Limited Breadth of the Protective Immunity Elicited by Simian Immunodeficiency Virus SIVmne gp160 Vaccines in a Combination Immunization Regimen

Abstract

We previously reported that immunization with recombinant simian immunodeficiency virus SIVmne envelope (gp160) vaccines protected macaques against an intravenous challenge by the cloned homologous virus, E11S. In this study, we confirmed this observation and found that the vaccines were effective not only against virus grown on human T-cell lines but also against virus grown on macaque peripheral blood mononuclear cells (PBMC). The breadth of protection, however, was limited. In three experiments, 3 of 10 animals challenged with the parental uncloned SIVmne were completely protected. Of the remaining animals, three were transiently virus positive and four were persistently positive after challenge, as were 10 nonimmunized control animals. Protection was not correlated with levels of serum-neutralizing antibodies against the homologous SIVmne or a related virus, SIVmac251. To gain further insight into the protective mechanism, we analyzed nucleotide sequences in the envelope region of the uncloned challenge virus and compared them with those present in the PBMC of infected animals. The majority (85%) of the uncloned challenge virus was homologous to the molecular clone from which the vaccines were made (E11S type). The remaining 15% contained conserved changes in the V1 region (variant types). Control animals infected with this uncloned virus had different proportions of the two genotypes, whereas three of four immunized but persistently infected animals had >99% of the variant types early after infection. These results indicate that the protective immunity elicited by recombinant gp160 vaccines is restricted primarily to the homologous virus and suggest the possibility that immune responses directed to the V1 region of the envelope protein play a role in protection.

Immunogenicity and protective efficacy of Gag/Pol/Env vaccines derived from temporal isolates of SIVmne against cognate virus challenge

“…Our observation that CL8 vaccines protected against homologous CL8 challenge is consistent with our previous findings [13,[31][32][33], although different challenge viruses and animal species were used (molecular clone and pig-tailed macaques in the current study vs. biological clone E11S and cynomolgus macaques in previous ones). Also in line with our previous observation [31,32] is the finding that CL8 vaccines failed to protect against a highly virulent virus 170. However, protective efficacy of the CL8 vaccines was not restricted to the minimally pathogenic homologous virus, as protection and substantial reduction of viral load was achieved in CL8-immunized macaques challenged by the 170/8 chimera, infection by which resulted in high and persistent viremia accompanied by progressive and irreversible CD4 + T cells loss.…”

Induction of potent local cellular immunity with low dose X4 SHIVSF33A vaginal exposure

“…Occult or silent infection, characterized by an undetectable antibody response and the ability to isolate or amplify virus from PBMC obtained at only a few time points, has also been reported after experimental simian immunodeficiency virus (SIV) challenge, a model commonly used for studying HIV-1 transmission and pathogenesis. Such infections occur following inoculation of non-human primates with low doses of virus, and are more frequently associated with mucosal (intravaginal, intrarectal or oral) (Miller et al, 1994;Pauza et al, 1993;Trivedi et al, 1996;Van Rompay et al, 1998) than intravenous routes of challenge (Petry et al, 1997;Polacino et al, 1999). Similar to findings in HIV-1 infection, virus-specific T cell immunity, such as proliferation and IFN-γ responses, has been detected (Ma et al, 2004;McChesney et al, 1998;McDermott et al, 2004;Murphey-Corb et al, 1999;Petry et al, 1997).…”

Molecular virology and immunology of HIV infection

“…111,112 A vaccine protocol involving priming with SIV-env gene in vaccinia and a boost with Env protein protected completely against SIV infection; however, the protection was only for a homologous viral challenge-a fact that underscores the importance of using epitopes that are shared by most strains. 113 A different protocol with Gag-pol genes in a modified vaccinia virus showed that the induction of cytotoxic Tcell Gag epitopes correlated with SIV viremia reduction, similar to the association of CD8 + T cells and disease progression found in human beings. 50,114 To date, few HIV vaccines have been tested in phase I trials and demonstrated to be safe, though only modest levels of HIV-specific CD4 + and CD8 + T-cell responses have been elicited.…”