While we have demonstrated an association between the expression of the MHC class I molecule Mamu-A*01
and delayed disease progression in rhesus monkeys infected with SHIV-89.P, this protective effect was apparent in the setting of prior vaccination but not in that of immunologically naive animals. In the previous studies demonstrating an association between Mamu-A*01
expression and clinical protection in monkeys, immunologically naive monkeys were experimentally infected with the pathogenic virus SIVmac251, SIVsmE660, or SIVmac239 (15
). The Mamu-A*01+
monkeys demonstrated lower set point viral loads, a greater preservation of CD4+
T lymphocytes, or increased survival compared to Mamu-A*01−
monkeys. Our inability to demonstrate significant clinical differences between naive Mamu-A*01+
monkeys infected with SHIV-89.6P may be explained by the dramatic loss of CD4+
T lymphocytes that is seen within the first few weeks following SHIV-89.6P infection.
Studies of both humans and monkeys have demonstrated that robust CD4+
T-helper-cell responses generated early after infection can ameliorate disease progression, most likely due to the ability of these cells to potentiate antiviral CD8+
T-cell and B-cell immunity (11
). However, monkeys infected with SHIV-89.6P have been shown to develop a rapid and almost complete depletion of CXCR4-expressing naïve and central memory CD4+
T cells (19
). Unvaccinated monkeys that are infected with SHIV-89.6P may therefore lose the CD4+
T-cell help needed to mount efficient effector CTL responses, thereby eliminating the contribution of the Mamu-A*01
-associated CTL-associated protection. The inability of unvaccinated Mamu-A*01+
monkeys infected with SHIV-89.6P to develop robust Gag-specific cellular immune responses is consistent with this hypothesis (Fig. ). Whether there are qualitative differences in the CTL populations generated in unvaccinated and vaccinated monkeys following SHIV-89.6P infection remains to be elucidated.
A recent study demonstrated attenuated disease progression in unvaccinated Mamu-A*01+
monkeys infected with SHIV-89.6P (29
). Infected monkeys expressing Mamu-A*01
were reported to develop lower viral loads in lymphoid tissues and better preservation of lymph node architecture than monkeys that were Mamu-A*01−
. These particular parameters of disease were not assessed in the present report. While Mamu-A*01+
monkeys in that earlier study had longer survival times than Mamu-A*01−
monkeys, no significant differences in acute or chronic plasma viral RNA levels or preservation of peripheral blood CD4+
T lymphocytes were observed following infection between these two groups of animals. The discrepancy in the duration of survival of Mamu-A*01+
monkeys between the earlier and present study may reflect other contributing genetic factors.
Following SHIV-89.6P infection, robust cellular immune responses were observed for all monkeys that had previously received experimental vaccines. The populations of virus-specific T cells that expanded in the vaccinated monkeys following infection likely contributed to a partial containment of viral replication and an associated blunting of the CD4+ T-cell loss during the first days after infection. Interestingly, the peak Gag-specific cellular immune responses elicited in Mamu-A*01+ and Mamu-A*01− monkeys following both the DNA prime and recombinant poxvirus or rAd boost immunizations were of similar frequencies. However, in the DNA prime/rAd boost-immunized monkeys, but not in the DNA prime/recombinant poxvirus-boosted monkeys, higher-frequency Gag-specific responses were detected in Mamu-A*01+ than in Mamu-A*01− monkeys on the day of challenge, 16 weeks following the last immunization. Whether rAd and recombinant poxvirus vectors differ in their abilities to generate long-lived CTL populations when utilized as vaccine-boosting modalities warrants evaluation. Following viral challenge, the Mamu-A*01+ monkeys in both vaccine studies generated significantly higher-frequency Gag-specific T-cell responses. Most or all of this differential in T-cell responses could be attributed to p11C-specific CTL. The fact that cellular immune responses to 89.6P Env were of similar magnitudes in vaccinated Mamu-A*01+ and Mamu-A*01− monkeys following infection (Fig. ) further suggests that the dominant CTL response to the p11C epitope provided the incremental protection observed in Mamu-A*01+ monkeys. Even the immunodominant Gag-specific CTL responses elicited in immunized Mamu-A*02+ monkeys were lower in frequency than the Mamu-A*01−-restricted p11C responses following challenge. These data suggest that Mamu-A*01+ monkeys may have a significant advantage in generating effective populations of T cells that can then expand rapidly following reexposure to antigen.