Session 17Oral Abstract Presentations HIV/SIV Vaccine Studies Session Day and Time: Wednesday 10 am - 12:30 pm Presentation Time: 10:00 Room: Ballroom B
76 High Frequency of Stereotypic Viral Escape from Dominant SIV Epitope-specific CTL in DNA-vaccinated Rhesus Monkeys D. H. Barouch*1, J. Kunstman2, J. Glowczwskie2, K. Kunstman2, M. Egan1, S. Santra1, F. Peyerl1, M. Kuroda1, J. Schmitz1, S. M. Wolinsky2, N. L. Letvin1 1Harvard Med Sch, Beth Israel Deaconess Med Ctr, Boston, MA and 2Northwestern Univ, Chicago, IL
Background: We have previously shown that viral escape from CTL recognition resulted in AIDS vaccine failure in one vaccinated rhesus monkey infected with SHIV-89.6P. Here we show the high frequency and pattern of viral escape from immunodominant CTL responses in a cohort of DNA vaccinated rhesus monkeys following a heterologous SIV challenge.
Methods: Rhesus monkeys expressing the Mamu-A*01 class I allele were immunized with sham plasmid (n = 5) or SIVmac239 gag DNA vaccine (n = 4) and then challenged with SIVsmE660. Virus-specific T-lymphocyte responses, viral RNA levels, viral sequence evolution, CD4+ T-lymphocyte counts, and clinical disease progression were monitored for 3 years following challenge.
Results: The DNA vaccinated monkeys demonstrated initial effective control of the heterologous SIVsmE660 challenge. This initial control was then lost by serial breakthroughs of viral replication and subsequent clinical disease progression in 3 of 4 animals over a 3-yr follow-up period. Loss of immune control and increased levels of viral RNA were temporally correlated with a marked decline of CD8+ T-lymphocyte tetramer responses and the emergence of viral mutations in the two dominant Gag and Env CTL epitopes. These mutations resulted in viral escape from CTL recognition. One vaccinated animal exhibited viral escape from CTL and subsequent disease progression after more than 2 yrs of undetectable plasma viral RNA. Four (4) of 5 control animals also developed CTL escape mutations in these same two dominant Gag and Env epitopes.
Conclusions: The initial effective control of a heterologous SIV challenge by DNA vaccine-elicited CTL responses was lost over time as a result of a stereotypic pattern of viral escape from dominant SIV epitope-specific CTL. A bell-shaped relationship was observed between the time required for escape and the initial level of setpoint viral RNA. No escape occurred in animals with the lowest and highest levels of viral RNA, whereas rapid escape occurred in animals with moderate levels of viral RNA and ongoing immune selection pressure. The high frequency of viral escape from CTL suggests that this problem may prove to be a major challenge for CTL-based AIDS vaccine strategies.
