Session 17Oral Abstract Presentations HIV/SIV Vaccine Studies Session Day and Time: Wednesday 10 am - 12:30 pm Presentation Time: 11:00 Room: Ballroom B
80 Enhanced Simian Immunodeficiency Virus Replication and Accelerated Progression to AIDS in Macaques Primed to Mount a CD4 But Not a CD8 T-cell Response to the Viral Envelope Protein S. I. Staprans*1, A. P. Barry2, G. Silvestri1, J. T. Safrit2, N. Kozyr2, H. McClure2, D. Montefiori3, J. L. Cohen4, M. B. Feinberg1 1Emory Univ Sch of Med, Atlanta, GA; 2Yerkes Natl Primate Res Ctr, Atlanta, GA; 3Duke Univ Med Ctr, Durham, NC; and 4Natl Inst of Allergy and Infectious Diseases, Bethesda, MD
Background: CD4 T-cells act as both key immune effector cells as well as important targets for HIV infection. Therefore, the relative balance of CD4 versus CD8 responses induced by candidate AIDS vaccines may be an important determinant of vaccine efficacy.
Methods: To characterize a live attenuated varicella zoster virus (VZV-OKA) as a recombinant AIDS vaccine, macaques were inoculated with VZV-OKA or an SIVsmH4 envelope-expressing recombinant, and then challenged with the heterologous SIVsmE660 strain. Vaccine-induced alterations in SIV replication were statistically analyzed with respect to correlations with diverse measures of cellular and humoral immune responses.
Results: The vaccine elicited protein-binding antibodies, but no neutralizing antibodies, and very limited CTL responses. In a dramatic and unexpected fashion, envelope-vaccinated animals manifested substantially higher levels of SIV replication and more rapid rates of CD4 depletion and disease progression compared to controls following SIV challenge. Enhanced SIV replication was directly correlated with vaccine-induced antibody titers present at the day of challenge, but infection-enhancing antibodies were not detected. Rather, enhanced peak and setpoint levels of SIV replication were directly correlated with increased CD4 T-cell proliferation in the env vaccinees 3 days post-SIV challenge (p < 0.036). This increased CD4 T-cell proliferation correlated significantly with ELISA antibody titers on the day of challenge (p = 0.009), suggesting that the proliferating lymphocytes represented SIV-specific memory CD4 T-cells.
Conclusions: Elicitation of an SIV env-specific CD4 memory response, in the absence of a strong CD8 response, can lead to enhanced SIV replication, presumably via the creation of greater numbers of virus-susceptible target cells. Although it is not clear whether our results are relevant to current HIV vaccine trials, they do raise the possibility that predominantly CD4-dependent antibody-inducing immunogens could prime hosts for enhanced HIV replication upon subsequent HIV exposure.