Simian Immunodeficiency Virus-Specific Cytotoxic T Lymphocytes and Protection Against Challenge in Rhesus Macaques Immunized with a Live Attenuated Simian Immunodeficiency Virus Vaccine

Abstract

In this study, we examined the role of simian immunodeficiency virus (SIV)-specific cytotoxic T lymphocytes (CTLs) in macaques immunized with an attenuated strain of simian immunodeficiency virus (SIVmac239Deltanef) in protection against pathogenic challenge with SIVmac251. Our results indicate that attenuated SIVmac239Deltanef can elicit specific CTL precursor cells (CTLp), but no correlation was observed between breadth or strength of CTLp response to structural proteins SIV-Env, -Gamg or -Pol (as measured by limiting dilution assay) and protection against infection. In one animal, we longitudinally followed the SIV-Gag-specific response to an MHC class I Mamu-A*01-restricted epitope p11C, C-M using a tetrameric MHC/peptide complex reagent. A low frequency of SIV p11C, C-M peptide-specific tetramer-reactive cells was present at the time of challenge but could be expanded in vitro. Surprisingly, the low level of Mamu-A*01/p11C, C-M-specific CTLs induced through attenuated SIVmac239Deltanef vaccination increased in the absence of detectable SIVmac251 or SIVmac239Deltanef proviral DNA. Overall, our results suggest that protection against infection in this model can be achieved through more than one mechanism, with SIV-specific CTLs being important in controlling SIVmac239Deltanef viral replication postchallenge.

High Attenuation and Immunogenicity of a Simian Immunodeficiency Virus Expressing a Proteolysis-resistant Inhibitor of NF-κB

“…No significant difference was observed in the number of IFN-␥ ϩ -CD8 ϩ T cells between the two groups of animals (p ϭ 0.89 by the Wilcoxon ranksum test). Consistent with previous reports in SIV-infected monkeys (34) and HIV-1-infected subjects (35), no statistically significant correlation was observed between the ability to control viremia and the levels of p11C Gag-specific T lymphocytes (p ϭ 0.11 by the Spearman rank test) or IFN-␥ ϩ -CD8 ϩ T cells (p ϭ 0.14 by the Spearman rank test).…”

CD8 + Lymphocytes Do Not Mediate Protection against Acute Superinfection 20 Days after Vaccination with a Live Attenuated Simian Immunodeficiency Virus

“…An unambiguous correlate of protection against superinfection has so far evaded identification. Cytotoxic T lymphocytes (CTL), virus neutralizing antibodies, innate immunity, and retroviral interference have all been reported as potential mechanisms of protection against superinfection conferred by inoculation with live attenuated SIV (2,24,32,37,50,54,59). Here we have evaluated the role of CD8 ϩ lymphocytes and, thereby, CD8 ϩ CTL in mediating protection against acute superinfection conferred by inoculation with live attenuated SIV.…”

“…Inoculation with live attenuated SIV generates significant SIV-specific CD8 ϩ CTL responses (16,25,32,56). The appearance of SIV-specific CD8 ϩ CTL responses during primary SIV infection coincides with clearance of plasma viremia and suppression of viral replication (41).…”

“…In addition, an inverse correlation has been reported between the precursor frequency of SIV-specific CD8 ϩ CTL responses elicited by certain vaccine approaches and virus load following challenge (20,55). Although several groups have reported a correlation between SIV-specific CD8 ϩ CTL responses in live attenuated SIV vaccinees and protection against superinfection with wild-type SIV (24)(25)(26)56), other groups have failed to corroborate such observations and dispute a role for SIVspecific CD8 ϩ CTL in mediating protection (1,32,44,50,52).…”

Using death to one's advantage: HIV modulation of apoptosis

“…Several vaccine approaches for limiting HIV infection are currently underway and many include a Tat component in the vaccine. Vaccines in clinical and pre-clinical trials have included: (1) Tat expression vectors (both soluble and endogenous forms of Tat); 75,76 (2) as part of a multiple DNA expression plasmids encoding for several HIV genes; 77 (3) in live attenuated HIV vaccines; [78][79][80][81][82][83] and (4) in virus-like particles (VLPs) both in DNA expression vectors and as purified protein. 84 Therefore, a better comprehension of Tat-induced apoptosis and immunosuppressive mechanisms are important for new vaccine designs.…”