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J Immunol. 2016 Apr 1;196(7):3064-78. doi: 10.4049/jimmunol.1500527. Epub 2016 Mar 4.

Achieving Potent Autologous Neutralizing Antibody Responses against Tier 2 HIV-1 Viruses by Strategic Selection of Envelope Immunogens.

Author information

1
Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006;
2
Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006; Military HIV Research Program, Silver Spring, MD 20889;
3
Vaccine and Gene Therapy Institute, Oregon Health and Science University, Portland, OR 97239;
4
Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006; Vaccine and Gene Therapy Institute, Oregon Health and Science University, Portland, OR 97239;
5
Seattle BioMed, Seattle, WA 98109;
6
Fred Hutchinson Cancer Research Center, Seattle, WA 98109;
7
Department of Surgery, Duke University Medical Center, Durham, NC 27708;
8
Department of Microbiology, University of Washington, Seattle, WA 98195; and.
9
Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006; Molecular Microbiology and Immunology, School of Medicine, Oregon Health & Science University, Portland, OR 97239 haigwoon@ohsu.edu.

Abstract

Advancement in immunogen selection and vaccine design that will rapidly elicit a protective Ab response is considered critical for HIV vaccine protective efficacy. Vaccine-elicited Ab responses must therefore have the capacity to prevent infection by neutralization-resistant phenotypes of transmitted/founder (T/F) viruses that establish infection in humans. Most vaccine candidates to date have been ineffective at generating Abs that neutralize T/F or early variants. In this study, we report that coimmunizing rhesus macaques with HIV-1 gp160 DNA and gp140 trimeric protein selected from native envelope gene sequences (envs) induced neutralizing Abs against Tier 2 autologous viruses expressing cognate envelope (Env). The Env immunogens were selected from envs emerging during the earliest stages of neutralization breadth developing within the first 2 years of infection in two clade B-infected human subjects. Moreover, the IgG responses in macaques emulated the targeting to specific regions of Env known to be associated with autologous and heterologous neutralizing Abs developed within the human subjects. Furthermore, we measured increasing affinity of macaque polyclonal IgG responses over the course of the immunization regimen that correlated with Tier 1 neutralization. In addition, we report firm correlations between Tier 2 autologous neutralization and Tier 1 heterologous neutralization, as well as overall TZM-bl breadth scores. Additionally, the activation of Env-specific follicular helper CD4 T cells in lymphocytes isolated from inguinal lymph nodes of vaccinated macaques correlated with Tier 2 autologous neutralization. These results demonstrate the potential for native Env derived from subjects at the time of neutralization broadening as effective HIV vaccine elements.

PMID:
26944928
PMCID:
PMC4797725
DOI:
10.4049/jimmunol.1500527
[Indexed for MEDLINE]
Free PMC Article

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