Analysis of immunoglobulin transcripts and hypermutation following SHIVAD8 infection and protein-plus-adjuvant immunization

Abstract

Developing predictive animal models to assess how candidate vaccines and infection influence the ontogenies of Envelope (Env)-specific antibodies is critical for the development of an HIV vaccine. Here we use two nonhuman primate models to compare the roles of antigen persistence, diversity and innate immunity. We perform longitudinal analyses of HIV Env-specific B-cell receptor responses to SHIVAD8 infection and Env protein vaccination with eight different adjuvants. A subset of the SHIVAD8-infected animals with higher viral loads and greater Env diversity show increased neutralization associated with increasing somatic hypermutation (SHM) levels over time. The use of adjuvants results in increased ELISA titres but does not affect the mean SHM levels or CDR H3 lengths. Our study shows how the ontogeny of Env-specific B cells can be tracked, and provides insights into the requirements for developing neutralizing antibodies that should facilitate translation to human vaccine studies.

Innate transcriptional effects by adjuvants on the magnitude, quality, and durability of HIV envelope responses in NHPs

“…Peripheral blood mononuclear cell, lymph node cell, plasma, and serum separation NHP blood processing was performed as previously reported, 60 and is described in the supplemental Methods.…”

Generation of a neutralization-resistant CCR5 tropic simian/human immunodeficiency virus (SHIV-MK38) molecular clone, a derivative of SHIV-89.6

“…In this study, we showed that the neutralization-resistant R5 tropic SHIV-MK38#818 molecular clone derived from SHIV-KS661 can cause stably persistent infection with high viral load via intrarectal inoculation despite the immune responses that occurred in the host. Currently, SHIV AD8 , categorized as a tier 2 neutralization-resistant phenotype, is widely used as a SHIV challenge virus for a variety of vaccine developments (Nishimura et al, 2010;Shingai et al, 2012Shingai et al, 2013;Gardner et al, 2015;Francica et al, 2015). However, use of SHIV AD8 as the only challenge virus is very risky for precise evaluation in vaccine candidates and anti-HIV-1 neutralizing antibodies.…”

Development of Broadly Neutralizing Antibodies and Their Mapping by Monomeric gp120 in Human Immunodeficiency Virus Type 1-Infected Humans and Simian-Human Immunodeficiency Virus SHIV SF162P3N -Infected Macaques

“…Human antibody sequences were analyzed using IMGT/V-QUEST (http://www.imgt.org/). Rhesus antibody sequences were analyzed using IgBLAST (47) to align them against a collection of rhesus germ line V genes (48,49) and to calculate hypermutation frequencies. The rhesus germ line V gene that gave the lowest hypermutation frequency for each query sequence was assigned and reported.…”