Tat-Vaccinated Macaques Do Not Control Simian Immunodeficiency Virus SIVmac239 Replication

Abstract

The regulatory proteins of human immunodeficiency virus may represent important vaccine targets. Here we assessed the role of Tat-specific cytotoxic T lymphocytes (CTL) in controlling pathogenic simian immunodeficiency virus SIVmac239 replication after using a DNA-prime, vaccinia virus Ankara-boost vaccine regimen. Despite the induction of Tat-specific CTL, there was no significant reduction in either peak or viral set point compared to that of controls.Recent reports have suggested that immune responses directed against the smaller regulatory proteins might be able to control human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) replication (7,8,10,17,19,21,22). We have recently shown that Mamu-A*01-positive rhesus macaques mount an immunodominant cytotoxic T-lymphocyte (CTL) response to an epitope in Tat (Tat 28-35 SL8) (1). This CTL response exerts significant selective pressure by eliminating wild-type virus replication by 4 weeks postinfection (p.i.) in the majority of Mamu-A*01-positive macaques. Additionally, the HIV Tat protein is highly variable, suggesting that CTL exert selective pressure on this region of the virus (12, 13). We therefore assessed whether vaccine-induced Tat-specific CTL might prove effective in controlling SIVmac239 replication.Induction of Tat 28-35 SL8-specific CTL by DNA/MVA. We employed a DNA-prime, attenuated vaccinia virus Ankara (MVA)-boost vaccination regimen to induce Tat-specific CTL in three Mamu-A*01-positive (animal 96016, 1975, and 97085) and one Mamu-A*01-negative (animal 97007) rhesus macaques. Four Mamu-A*01-positive macaques (animal 96111, 95086, 93057, and 85013) served as controls. Vaccinees were immunized three times with DNA at 6-week intervals as previously described (2). Two DNA vectors were employed. One vector encoded full-length SIVmac239 Tat, and the second vector encoded a single Mamu-A*01-restricted CTL epitope Tat 28-35 SL8 (STPESANL) inserted within the immunodominant region of hepatitis B core antigen. A gene gun was used to deliver gold particles coated with plasmid DNA into the epidermis. Each immunization consisted of a total of 32 g of DNA administered at eight skin sites over the abdominal and inguinal lymph nodes, as previously described (2) Following the final DNA immunization, tetramer analysis detected Tat 28-35 SL8-specific CTL in fresh peripheral blood mononuclear cells (PBMC) of two of the three Mamu-A*01-positive vaccinees (4.7 and 0.64% of all CD3/CD8 T lymphocytes) (Fig. 1A). Background tetramer staining in control animals was less than 0.08%. Surprisingly, in one of these animals (macaque 1975), the Tat 28-35 SL8 response reached levels in excess of 4%, a magnitude of CTL response not previously observed in rhesus macaques following DNA vaccination alone (2-5, 11).One month after receiving the last DNA immunization, rhesus macaques were then boosted intradermally with 5 ϫ 10 8

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

“…Recently, results have been reported showing that the immunization of rhesus monkeys with the Tat protein [67,68] was safe and immunogenic but failed to induce a significant control of viral replication following challenge with SIV or SHIV89.6P pathogenic viruses. However, several and key differences in the study design including dose and type of Tat (SIV and HIV), monkey species, adjuvant, dose and schedule of immunization, virus dose and route of challenge may account for these conflicting results.…”

Engineering RENTA, a DNA prime-MVA boost HIV vaccine tailored for Eastern and Central Africa

“…Despite initial successful reports, 31,32 subsequent studies failed to demonstrate protective efficacy of Tat-specific CTL only. 33,34 Nevertheless, simian immunodeficiency virus (SIV) Tat is an early protein against which responses impose a selective pressure on incoming virus, 35 and therefore it is an important component for a prophylactic vaccine. RT was included into the RENTA immunogen because it is a relatively conserved protein with a large number of identified CTL epitopes.…”

Comparative study of Tat vaccine regimens in Mauritian cynomolgus and Indian rhesus macaques: Influence of Mauritian MHC haplotypes on susceptibility/resistance to SHIV89.6P infection

“…Immunizations of rhesus macaques with Tat protein, vectored tat, Tat toxoid or Tat peptides have elicited no protection [22,23] or partial protection [24,25] against SIV mac239, SHIV 33, or SHIV 89.6P challenges, while immunizations of cynomolgus macaques with native Tat protein or DNA encoding tat have shown strong, long-term protective efficacy against SHIV 89.6P [26][27][28][29].These contrasting results might reflect species differences with regard to immunogenicity or host resistance factors, or differences in vaccine characteristics, vaccination routes, delivery systems, timing of immunizations or challenge protocols. Here we addressed these issues, eliminating the latter variables by conducting two identical immunization and challenge protocols in Indian rhesus and Mauritian cynomolgus macaques.…”