HIV-1 Envelope Glycoproteins from Diverse Clades Differentiate Antibody Responses and Durability among Vaccinees.

Nicole L Yates,Sheetal Sawant,Punnee Pitisuttithum,Merlin L Robb,Peter Hraber,Georgia D Tomaras,Carmela Irene,Phillip W Berman,David C Montefiori,Barton F Haynes,Sorachai Nitayapan,Linda J Harris,Supachai Rerks-Ngarm,Abraham Pinter,Giuseppe Pantaleo,S Munir Alam,Xiaoying Shen,Allan C Decamp,Bette Korber ,Hua‐Xin Liao ,Susan Zolla‐Pazner ,James W Peacock

doi:10.1128/jvi.01843-17

Abstract

ABSTRACTInduction of broadly cross-reactive antiviral humoral responses with the capacity to target globally diverse circulating strains is a key goal for HIV-1 immunogen design. A major gap in the field is the identification of diverse HIV-1 envelope antigens to evaluate vaccine regimens for binding antibody breadth. In this study, we define unique antigen panels to map HIV-1 vaccine-elicited antibody breadth and durability. Diverse HIV-1 envelope glycoproteins were selected based on genetic and geographic diversity to cover the global epidemic, with a focus on sexually acquired transmitted/founder viruses with a tier 2 neutralization phenotype. Unique antigenicity was determined by nonredundancy (Spearman correlation), and antigens were clustered using partitioning around medoids (PAM) to identify antigen diversity. Cross-validation demonstrated that the PAM method was better than selection by reactivity and random selection. Analysis of vaccine-elicited V1V2 binding antibody in longitudinal samples from the RV144 clinical trial revealed the striking heterogeneity among individual vaccinees in maintaining durable responses. These data support the idea that a major goal for vaccine development is to improve antibody levels, breadth, and durability at the population level. Elucidating the level and durability of vaccine-elicited binding antibody breadth needed for protection is critical for the development of a globally efficacious HIV vaccine.IMPORTANCE The path toward an efficacious HIV-1 vaccine will require characterization of vaccine-induced immunity that can recognize and target the highly genetically diverse virus envelope glycoproteins. Antibodies that target the envelope glycoproteins, including diverse sequences within the first and second hypervariable regions (V1V2) of gp120, were identified as correlates of risk for the one partially efficacious HIV-1 vaccine. To build upon this discovery, we experimentally and computationally evaluated humoral responses to define envelope glycoproteins representative of the antigenic diversity of HIV globally. These diverse envelope antigens distinguished binding antibody breadth and durability among vaccine candidates, thus providing insights for advancing the most promising HIV-1 vaccine candidates.

Highlights

Induction of broadly cross-reactive antiviral humoral responses with the capacity to target globally diverse circulating strains is a key goal for HIV-1 immunogen design
Based on RV144 responses, all Env gp120 and gp140 proteins exhibit a highly significant ability to detect a vaccine-induced response compared to that of placebo; none of the antigens were excluded from consideration based on the requirement for detecting vaccine-elicited, Env-specific binding antibodies
The difference in magnitudes was significantly higher in the RV144 vaccine recipients than in the placebo recipients for all V1V2 antigens; none of the 42 V1V2 antigens were removed from consideration for down-selection based on that criterion

Summary

Introduction

Induction of broadly cross-reactive antiviral humoral responses with the capacity to target globally diverse circulating strains is a key goal for HIV-1 immunogen design. Antibodies that target the envelope glycoproteins, including diverse sequences within the first and second hypervariable regions (V1V2) of gp120, were identified as correlates of risk for the one partially efficacious HIV-1 vaccine. To build upon this discovery, we experimentally and computationally evaluated humoral responses to define envelope glycoproteins representative of the antigenic diversity of HIV globally. These diverse envelope antigens distinguished binding antibody breadth and durability among vaccine candidates, providing insights for advancing the most promising HIV-1 vaccine candidates. The diversity among HIV-1 isolates presents a challenge for vaccine candidates that aim to broadly target diverse circulating transmitted/founder (T/F) HIV-1 strains [17]

Methods

Results

Conclusion