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29 Mucosal AIDS Vaccine Reduces Disease and Viral Load in Gut Reservoir and Blood after Mucosal Infection of Macaques
I. M. Belyakov*1, Z. Hel1, B. Kelsall2, V. A. Kuznetsov3, J. D. Ahlers1, J. Nacsa1, D. I. Watkins4, T. M. Allen4, A. Sette5, J. Altman6, R. Woodward7, P. D. Markham7, J. D. Clements8, G. Franchini1, W. Strober2, and J. A. Berzofsky1
1NCI, Bethesda, MD, USA; 2NIAID, Bethesda, MD, USA; 3NICHHD, Bethesda, MD, USA; 4Wisconsin Reg. Primate Res. Ctr., Madison, USA; 5Epimmune, San Diego, CA, USA; 6Emory Univ., Atlanta, GA, USA; 7ABL Inc., Kensington, MD, USA; and 8Tulane Univ., New Orleans, LA, USA
Background: Recent studies from our lab and others of the mucosal viral transmission in mice, monkeys, and humans indicate that CTL are an important component of the mucosal immune barrier. We hypothesize that CTL generated in the gut mucosa by mucosal immunization may be more effective at clearing the virus than CTL generated elsewhere by systemic immunization.
Methods: Mamu-A*01-positive MHC type was determined by PCR-sequence-specific primers; determination of viral load was done by NASBA; CTL by 51Cr release assay; tetramer staining of CM9 Gag-specific CD3+ CD8+ T lymphocytes by flow cytometry; statistical analysis by Lehmann-Mack, Kruskal-Wallis.
Results: Here we demonstrate that mucosal SIV-specific CTL responses can be induced by intrarectal immunization of Mamu A*01-positive monkeys with synthetic HIV/SIV peptide vaccines in the presence of a mucosal adjuvant LT(R192G). After intrarectal challenge with pathogenic SHIV-Ku, monkeys immunized intrarectally with the HIV/SIV peptide vaccine showed a rapid decline of viral titer to undetectable levels both in blood and in the gut reservoir, a significantly lower set point than with subcutaneously immunized animals and adjuvant only controls, perhaps because the CTL were focused on the major site of SHIV replication. The number of CD4+ cells of intrarectally immunized animals was also better preserved in intrarectally immunized monkeys, and the colonic CTL directly ex vivo were higher 200 days after challenge than in the other groups. Moreover, reduction of viremia correlated with post-infection CTL activity in the gut and with clearance of SHIV from the gut mucosal tissues, which were probably the major sites seeding virus into the blood stream.
Conclusions: These data thus for the first time provide important support for the concept in primates that the induction of SIV- or HIV-specific CTL responses in the mucosa, the main site of SIV/HIV replication, is at least as important as inducing high level systemic CTL responses in protection against HIV/SIV infection(not just because of mucosal transmission, but because the gut is a major reservoir of virus. This fundamental concept will be important for the optimal design of effective AIDS vaccine.
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