Session 25Oral Abstract Presentations Viral Pathogenesis Session Day and Time: Thursday 10 am - 12:30 pm Presentation Time: 10:15 Room: Ballroom A
121 Increased SIV Viremia Following In Vivo CD8+ T-lymphocyte Depletion in Sooty Mangabeys with Natural SIV Infection Z. Wang1, N. Kassis1, S. Staprans2, M. Elliott1, S. O’Neil1, J E Schmitz3, K. A. Reimann3, H. M. McClure2, R. P. Johnson1, A. Kaur*1 1New England Regional Primate Res Ctr, Southborough, MA; 2Yerkes Natl Primate Res Ctr, Emory Univ, Atlanta, GA; and 3Beth Israel Deaconess Med Ctr, Boston, MA
Background: Sooty mangabeys naturally-infected with SIV do not develop AIDS despite evidence of cytopathic infection, high viral load, and high viral turnover rate. However, unlike pathogenic lentiviral infection, increased lymphocyte turnover is not detected, suggesting that there is decreased bystander cell lysis in SIV-infected mangabeys. In order to investigate whether CD8+ T-lymphocytes play a role in controlling SIV replication in vivo, we investigated the effect of CD8+ T-cell depletion on plasma SIV viremia in naturally-infected mangabeys.
Methods: CD8 depletion was achieved in 4 SIV+ mangabeys using the mouse-human chimeric anti-CD8 mAb cM-T807. A control mouse-human chimeric anti-RSV mAb was administered to 2 SIV+ mangabeys. Plasma SIV RNA was quantitated by real time RT-PCR. Immunophenotyping of CD8-expressing cells in the peripheral blood and lymph node was performed with the anti-CD8 mAb Clone DK25 which recognizes CD8+ lymphocytes coated with the cM-T807 mAb. SIV load and CD8 depletion in lymph nodes is also being examined by in situ hybridization and immunohistochemistry.
Results: Administration of cM-T807, but not the control mAb, resulted in undetectable CD8+ T-lymphocytes in the peripheral blood for a period ranging between 18 to 28 days. There were no significant changes in peripheral B lymphocyte or CD4+ T-lymphocyte counts during this period. In the peripheral lymph nodes, the percent of CD8+ T-lymphocytes had declined to < 7% (Range 2.4 %-6.8%) 7-14 days following administration of the anti-CD8 mAb. During the period of peripheral CD8 depletion, a greater than 100-fold increase in plasma SIV RNA was seen in 3/4 mangabeys. In all 3 animals, the plasma SIV RNA rose steadily over 14-18 days to reach peak viremia levels of 107 to 108 copies/ml that were sustained for 7-14 days. The decline in plasma viremia to near baseline levels coincided with the recovery of CD8+ T-lymphocytes, the majority of which were proliferating and expressed Granzyme B. In mangabeys that received the control mAb, plasma SIV RNA fluctuations were generally less than 5-fold and did not exceed 10-fold.
Conclusions: CD8+ T-lymphocytes substantially inhibit SIV replication in vivo in naturally SIV-infected sooty mangabeys. Despite this inhibition, plasma viral loads are maintained at levels above 104 SIV RNA copies/ml. Whether the viral inhibitory effect is essential for maintaining nonpathogenic infection remains to be determined.
