Cytotoxic T Lymphocyte–based Control of Simian Immunodeficiency Virus Replication in a Preclinical AIDS Vaccine Trial

Abstract

Recently, encouraging AIDS vaccine trials in macaques have implicated cytotoxic T lymphocytes (CTLs) in the control of the simian human immunodeficiency virus SHIV89.6P that induces acute CD4+ T cell depletion. However, none of these vaccine regimens have been successful in the containment of replication of the pathogenic simian immunodeficiency viruses (SIVs) that induce chronic disease progression. Indeed, it has remained unclear if vaccine-induced CTL can control SIV replication. Here, we show evidence suggesting that vaccine-induced CTLs control SIVmac239 replication in rhesus macaques. Eight macaques vaccinated with DNA-prime/Gag-expressing Sendai virus vector boost were challenged intravenously with SIVmac239. Five of the vaccinees controlled viral replication and had undetectable plasma viremia after 5 wk of infection. CTLs from all of these five macaques rapidly selected for escape mutations in Gag, indicating that vaccine-induced CTLs successfully contained replication of the challenge virus. Interestingly, analysis of the escape variant selected in three vaccinees that share a major histocompatibility complex class I haplotype revealed that the escape variant virus was at a replicative disadvantage compared with SIVmac239. These findings suggested that the vaccine-induced CTLs had “crippled” the challenge virus. Our results indicate that vaccine induction of highly effective CTLs can result in the containment of replication of a highly pathogenic immunodeficiency virus.

Understanding the Failure of CD8+T-Cell Vaccination against Simian/Human Immunodeficiency Virus

“…CD8 ϩ T cells are also known to be important in controlling simian immunodeficiency virus (SIV) and human immunodeficiency virus (HIV) infection because (i) the depletion of CD8 ϩ T cells during chronic SIV infection in monkeys increases the viral load (46,60,85), (ii) human HIV-positive patients who are heterozygous at class I HLA loci have slower rates of disease progression (18), and (iii) the virus accumulates mutations in CD8 ϩ T-cell epitopes (33,37,59). The various epitope-specific CD8 ϩ T-cell responses during chronic viral infection with HIV can amount to up to 10% of the total number of CD8 ϩ T cells (13).…”

HIV-189.6 Gag expressed from a replication competent HSV-1 vector elicits persistent cellular immune responses in mice

“…Predictive correlates of protection have not yet been established for CMI elicited by an HIV vaccine. However, HIV and/or SIV-specific CD8+ responses are associated with viral suppression in the course of natural infection and protection of immunized NHPs from advanced disease, following pathogenic retrovirus challenge [12][13][14][15][16][17]54]. As long as vaccines with neutralizing immunity remain elusive, the best hope for the field lies with the development of vaccines effective at reducing viral loads in the infected host.…”

“…HIV-specific CTL responses can recognize and kill HIV infected cells and are effective in controlling HIV-1 replication during the course of natural infection [7][8][9]. Vaccines which elicit these types of responses can also control the replication of pathogenic retroviruses and protect against the development of immunodeficiency and death in nonhuman primate (NHP) models [10][11][12][13][14][15][16][17][18][19]. The current mechanisms for induction of potent CTL mediated immunity include immunogen delivery by attenuated viral vectors, bacterial vectors, direct plasmid DNA injection, and co-delivery of vaccine adjuvants (reviewed in [20][21][22]).…”

Vaccine-based, long-term, stable control of simian/human immunodeficiency virus 89.6PD replication in rhesus macaques

“…In a model of X4-tropic simian/human immunodeficiency virus (SHIV) 89.6P or 89.6PD infection (Reimann et al, 1996;Lu et al, 1998), which causes rapid CD4 + T-cell depletion leading to an acute crash of the host immune system in macaques, several pre-clinical trials of prophylactic AIDS vaccines have successfully shown that efficient CTL induction results in control of virus replication and prevention of acute AIDS progression (Barouch et al, 2000;Amara et al, 2001;Matano et al, 2001;Rose et al, 2001;Shiver et al, 2002;Willey et al, 2003 We have developed a prophylactic AIDS vaccine using a DNA-prime/Gag-expressing Sendai virus (SeV-Gag) vector boost system and have shown its potential for efficient induction of Gag-specific CTL responses in Burmese rhesus macaques (Kano et al, 2002;Matano et al, 2004). In preclinical trials in an acute AIDS model, all of the macaques vaccinated with the DNA-prime/SeV-Gag vector boost system controlled SHIV89.6PD replication after challenge (Matano et al, 2001;Takeda et al, 2003).…”

“…Furthermore, a trial of the prophylactic DNA-prime/SeV-Gag boost vaccine showed control of SIVmac239 replication leading to undetectable set-point plasma viraemia in five out of eight vaccinees (referred to as SIV controllers), despite failure of virus control in the other three vaccinees (referred to as SIV non-controllers) (Matano et al, 2004). All of the SIV controllers showed rapid selection of viral CTL escape mutations, and analysis of the rhesus major histocompatibility complex (MHC) suggested that SIV control was associated with particular MHC haplotypes such as 90-120-Ia and 'elite' CTL responses specific for the MHC-restricted epitopes (Matano et al, 2004). Follow up of these SIV controllers revealed that some lost this control with accumulation of multiple viral CTL escape mutations (Kawada et al, 2006).…”