New prospects for the development of a vaccine against human immunodeficiency virus type 1. An overview

During the past few years, definite progress has been made in the field of human immunodeficiency virus type 1 (HIV-1) vaccines. Initial attempts usin g envelope gp120 or gp140 from T-cell line-adapted (TCLA) HIV-1 strains to vaccinate chimpanzees showed that neutralizing antibody-based immune respon ses were protective against challenge with homologous TCLA virus strains or strains with low replicative capacity, but these neutralizing antibodies r emained inactive when tested on primary HIV-1 isolates, casting doubts on t he efficacy of gp120-based vaccines in the natural setting. Development of a live attenuated simian immunodeficiency virus (SIV) vaccine was undertake n in the macaque model using whole live SIV bearing multiple deletions in t he nef, vpr and vpx genes. This vaccine provided remarkable protective effi cacy against wi Id-type SIV challenge, but the deletion mutants remain path ogenic, notably in neonate monkeys. Study of the mechanisms of protection i n the SIV model unraveled the importance of the T-cell responses, whether i n the form of cytotoxic T-lymphocyte (CTL) killing activity, or in that of antiviral factor secretion of cytokines, beta-chemokines and other unidenti fied antiviral factors by CD8(+) T-cells. Induction of such a response is b eing sought at this time using various live recombinant virus vaccines, eit her poxvirus or alphavirus vectors or DNA vectors, which can be combined to gether or with a gp120/gp140 boost in various prime-boost combination strat egies. New vectors include attenuated vaccinia virus NYVAC, modified vaccin ia strain Ankara (MVA), Semliki Forest virus, Venezuelan equine encephaliti s virus, and Salmonellas. Recent DNA prime-poxvirus boost combination regim ens have generated promising protection results against SIV or SIV/HIV (SHI V) challenge in macaque models. Emphasis is also put on the induction of a mucosal immune response, involving both a secretory IgA response and a muco sal CTL response which could constitute a 'first line of defence' in the va ccinated host. Finally, a totally novel vaccine approach based on the use o f Tat or Tat and Rev antigens has been shown to induce efficient protection from challenge with pathogenic SIV or SHIV in vaccinated macaques. The onl y vaccine in phase 3 clinical trials in human volunteers is a gp120-based v accine, AIDSVAX(TM). A prime-boost combination of a recombinant canarypoxvi rus and a subunit gp120 vaccine is in phase 2. Emphasis has been put recent ly on the necessity of testing prototype vaccines in developing countries u sing immunogens derived from local virus strains. Trial sites have thus bee n identified in Kenya, Uganda, Thailand and South Africa where phase I tria ls have begun or are expected to start presently. (C) 1999 Academie des sci ences/Editions scientifiques et medicales Elsevier SAS.