SHIV89.6P pathogenicity in cynomolgus monkeys and control of viral replication and disease onset by human immunodeficiency virus type 1 Tat vaccine

Abstract

The Tat protein of human immunodeficiency virus (HIV) is produced very early after infection, plays a key role in the virus life cycle and in acquired immunodeficiency syndrome (AIDS) pathogenesis, is immunogenic and well conserved among all virus clades. Notably, a Tat-specific immune response correlates with non-progression to AIDS. Here, we show that a vaccine based on the Tat protein of HIV blocks primary infection with the simian/human immunodeficiency virus (SHIV)89.6P and prevents the CD4 T cell decline and disease onset in cynomolgus monkeys. No signs of virus replication were found in five out of seven vaccinated macaques for almost 1 year of follow-up. Since the inoculated virus (derived from rhesus or from cynomolgus macaques) is shown to be highly pathogenic in cynomolgus macaques, the results indicate efficacy of Tat vaccination in protection against highly pathogenic virus challenge. Finally, the studies of the Tat-specific immunological responses indicate a correlation of protection with a cytotoxic T cell response. Thus, a Tat-based vaccine is a promising candidate for preventive and therapeutic vaccination in humans.

Long-term protection against SHIV89.6P replication in HIV-1 Tat vaccinated cynomolgus monkeys

“…At each time-point bleedings were performed for routine blood chemistry tests and immunological determinations. The vaccination protocols and schedules have been reported elsewhere [34][35][36]. After 14-18 weeks from the last boost, all animals were challenged intravenously (i.v.)…”

“…The virus stock used was derived from a cynomolgus macaque inoculated with the original SHIV89.6P from rhesus monkeys [42]. Both the original viral stock grown in a rhesus macaque and the one grown in a cynomolgus monkey were highly pathogenic in M. fascicularis [34,35]. The pathogenicity in cynomolgus monkeys of both virus stocks was confirmed by the progression to AIDS and death (within 46 weeks from the inoculum) of four out of six and four out of seven cynomolgus monkeys infected, respectively, with the rhesus-or cynos-derived viral stock [35].…”

“…Both the original viral stock grown in a rhesus macaque and the one grown in a cynomolgus monkey were highly pathogenic in M. fascicularis [34,35]. The pathogenicity in cynomolgus monkeys of both virus stocks was confirmed by the progression to AIDS and death (within 46 weeks from the inoculum) of four out of six and four out of seven cynomolgus monkeys infected, respectively, with the rhesus-or cynos-derived viral stock [35]. The two naive control animals, monkeys 2 and 12, included as additional control at the time of the challenge, were inoculated with a three-fold higher (28 MID 50 ) or three-fold lower (2.8 MID 50 ) viral inoculum, respectively [34][35][36].…”

“…Virus isolation and cytoviremia were performed by co-culturing CD8-depleted PBMCs with CEMx174 cells in the presence of phytohemoagglutinin (PHA, 2 g/ml) and recombinant human interleukin-2 (rhIL-2) (50 IU/ml), as already described [34][35][36].…”

“…Pre-clinical studies in mice and monkeys have shown that vaccination with a biologically active native HIV-1 Tat protein or with tat DNA is safe [34][35][36][37][38], elicits both humoral and cell-mediated Tat-specific immune responses [34][35][36][37][38], and, in cynomolgus monkeys, controls infection with the highly pathogenic SHIV89.6P virus, preventing CD4 T-cell decline and disease onset in the protected animals [34][35][36]. Similar results of protection were reported in the SIV model with viral vectors (Semliki Forest Virus and Modified Vaccinia Ankara Virus) expressing the SIV-Tat and -Rev genes [39].…”