The ability to induce antibodies that neutralize (nAb) circulating HIV-1 strains will be critical for a vaccine to exhibit optimal protective efficacy aganst HIV-1. To define the epitopes that can stimulate these responses, monoclonal antibodies (mAb) with broad and potent neutralization capacity have been recovered from a few chronically infected individuals that exhibited superior plasma nAb, but the viral and host B cell events that preceded this broad and potent neutralization phenotype have not been defined. Samples from early infection have not been available from these broadly neutralizing individuals, so questions about how nAb breadth developed cannot yet be answered. Here we identified 5 subtype A and C HIV-1 infected seroconvertors, out of 17, who developed relatively potent cross-clade nAb breadth at ~3 years post-infection. This proposal will investigate how and why nAb breadth developed in these individuals, but not in others who had low or undetectable levels of breadth. Our Preliminary Data suggest that there are fundamental virologic and immune differences between these two patient populations that could explain why early nAb are strain-specific, but later nAb go on to develop heterologous breadth in a subset of subjects. This focus on early infection is consistent with the observation that nAb breadth is generally either present or absent by ~3 years post-infection. Furthermore, our Preliminary Data show that autologous nAb from broad neutralizers in our panel targeted V1V2 and the CD4 binding site, both targets of mAbs with 'elite'heterologous neutralizing activity. We will utilize stored plasma and viable PBMC samples to define the initial nAb targets and viral escape pathways in 5 subjects with nAb breadth and 5 subjects without. We will recover mAbs from single B cell sorts using envelope (Env) gp140 B cell probes and PBMC samples collected at two early time points, and ~3 years post-infection, from these 10 subjects. The mAbs will be characterized genetically and functionally, and a representative subset, including those with breadth, will also be crystallized. To our knowledge, this type of comparative investigation into the early viral and immune determinants of neutralization breadth has not been performed. The proposed aims also provide a strong likelihood of recovering and characterizing broadly neutralizing mAbs that could represent early versions of those isolated from chronic infection. Our hypothesis is that the initil targeting of certain nAb epitopes, such as the CD4 binding site or V1V2, combined with the subsequent influence of escape pathways, leads to the development of nAb breadth in a subset of HIV-1 infected individuals. Specifically, the aims are to (i) Identify the initial neutralizing antibody target and define the viral escape pathways in 5 recently infected subjects who developed heterologous neutralization breadth and 5 subjects that lack breadth and (ii) Determine the genotypic, functional, and structural characteristics of early mAbs that are strain-specific and those that have acquired autologous or heterologous neutralization breadth.

Public Health Relevance

It is a widely held view in the HIV-1 research community that induction of broadly neutralizing antibodies by a vaccine could enhance protective efficacy;however, it is not known how to induce this type of antibody response by immunization. We will combine analyses of viral evolution and autologous monoclonal antibodies in early HIV-1 infection to understand how and why neutralization breadth developed in some subjects, but not others. Our investigations will be among the first to define the early determinants of neutralization breadth, and will lead to the development of envelope immunogen panels that exploit the virus's own immune evasion tactics to elicit neutralization breadth via immunization.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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AIDS Immunology and Pathogenesis Study Section (AIP)
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Sharma, Opendra K
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Emory University
Schools of Medicine
United States
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Kasturi, Sudhir Pai; Kozlowski, Pamela A; Nakaya, Helder I et al. (2017) Adjuvanting a Simian Immunodeficiency Virus Vaccine with Toll-Like Receptor Ligands Encapsulated in Nanoparticles Induces Persistent Antibody Responses and Enhanced Protection in TRIM5? Restrictive Macaques. J Virol 91:
Smith, S Abigail; Kilgore, Katie M; Kasturi, Sudhir Pai et al. (2016) Signatures in Simian Immunodeficiency Virus SIVsmE660 Envelope gp120 Are Associated with Mucosal Transmission but Not Vaccination Breakthrough in Rhesus Macaques. J Virol 90:1880-7
Cartwright, Emily K; Spicer, Lori; Smith, S Abigail et al. (2016) CD8(+) Lymphocytes Are Required for Maintaining Viral Suppression in SIV-Infected Macaques Treated with Short-Term Antiretroviral Therapy. Immunity 45:656-668
Gu, Linlin; Krendelchtchikova, Valentina; Krendelchtchikov, Alexandre et al. (2016) Adenoviral vectors elicit humoral immunity against variable loop 2 of clade C HIV-1 gp120 via ""Antigen Capsid-Incorporation"" strategy. Virology 487:75-84
Kilgore, Katie M; Murphy, Megan K; Burton, Samantha L et al. (2015) Characterization and Implementation of a Diverse Simian Immunodeficiency Virus SIVsm Envelope Panel in the Assessment of Neutralizing Antibody Breadth Elicited in Rhesus Macaques by Multimodal Vaccines Expressing the SIVmac239 Envelope. J Virol 89:8130-51
Musich, Thomas; O'Connell, Olivia; Gonzalez-Perez, Maria Paz et al. (2015) HIV-1 non-macrophage-tropic R5 envelope glycoproteins are not more tropic for entry into primary CD4+ T-cells than envelopes highly adapted for macrophages. Retrovirology 12:25
Yue, Ling; Pfafferott, Katja J; Baalwa, Joshua et al. (2015) Transmitted virus fitness and host T cell responses collectively define divergent infection outcomes in two HIV-1 recipients. PLoS Pathog 11:e1004565
Elliott, Sarah T C; Wetzel, Katherine S; Francella, Nicholas et al. (2015) Dualtropic CXCR6/CCR5 Simian Immunodeficiency Virus (SIV) Infection of Sooty Mangabey Primary Lymphocytes: Distinct Coreceptor Use in Natural versus Pathogenic Hosts of SIV. J Virol 89:9252-61
Smith, S Abigail; Derdeyn, Cynthia A (2015) A pathway to HIV-1 neutralization breadth. Nat Med 21:1246-7
Peters, Paul J; Gonzalez-Perez, Maria Paz; Musich, Thomas et al. (2015) Infection of ectocervical tissue and universal targeting of T-cells mediated by primary non-macrophage-tropic and highly macrophage-tropic HIV-1 R5 envelopes. Retrovirology 12:48

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