16th International AIDS Conference Toronto, Canada - August 13 - 18, 2006

DIFFERENTIAL CYTOKINE RESPONSIVENESS TO TOLL-LIKE RECEPTOR (TLR) LIGAND STIMULATION IN HIV-1 RESISTANT SEX WORKERS FROM NAIROBI, KENYA

Int Conf AIDS. 2006 Aug 13-18;16 Abstract No. WeAa0301

Ball T.B.¹, Lester R.¹, Wachihi C.², Marlin C.¹, Plummer F.¹, HayGlass K.^3
1 University of Manitoba, Medical Microbiology, Winnipeg, Canada, ² University of Nairobi, Medical Microbiology, Nairobi, Kenya, ³ University of Manitoba, Immunology, Winnipeg, Canada

BACKGROUND: HIV-resistant women from Nairobi, Kenya offer a natural model of resistance to infection by HIV-1. Resistance associates with HIV-1 specific adaptive immune responses, including systemic cellular and compartmentalized humoral responses. What is unknown is what determines an HIV resistant women's ability to develop these putatively protective responses, while the majority of exposed individuals become infected. Innate pattern recognition receptors, including toll-like receptors (TLRs), are critical in the induction and instruction of adaptive responses. We hypothesize that HIV resistance in part, may be mediated by altered innate responses, such that resistant women are able to generate protective, adaptive response to HIV-1.

METHODS: Peripheral blood mononuclear cells (PBMC) were isolated from HIV resistant women, as well as uninfected sex-worker and low-exposure controls. PBMC were stimulated for 18 hours with ligands for TLR-2, TLR-4 and TLR-7, known to be important in instructing the adaptive immune response, as well as recognizing HIV-1 RNA sequences (TLR7). We measured the induction of cytokines critical for the induction of cellular immunity (IL-12, IFN-α, and IFN-γ) as well as the immunosuppressive cytokine IL-10 and compared magnitude of cytokine responses between groups.

RESULTS: Surprisingly, we found that PBMCs from HIV-resistant women had elevated IL-10 responses to TLR-2 and 7 stimuli (p=0.001 and 0.021) while IFN-γ responses to TLR-4 and 7 stimuli were significantly depressed (p=0.021 and 0.013) compared to HIV uninfected controls, demonstrating an altered ability to respond to innate stimuli in resistant women.

CONCLUSIONS: Resistant women have significantly altered innate responses to some TLR ligands compared to uninfected controls, which may reflect their ability to mount a protective adaptive response to HIV-1. Interestingly cytokines known to induce cellular immunity were depressed while these women had elevated immunosuppressive cytokine responses. HIV resistance may therefore be associated with a hyporesponsive innate response rather than a preference to generate cellular immune responses.

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2006-08-13
WeAa0301

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