16th International AIDS Conference Toronto, Canada - August 13 - 18, 2006

DESIGNING A VACCINE STRATEGY: IMPLICATIONS OF VIRAL ESCAPE AND SHIV-SPECIFIC CD8 T CELLS AT TRANSMISSION AND DURING ACUTE INFECTION

Int Conf AIDS. 2006 Aug 13-18;16 Abstract No. WeAa0201

Fernandez C.S.¹, Smith M.Z.¹, Batten C.J.¹, De Rose R.¹, Reece J.¹, Rollman E.¹, Venturi V.², Davenport M.P.², Kent S.J.^1
1 University of Melbourne, Department of Microbiology and Immunology, Parkville, Australia, ² University of NSW, Department of Haematology, Prince of Wales Hospital, and Centre for Vascular Research, Kensington, New South Wales, Australia

BACKGROUND: CD8 T cells are important in the control of HIV/SHIV infection. Escape from virus-specific CD8 T cells can impart a fitness cost. We used vaccinated, MHC-matched Macaca nemestrina (pigtail macaques) to study the relationship between SIV Gag_164-172 KP9-specific CD8 T cells with escape at KP9.

METHODS: Ten of 14 Mane-A*10+ macaques enrolled in the study were vaccinated for KP9-specific CD8 T cells. All 14 macaques were challenged with an escape mutant (EM) strain of SHIVmn229 consisting of 91% KP9 (KK165RFGAEVVP) EM virus. Plasma SHIV was cloned and sequenced across KP9 at closely spaced time-points following challenge. An MHC Class I tetramer (Mane-A*10/KP9) was used to detect KP9-specific CD8 T cells.

RESULTS: Variable levels of transient reversion to wild-type (WT) KP9 sequence followed by re-escape were observed during acute infection. Reversion to WT KP9 at day 10, 13, and 20 post-challenge correlated inversely with KP9-specific T cells present at virus exposure (r<–0.68, p<0.01, Spearman rank test). Expansion of KP9-specific T cells 7 days after challenge also inversely correlated with reversion to WT KP9 sequence at day 10 and day 13 (p<0.01).

The reversion to WT also influenced viremia. The proportion of KP9 WT virus sequence at the peak of viral load inversely correlated with the timing of that peak (p=0.03) since the fitter WT virus results in faster viral replication and an earlier peak in viral load. The proportion of WT virus at the peak viral load also correlated with the set point viral load at day 42 (p=0.02).

CONCLUSIONS: Effector T cells present at transmission and capable of rapid expansion are vital for the prevention of reversion to wild-type and control of HIV/SHIV viremia.

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2006-08-13
WeAa0201

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