Induction of Neutralizing Antibodies and Gag-Specific Cellular Immune Responses to an R5 Primary Isolate of Human Immunodeficiency Virus Type 1 in Rhesus Macaques

Abstract

The ability to generate antibodies that cross-neutralize diverse primary isolates is an important goal for human immunodeficiency virus type 1 (HIV-1) vaccine development. Most of the candidate HIV-1 vaccines tested in humans and nonhuman primates have failed in this regard. Past efforts have focused almost entirely on the envelope glycoproteins of a small number of T-cell line-adapted strains of the virus as immunogens. Here we assessed the immunogenicity of noninfectious virus-like particles (VLP) consisting of Gag, Pro (protease), and Env from R5 primary isolate HIV-1_Bx08. Immunogens were delivered to rhesus macaques in the form of either purified VLP, recombinant DNA and canarypox (ALVAC) vectors engineered to express VLP, or a combination of these products. Seroconversion to Gag and Pro was detected in all of the immunized animals. Antibodies that could neutralize HIV-1_Bx08were detected in animals that received (i) coinoculations with DNA_Bx08and VLP_Bx08, (ii) DNA_Bx08followed by ALVAC_Bx08boosting, and (iii) VLP_Bx08alone. The neutralizing antibodies were highly strain specific despite the fact that they did not appear to be directed to linear epitopes in the V3 loop. Virus-specific cellular immune responses also were generated, as judged by the presence of Gag-specific gamma interferon (IFN-γ)-producing cells. These cellular immune responses required the inclusion of DNA_Bx08in the immunization modality, since few or no IFN-γ-producing cells were detected in animals that received either VLP_Bx08or ALVAC_Bx08alone. The results demonstrate the feasibility of generating neutralizing antibodies and cellular immune responses that target an R5 primary HIV-1 isolate by vaccination in primates.