319 SIV-specific Cytotoxic T-cell Development in SIV Infection R. S. Veazey*1, J. E. Schmitz2, J. D. Lifson3, M. Piatak3, A. A. Lackner1 1Tulane Natl Primate Res Ctr, Tulane Univ Hlth Sci Ctr, Covington, LA; 2Beth Israel Deaconess Med Ctr, Harvard Med Sch, Boston, MA; and 3Sci Applications Intl Corp Frederick, NCI-FCRDC, MD
Background: Although several studies have examined HIV viral specific T-cells in the blood of HIV-infected humans and SIV infected macaques, few have examined the development and persistence of viral specific cytotoxic T-cells in tissues. In this study, we examined the development of gag-specific CTL in the intestine, lymph nodes, spleen, and other lymphoid tissues of acute and chronically infected rhesus macaques by tetramer technology.
Methods: To compare CTL in various lymphoid tissues of SIV-infected macaques, 14 MamuA*01+ rhesus macaques were intravenously infected with SIVmac251. Lymphocytes from blood, lymph node, and endoscopic intestinal biopsies were prospectively examined from 4 macaques throughout infection. Two (2) macaques were euthanized at 8, 10, and 13 days post infection (d.p.i.), 4 at 21 d.p.i., and 3 with AIDS. Lymphocytes from blood, intestines, lymph nodes, spleen, thymus, and bone marrow were examined for SIV-specific CTL by gag p11c tetramer analySIV-specific Cytotoxic T-cell development in SIV infections of CD3+CD8+ T-cells.
Results: No tetramer positive cells were detected in any tissue before 13 d.p.i. However, by day 13, CTL were detectable in all tissues examined. In primary (13-21 days p.i.) percentages of SIV-specific CTL emerging in the blood and intestine were similar and peak gag-specific CTL responses occurred between day 13-17 (mean of 7.8% ± 5.8 SD of blood and 7.4% ±5.1 SD of intestinal CD3+CD8+ T-cells. However, in chronic infection, SIV-specific CTL declined in blood (mean 1.3%-4.6%), but were maintained in the intestine (mean 3.5%-13.9%). In general, plasma viral loads correlated with CTL in the intestine, until the onset of AIDS, when few CTL were detectable. SIV-specific CTL were always rare in the thymus and bone marrow, yet frequently high in the spleen.
Conclusions: These studies indicate that SIV-specific CTL emerge simultaneously in multiple tissues, and at similar levels in primary infection of intravenously infected macaques. Moreover, CTL appear to develop in secondary rather than primary lymphoid tissues. After primary infection, higher percentages of CTL are detected in the intestine and spleen suggesting local development in tissues that serve as major sites of viral replication and persistence. Finally, CTL diminish in tissues as animals progress to AIDS, consistent with profound immunodeficiency and/or exhaustion of CTL progenitors.
