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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI058706-11A1
Application #
8541334
Study Section
AIDS Immunology and Pathogenesis Study Section (AIP)
Program Officer
Sharma, Opendra K
Project Start
2004-03-01
Project End
2017-03-31
Budget Start
2013-04-15
Budget End
2014-03-31
Support Year
11
Fiscal Year
2013
Total Cost
$802,340
Indirect Cost
$332,858
Name
Emory University
Department
Pathology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
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
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
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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
Smith, S Abigail; Derdeyn, Cynthia A (2015) A pathway to HIV-1 neutralization breadth. Nat Med 21:1246-7
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
Burton, Samantha L; Kilgore, Katie M; Smith, S Abigail et al. (2015) Breakthrough of SIV strain smE660 challenge in SIV strain mac239-vaccinated rhesus macaques despite potent autologous neutralizing antibody responses. Proc Natl Acad Sci U S A 112:10780-5

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