Factors Associated with Slow Disease Progression in Macaques Immunized with an Adenovirus-Simian Immunodeficiency Virus (SIV) Envelope Priming-gp120 Boosting Regimen and Challenged Vaginally with SIVmac251

Abstract

Rhesus macaques were immunized with a combination vaccine regimen consisting of adenovirus type 5 host range mutant-simian immunodeficiency virus envelope (Ad5hr-SIVenv) recombinant priming and boosting with native SIV gp120. Upon intravaginal challenge with SIVmac251, both persistently and transiently viremic animals were observed (. 71:8531-8541, 1997). Long-term follow-up of the persistently viremic immunized macaques, which displayed significantly reduced viral burdens during the first 18 weeks postchallenge compared to controls, has now shown that one of four became a slow progressor, clearing virus from plasma and remaining asymptomatic with stable CD4 counts for 134 weeks postchallenge. Reboosting of the transiently viremic macaques did not reactivate latent virus. Rechallenge with two sequential SIVmac251 intravaginal exposures again resulted in partial protection of one of two immunized macaques, manifested by viral clearance and stable CD4 counts. No single immune parameter was associated with partial protection. Development of a strong antibody response capable of neutralizing a primary SIVmac251 isolate together with SIV-specific cytotoxic T lymphocytes were implicated, while CD8 ؉ T-cell antiviral activity and mucosal immune responses were not associated with delayed disease progression. Our data show that even a third immunization with the same Ad5hr-SIVenv recombinant can elicit significant immune responses to the inserted gene product, suggesting that preexisting Ad antibodies may not preclude effective immunization. Further, the partial protection against a virulent, pathogenic SIV challenge observed in two of six macaques immunized with a vaccine regimen based solely on the viral envelope indicates that this vectored-vaccine approach has promise and that multicomponent vaccines based in the same system merit further investigation.

Molecular virology and immunology of HIV infection

“…107 Adenoviral and poliovirus vectors have been used to stimulate the mucosal immune system of macaques through nasal and oral immunization, respectively, with moderate protection against vaginal challenge in macaques and induction of systemic mucosal response. 108,109 Initial vaccine efforts focused on Env-derived peptides, which have been shown to induce an antibody response with poor viral neutralizing efficacy. 110 Other studies have provided evidence for the need to induce a specific CD8 + T-cell response.…”

Effects of intestinal survival surgery on systemic and mucosal immune responses in SIV‐infected rhesus macaques

“…Three multiparous female rhesus macaques used previously in a vaccine experiment were studied [3,4]. The macaques had received an immunization regimen including priming with Ad5hr-SIV env recombinant and boosting with SIV gp120 protein.…”

“…Following a single intravaginal exposure to SIV, macaques 354 and 358 became proviral DNA positive, but exhibited occult infection, never becoming viremic [4]. Sixty-four weeks after the first challenge, macaques 354 and 358 were again immunized with Ad5hr-SIVenv and SIV gp120 protein, and 2 weeks later were rechallenged intravaginally with two doses of SIV mac251 : once in the morning and once in the evening [3]. Macaque 354 became transiently viremic, thereafter exhibiting an undetectable viral burden and normal CD4 counts for the next year.…”

“…Use of an Ad5 host range mutant (Ad5hr) recombinant carrying the SIVsmH4 env gene [5] has allowed us to extend vaccine studies to the rhesus macaque system. There we have shown the combination vaccine approach of priming with Ad5hr-SIVenv and boosting with SIV gp120 elicited humoral, cellular, and mucosal immune responses, and resulted in a 2-log decrease in acute phase viral load following an intravaginal challenge with the pathogenic SIV mac251 isolate [3,4]. An advantage of the Ad-recombinant priming approach is that the viral vector replicates in the epithelium of the upper respiratory tract and the gut.…”

“…The immunization regimen of these macaques prior to the first intravaginal SIV mac251 challenge has been described[4]. Macaques 354 and 358 were reboosted with Ad-SIVenv recombinant and subunit protein 2 weeks prior to the second intravaginal challenge[3]. Times of the intravaginal challenges with SIV mac251 are marked with the open arrows.…”