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Session 52 Poster Session Pathogenesis Studies in Animal Models Session Time: 4:30-6:30 pm Room 4E-F

335-W. Importance of the Thymus toward Disease Progression in SIV-Infected Macaques A. Muthukumar1, D. C. Douek2, A. Wozniakowski1, F. Ware1, V. Hirsch3, R. P. Johnson4, R. A. Koup2, and D. L. Sodora*1 1Univ. of Texas, Southwestern Med. Ctr., Dallas; 2NIAID Vaccine Res. Ctr., NIH, Bethesda, MD; 3NIAID, NIH, Bethesda, MD; and 4New England Regional Primate Res. Ctr., Southborough, MA Background: The thymus is responsible for de novo production of CD4+ and CD8+ T cells, and therefore is important for T-cell renewal. SIV infection of macaques, as well as HIV infection of humans, can result in thymic atrophy, suggesting a decrease in T-cell production. Here we assess thymic function by measuring the levels of T-cell receptor excision circles (TREC) within the peripheral blood. TREC containing cells are termed recent thymic emigrants. These DNA markers do not replicate and are diluted out during subsequent T cell division in the periphery. Methods: Decreases in TREC levels within 5 macaques previously infected with a pathogenic SIV isolate prompted the infection and assessment of 3 additional macaques with SIVmac239. Results: Within these macaques (RSm succumbed to AIDS at 9 months, RTq at 15 months, Ruh a nonprogressor), TREC levels declined after 20-35 weeks post-infection in both CD4+ and CD8+ T cells irrespective of the rate of disease progression. This decline in TREC levels could not be fully attributed to either the level of circulating naïve cells (CD45RA+/CD62L+) or cellular replication (Ki67), suggesting that decreased thymic output was a contributing factor. This was further confirmed at necropsy of RTq as the thymic tissue was determined to have an increased percentage of mature CD8+ cells and an increased level of apoptotic/TUNEL+ cells. In addition, we assessed the role of the thymus directly by its removal from 3 macaques prior to SIV infection (RWp succumbed to AIDS at 8.5 months, RPc at 11.5 months, RHj at 13.5 months). In these macaques, absence of a thymus resulted in a more rapid decline in TREC levels. Levels of Ki67 within the CD4+ and CD8+ T cells were elevated at many of the time points assessed. Conclusions: SIV infection of macaques results in decreased thymic output, as evidenced by a reduced level of recent thymic emigrants in the peripheral blood CD4+ and CD8+ cells. In addition, we observed increased levels of mature T cells and apoptotic cells within the thymus. Removal of the thymus prior to infection resulted in macaques acquiring AIDS slightly earlier and TREC levels decreasing more rapidly. These data support a model in which the thymus may be important for the maintenance of a broad T cell repertoire during SIV/HIV infections and the accompanying immune activation/cell death associated with these infections.

©2002 9th Conference on Retroviruses and Opportunistic Infections