Induction of neutralizing antibodies and gag-specific cellular immune responses to an R5 primary isolate of human immunodeficiency virus type 1 in rhesus macaques

The ability to generate antibodies that cross-neutralize diverse primary is olates 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 focuse d 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 immu nogenicity of noninfectious virus-like particles (VI;P) consisting of Gag, Pro (protease), and Env from R5 primary isolate HIV-1(Bx08). Immunogens wer e delivered to rhesus macaques in the form of either purified VLP, recombin ant DNA and canarypox (ALVAC) vectors engineered to express VLP, or a combi nation of these products. Seroconversion to Gag and Pro was detected in all of the immunized animals. Antibodies that could neutralize HIV-1(Bx08) wer e detected in animals that received (i) coinoculations with DNA(Bx08) and V LPBx08 (ii) DNA(Bx08) followed by ALVAC(Bx08) boosting, and (iii) VLPBx08 a lone. The neutralizing antibodies were highly strain specific despite the f act that they did not appear to be directed to linear epitopes in the V3 lo op. Virus-specific cellular immune responses also were generated, as judged by the presence of Gag-specific gamma interferon (IFN-gamma)-producing cel ls. These cellular immune responses required the inclusion of DNA(Bx08) in the immunization modality, since few or no IFN-gamma -producing cells were detected in animals that received either VLPBx08 or ALVAC(Bx08) alone. The results demonstrate the feasibility of generating neutralizing antibodies a nd cellular immune responses that target an R5 primary HIV-1 isolate by vac cination in primates.