866 Tat-specific Cytotoxic T-lymphocytes Select for SIV Escape in Acutely Infected Rhesus Newborns M-C. Gauduin *1, D. O’Connor 2, E. Dodds2, J. D. Lifson3, D. I. Watkins 2, R. P. Johnson1 1New England Reg Primate Res Ctr, Southborough, MA; 2Wisconsin Reg Primate Res Ctr, Univ of Wisconsin, Madison; and 3Sci Applications Intl Corp Frederick, NCI-FCRDC, MD
Background: CD4+ T-cell depletion and progression to AIDS are more rapid in infants and children than in adults infected with HIV-1. Although the mechanisms responsible for accelerated disease progression in HIV-infected infants remain poorly understood, several reports have suggested that weak or absent HIV-1 specific CD8+ T-cell responses may play a role. However, little information is available on the generation of virus-specific CD8+ T-cell responses in infants early after infection or on the ability of CD8+ T-cell responses to select for escape mutations. We addressed these questions in neonatal rhesus macaques infected with SIVmac239.
Methods: Ten (10) newborn rhesus macaques, 7 of which expressed the MHC class I Mamu-A*01 allele, were inoculated IV with SIVmac239 at day 1 or 2 of life and were followed longitudinally at weeks 1, 2, 3, and 4 after infection, and then every 2 wks. Monitoring of virologic and immunologic parameters at each time point included: SIV plasma viral RNA, SIV-specific CD8+ T-cells using Mamu-A*01 MHC tetramers complexed with Gag181-189 (CM9) or Tat28-35 (SL8) peptides, flow cytometric analysis of circulating T-lymphocytes, and sequencing of newborn-derived virus determined by RT-PCR.
Results: Newborn macaques developed persistent mean levels of plasma viremia of 3.9 x 10^8 copies/ml that peaked between 5-9 days post SIVmac239 infection. Analysis of SIV-specific CD8+ responses in the Mamu-A*01+ animals revealed that significant levels of both Mamu-A*01/Gag181-189 and Tat28-35 tetramer-binding cells were detected in all newborns (mean values of 1% and 0.45%, respectively) and peaked between 3 to 4 wks after infection. Mutations in the Tat28-35 epitope have been observed in all 7 Mamu-A*01 neonates and likely represent escape mutations.
Conclusions: Taken together, these results suggest that SIV-specific CD8+ T-cells from SIV-infected newborns are able to exert sufficient selective pressure in vivo to drive the emergence of escape mutations.
