Mechanisms of protection induced by live attenuated simian immunodeficiency virus

Self Cite

In order to test the hypothesis that CD8 ؉ cytotoxic T lymphocytes mediate protection against acute superinfection, we depleted >99% of CD8 ؉ lymphocytes in live attenuated simian immunodeficiency virus macC8 (SIVmacC8) vaccinees from the onset of vaccination, maintained that depletion for 20 days, and then challenged with pathogenic, wild-type SIVmacJ5. Vaccinees received 5 mg per kg of humanized anti-CD8 monoclonal antibody (MAb) 1 h before inoculation, followed by the same dose again on days 3, 7, 10, 13, and 17. On day 13, peripheral CD8 ؉ T lymphocytes were >99% depleted in three out of four anti-CD8 MAb-treated vaccinees. At this time attenuated SIVmacC8 viral RNA loads in anti-CD8 MAb-treated vaccinees were significantly higher than control vaccinees treated contemporaneously with nonspecific human immunoglobulin. Lymphoid tissue CD8 ؉ T lymphocyte depletion was >99% in three out of four anti-CD8 MAb-treated vaccinees on the day of wild-type SIVmacJ5 challenge. All four control vaccinees and three out of four anti-CD8 MAb-treated vaccinees were protected against detectable superinfection with wild-type SIVmacJ5. Although superinfection with wild-type SIVmacJ5 was detected at postmortem in a single anti-CD8 MAb-treated vaccinee, this did not correlate with the degree of preceding CD8 ؉ T lymphocyte depletion. Clearance of attenuated SIVmacC8 viremia coincided with recovery of normal CD8 ؉ T lymphocyte counts between days 48 and 76. These results support the view that cytotoxic T lymphocytes are important for host-mediated control of SIV primary viremia but do not indicate a central role in protection against acute superinfection conferred by inoculation with live attenuated SIV.

Section: Discussionmentioning

confidence: 99%

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

Stebbings¹,

Berry²,

Waldmann

et al. 2005

Self Cite

“…However, the passive transfer of serum or immunoglobulin from vaccinated animals has largely been unsuccessful at preventing infection (2,22). A variety of SIV-specific cellular immune responses have also been documented for monkeys vaccinated with live attenuated SIVs (15,16,23,36,48,49), and major histocompatibility complex (MHC) class I-restricted CTL responses have been correlated with protection against pathogenic virus challenges (23,40). However, the immune mechanisms responsible for this potent vaccine-induced protection remain largely inferred and have never been experimentally evaluated.…”

Section: Although Live Attenuated Vaccines Can Provide Potent Protectmentioning

confidence: 99%

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

Schmitz

Johnson

McClure

et al. 2005

114

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

“…These explanations range from viral interference to a robust vaccine-elicited immune response (19,43,45,47). We currently understand several aspects of live-attenuated vaccination with SIVmac239⌬nef.…”

mentioning

confidence: 99%

Extralymphoid CD8 ⁺ T Cells Resident in Tissue from Simian Immunodeficiency Virus SIVmac239Δnef-Vaccinated Macaques Suppress SIVmac239 Replication Ex Vivo

Greene

Lhost

Burwitz

et al. 2010

Live-attenuated vaccination with simian immunodeficiency virus (SIV) SIVmac239⌬nef is the most successful vaccine product tested to date in macaques. However, the mechanisms that explain the efficacy of this vaccine remain largely unknown. We utilized an ex vivo viral suppression assay to assess the quality of the immune response in SIVmac239⌬nef-immunized animals. Using major histocompatibility complex-matched Mauritian cynomolgus macaques, we did not detect SIV-specific functional immune responses in the blood by gamma interferon (IFN-␥) enzyme-linked immunospot assay at select time points; however, we found that lung CD8 ؉ T cells, unlike blood CD8 ؉ T cells, effectively suppress virus replication by up to 80%. These results suggest that SIVmac239⌬nef may be an effective vaccine because it elicits functional immunity at mucosal sites. Moreover, these results underscore the limitations of relying on immunological measurements from peripheral blood lymphocytes in studies of protective immunity to HIV/SIV.