Research Article: Targeted Isolation of Antibodies Directed against Major Sites of SIV Env Vulnerability

Date Published: April 11, 2016

Publisher: Public Library of Science

Author(s): Rosemarie D. Mason, Hugh C. Welles, Cameron Adams, Bimal K. Chakrabarti, Jason Gorman, Tongqing Zhou, Richard Nguyen, Sijy O’Dell, Sabrina Lusvarghi, Carole A. Bewley, Hui Li, George M. Shaw, Zizhang Sheng, Lawrence Shapiro, Richard Wyatt, Peter D. Kwong, John R. Mascola, Mario Roederer, Alexandra Trkola.

http://doi.org/10.1371/journal.ppat.1005537

Abstract

The simian immunodeficiency virus (SIV) challenge model of lentiviral infection is often used as a model to human immunodeficiency virus type 1 (HIV-1) for studying vaccine mediated and immune correlates of protection. However, knowledge of the structure of the SIV envelope (Env) glycoprotein is limited, as is knowledge of binding specificity, function and potential efficacy of SIV antibody responses. In this study we describe the use of a competitive probe binding sort strategy as well as scaffolded probes for targeted isolation of SIV Env-specific monoclonal antibodies (mAbs). We isolated nearly 70 SIV-specific mAbs directed against major sites of SIV Env vulnerability analogous to broadly neutralizing antibody (bnAb) targets of HIV-1, namely, the CD4 binding site (CD4bs), CD4-induced (CD4i)-site, peptide epitopes in variable loops 1, 2 and 3 (V1, V2, V3) and potentially glycan targets of SIV Env. The range of SIV mAbs isolated includes those exhibiting varying degrees of neutralization breadth and potency as well as others that demonstrated binding but not neutralization. Several SIV mAbs displayed broad and potent neutralization of a diverse panel of 20 SIV viral isolates with some also neutralizing HIV-27312A. This extensive panel of SIV mAbs will facilitate more effective use of the SIV non-human primate (NHP) model for understanding the variables in development of a HIV vaccine or immunotherapy.

Partial Text

Generating protective antibody responses by vaccination is the ultimate goal of an effective HIV vaccine [1–4]. As such, a number of highly potent bnAbs targeting major sites of HIV-1 Env vulnerability such as the CD4bs [5–8], peptido-glycans of variable loops V1, V2 and V3 [9–12], the membrane-proximal external region (MPER) [13–15] and the gp41-gp120 interface [16, 17] have been isolated and examined for their potential impact on HIV vaccine design [18–20]. The specificity and effector functions of protective, non-neutralizing antibodies (pnnAbs) are likewise being scrutinized for their potential complementary role toward protection against HIV infection [21–24]. However, recent studies highlight the challenges to developing an effective HIV-1 vaccine [25–34] and suggest that a better understanding of SIV Env-specific antibody responses might complement and inform HIV vaccine design. This possibility is underscored by the protective effects of Env targeted antibodies elicited by adenovirus-vectored immunogens in SIV protection trials [35–38] and the surprising discovery that HIV-2, a derivative of SIVsmm, commonly elicits bNabs in natural human infection [39–41]. A better understanding of protective SIV Env-specific antibody responses may thus facilitate more effective use of the SIV challenge model to evaluate candidate vaccines and immunotherapies before proceeding to costly, time consuming and resource intensive human clinical trials.

The SIV NHP model for HIV-1 is useful for studying vaccine mediated and immune correlates of protection but little is known about binding or neutralizing epitopes on SIV Env. Our goal was to isolate and characterize SIV Env-specific mAbs that might facilitate effective use of this NHP model for understanding the variables in development of a HIV vaccine or immunotherapy. We demonstrate the use of a novel competitive probe binding strategy for the targeted isolation of SIV Env-specific mAbs from rhesus macaques and present a detailed assessment of nearly 70 SIV mAbs targeting the CD4bs, CD4i-site, CVNbs and V1, V2 and V3 loops of SIV Env. We characterized individual SIV mAbs with regard to immunoglobulin genetics, epitope specificity, peptide and protein binding as well as virus neutralization breadth and potency.

 

Source:

http://doi.org/10.1371/journal.ppat.1005537

 

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