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

329-W. Vaginal CD4+ T Cells are Rapidly Depleted in SIV Infection R. Veazey*1, P. Marx1,2, and A. Lackner1 1Tulane Regional Primate Res. Ctr., Covington, LA and 2Aaron Diamond AIDS Res. Ctr., Rockefeller Univ., New York, NY Introduction: Worldwide, the vast majority of HIV-1 cases occur through heterosexual transmission. Although the initial events involved in vaginal transmission are uncertain, studies in the SIV macaque model suggest that dendritic cells in the superficial vaginal epithelium may be involved in the initial trapping of viral particles on the mucosal surface, and transporting them to CD4+ T lymphocytes in the mucosa. However, very little is known regarding the immunophenotype, chemokine receptor expression, and/or dynamics of CD4+ T cells in the vaginal mucosa in HIV-1 infection. Methods: Lymphocytes were isolated from the lymph nodes, blood, and vagina from 14 female macaques (5 uninfected and 9 infected with SIVmac). Lymphocytes were isolated from the vagina using a modification of techniques previously applied to isolate intestinal lymphocytes and then stained with monoclonal antibodies for CD4, CD8, CD45RA, CD25, CD69, CXCR4, and CCR5, for 30 minutes at 4*, fixed, and analyzed with a FACS Calibur flow cytometer. Results: Numerous CD4+ T cells were observed in the vaginal mucosa of uninfected female macaques. Between 32% and 58% of the T cells in the vaginal mucosa were CD4+, whereas 38-77% expressed CD8. Most CD4+ and CD8+ lymphocytes in the vaginal mucosa exhibited an activated (CD69+), memory (CD45RA negative, CD62L negative) phenotype. Chemokine receptor expression was also markedly different on vaginal lymphocytes compared to peripheral lymphocytes. From 45% to 67% of the CD4+ T cells in the vagina of uninfected macaques expressed high levels of CCR5, whereas 93-99% co-expressed CXCR4. In acutely infected macaques, profound and rapid depletion of CD4+ T cells occurred in the vaginal mucosa. Furthermore, 4 of the 5 macaques euthanatized with AIDS demonstrated marked, persistent CD4+ T-cell depletion. Surprisingly, 1 SIV-infected macaque with AIDS had substantial numbers of CD4+ T cells remaining in the vaginal mucosa. However, none of the remaining CD4+ T cells co-expressed CCR5. Furthermore, residual CD4+ T cells in all SIV infected macaques had a naïve phenotype and lacked CCR5 expression. Conclusions: This study demonstrates that by 14 days of SIV infection, CD4+ T cells are markedly depleted in the vaginal mucosa. This suggests that in early SIV infection, vaginal mucosal immune responses may be markedly impaired. Moreover, this demonstrates that there are large numbers of activated, CD4+ T cells co-expressing CCR5 residing within the vaginal mucosa of normal, uninfected macaques and that these cells are specifically targeted for infection, viral amplification, and elimination by lytic viral replication in early SIV infection.

©2002 9th Conference on Retroviruses and Opportunistic Infections