10th Conference on Retroviruses and Opportunistic Infections Boston, MA USA - February 10 -14, 2003

Conf Retroviruses Opportunistic Infect 2003 Feb 10-14;10th: abstract no. 29
D. M. Brainard¹ , W. G. Tharp¹, I. T. Olszak¹, A. Trocha¹, S. A. Kalams¹, B. D. Walker¹, R. Wyatt², J. Sodroski², M. C. Poznansky¹

BACKGROUND: We have previously shown that human T-lymphocytes move away from the chemokine, SDF-1, in a concentration-dependent and CXCR4 receptor-mediated manner. HIV gp120 has been shown to cause CD8 T-cell migration via binding to the chemokine receptor, CXCR4. We hypothesize that gp120 causes movement of HIV-specific cytotoxic T-cells (CTLs) away from HIV-infected target cells and, thereby, decreases the efficacy of the CTLs for killing HIV-infected cells.

METHODS: The migratory responses of HIV-specific CTLs to varying concentrations of recombinant HIV_IIIB gp120 were assessed using in vitro and in vivo transmigration assay systems. HIV-specific CTL clones were tested by chromium release assays and flow cytometry for their ability to kill target cells expressing gp120. Altering cell density and employing flat bottom plates in the cytotoxicity assays allowed for the evaluation of cell migration on killing efficacy. Time-lapse video-microscopy was used to confirm quantitative results.

RESULTS: CXCR-4-specific recombinant gp120 elicited a migratory response of T-cells including HIV-specific CTL movement away from the recombinant HIV protein. Migration away from gp120 was concentration dependent, CD4-independent and was inhibited by anti-CXCR-4, pertussis toxin and 8-Br-cAMP. Recombinant gp120 was also shown to be active in vivo in significantly reducing T-cell infiltration at a site of antigen challenge. It was also demonstrated that the active movement of HIV-specific CTL clones was essential for their ability to kill target cells with decreased cell lysis seen in response to lower cell density, despite maintenance of equal effector:target ratios. Time-lapse video-microscopy allowed for qualitative confirmation of the CTL/target cell interaction at various cell densities.

CONCLUSIONS: CTL migration contributes to the efficacy with which HIV-specific CTL kill target cells. HIV gp120 dysregulates immune cell localization in vitro. The distinct phenomenon of movement away from a chemokine or chemokinetic agent such as gp120, which we term fugetaxis (fugere: to flee from; taxis: movement) represents a novel mechanism of regulating the movement of mature T-cells away from specific sites and may provide a mechanism by which HIV evades challenge by immune effector cells in vivo. Novel treatment strategies might be developed based on inhibiting the effect of HIVgp-120 on the migration of HIV-specific CTLs.

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