV-1 acquisition and that plasma envelope (Env)-specific IgA antibodies were directly correlated with risk. RV144 and recent nonhuman primate challenge studies suggest that Env is essential, and perhaps sufficient, to induce protective antibody responses against mucosal HIV-1 acquisition. Follow-up clinical trials are ongoing to further dissect the immune responses elicited by the RV144 ALVAC-HIV and AIDSVAX® B/E regimen. The study of gp120 Env immunogens and immune correlates of risk has resulted in the development of improved antigens. Whether the RV144 immune correlates of risk will generalize to other populations vaccinated with similar immunogens with different modes and intensity of transmission remains to be demonstrated. Efficacy trials are now planned in heterosexual populations in southern Africa and men who have sex with men in Thailand. © 2015 by Annual Reviews. Source

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