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289 Dendritic Cell Amplification of Cryptic HIV-1-Specific T-Cell Responses in Exposed, Seronegative Individuals
B. L. Shacklett*1,5, R. Means2, M. Larsson3, D. Wilkens1, T. Beadle1, M. Merritt1, N. Bhardwaj3, J. Skurnick4, D. Louria4, P. Palumbo4, and D. F. Nixon1-5
1Aaron Diamond AIDS Res. Ctr., New York, NY, USA; 2New England Primate Res. Ctr., Southborough, MA, USA; 3Rockefeller Univ., New York, NY, USA; 4New Jersey Med. Sch., Newark, USA; and 5Gladstone Inst. of Virology and Immunology, San Francisco, CA, USA
Background: In the Heterosexual AIDS Transmission Study (HATS), the frequency of high-risk activity as well as viral load and CD3+CD8+ T-cell counts in the seropositive partner have been shown to correlate with transmission. However, these parameters cannot account for the status of some exposed, seronegative (ESN) individuals who remain uninfected despite several years of exposure. To test the hypothesis that antiviral immune responses are a correlate of nontransmission in these individuals, we developed 2 sensitive methods for assessing humoral and cell-mediated responses.
Methods: To quantify T-cell responses, autologous mature dendritic cells (DC) were used as antigen presenting cells to elicit HIV-1-specific IFN-gamma production by ELISPOT. Antibody responses to HIV-1 gp120 were assessed in a combination immunoprecipitation-Western blot (IP-WB).
Results: Previous studies of this cohort using limiting dilution analysis did not reveal HIV-1-specific CTL activity. However, when autologous DC were used to present HIV-1 antigens, T cells from 3 of 8 ESN women (38%) responded by producing IFN-gamma. T cells from 3 of 4 seropositive partners responded to HIV-1 antigens, whereas 5 low-risk controls did not. The use of autologous DC as antigen-presenting cells increased sensitivity by 3- to 20-fold relative to standard ELISPOT. Using the IP-WB, low levels of gp120-reactive antibodies were detected in plasma from only 1 of 15 ESN women.
Conclusions: In contrast to previous findings from this cohort, these results support the hypothesis that HIV-specific CD8+ T-cell responses play a role in immune surveillance in this cohort of North American serodiscordant couples. This report also demonstrates the ability of dendritic cells to reveal low-frequency T-cell responses that might be overlooked by other methods.
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