Effect of CD8 ⁺ Lymphocyte Depletion on Virus Containment after Simian Immunodeficiency Virus SIVmac251 Challenge of Live Attenuated SIVmac239Δ3-Vaccinated Rhesus Macaques

Abstract

Although live attenuated vaccines can provide potent protection against simian immunodeficiency virus (SIV) and simian-human immunodeficiency virus challenges, the specific immune responses that confer this protection have not been determined. To test whether cellular immune responses mediated by CD8؉ lymphocytes contribute to this vaccine-induced protection, we depleted rhesus macaques vaccinated with the live attenuated virus SIVmac239⌬3 of CD8 ؉ lymphocytes and then challenged them with SIVmac251 by the intravenous route. While vaccination did not prevent infection with the pathogenic challenge virus, the postchallenge levels of virus in the plasmas of vaccinated control animals were significantly lower than those for unvaccinated animals. The depletion of CD8 ؉ lymphocytes at the time of challenge resulted in virus levels in the plasma that were intermediate between those of the vaccinated and unvaccinated controls, suggesting that CD8؉ cell-mediated immune responses contributed to protection. Interestingly, at the time of challenge, animals expressing the Mamu-A*01 major histocompatibility complex class I allele showed significantly higher frequencies of SIV-specific CD8 ؉ T-cell responses and lower neutralizing antibody titers than those in Mamu-A*01 ؊ animals. Consistent with these findings, the depletion of CD8 ؉ lymphocytes abrogated vaccineinduced protection, as judged by the peak postchallenge viremia, to a greater extent in Mamu-A*01 ؉ than in Mamu-A*01 ؊ animals. The partial control of postchallenge viremia after CD8 ؉ lymphocyte depletion suggests that both humoral and cellular immune responses induced by live attenuated SIV vaccines can contribute to protection against a pathogenic challenge and that the relative contribution of each of these responses to protection may be genetically determined.Several unique biological features render human immunodeficiency virus (HIV) infection an especially challenging infection to prevent by vaccination (7,12,34). The development of an AIDS vaccine is further hindered by a lack of information on the types of immune responses that a vaccine should elicit in order to block or limit HIV infection (25). Both clinical observations of HIV-infected humans and experimental data from nonhuman primate models have indicated that antibodies induced by currently available immunogens are unlikely to elicit broadly protective immunity (6, 7). The temporal concordance of emerging virus-specific responses by CD8 ϩ T cells with declining viremia during primary HIV-1 infection (26), together with observations in nonhuman primates demonstrating that the experimental depletion of CD8 ϩ lymphocytes results in striking increases in virus levels (21,45), suggests that the induction of virus-specific cytotoxic T lymphocyte (CTL) responses should be a key objective of vaccine development strategies. However, vaccine approaches that elicit high-frequency virus-specific CTL responses have proven incapable of

Emergence of Simian Immunodeficiency Virus-Specific Cytotoxic CD4+ T Cells and Increased Humoral Responses Correlate with Control of Rebounding Viremia in CD8-Depleted Macaques Infected with Rev-Independent Live-Attenuated Simian Immunodeficiency Virus

“…In accordance with this observation, the animals in our study were 6.7 y of age, which is most likely responsible for the observed long-term effect of CD8 depletion obtained despite a single Ab treatment. Only macaque 31469 showed a substantial recovery of the CD8 + T cell population in the blood, concomitant with control of viremia, similar to data reported by others (28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40). Importantly, despite the observed longterm CD8 + depletion, rapid control of viremia was observed in all the animals, suggesting that additional mechanisms, independent of CD8 + T cells, were responsible for this phenomenon.…”

“…For instance, rapid viral rebound was reported in animals infected with SIVmac239Dnef (38), but not in macaques infected with SIVmac239D3 (34), suggesting lower chronic viremia in the latter, which could not be reactivated even in the absence of CD8 + cells. It was further found that depletion of CD8 + cells on the day of SIVmac251 challenge resulted in impaired control of the challenge virus as compared with non-CD8 + -depleted LASIV-infected controls (34) and resulted in higher viremia than in nondepleted macaques, but lower (100-fold) viremia than in naive monkeys, suggesting that significant viral control is also mediated by mechanisms other than CD8 + cells. TheRev-independentLASIVstrainsusedinthisstudy producedall the SIV proteins found in the parental SIVmac239 molecular clone, except Rev, or except Rev and Nef (11,13).…”

“…The importance of CD8 + responses in the control of SIV infection has been elegantly demonstrated by systemic depletion of macaque CD8 + cells after injection of a cytotoxic anti-CD8 mAb (28)(29)(30)(31)(32)(33)(34)(35)(36)(37). In these studies, transient depletion of CD8 + cells resulted in rapid rebound of viremia, which was attributed to the loss of viral control mediated by SIV-specific CD8 + CTL responses, a conclusion that was reinforced by the observation that rebounding virus control occurred simultaneously with the recovery of the CD8 + T cell population.…”

“…+ cell depletion in macaques infected with live-attenuated or avirulent strains of SIV has also been performed (34,(38)(39)(40). The outcomes of these depletion studies were different depending on the strain of LASIV used for infection.…”

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

“…Therefore, there may be significant differences in the mechanism of protection between these models (40). However, when superinfection occurs before the onset of full protection, significant control of primary viremia is still observed (9,49,51).…”