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

CXCR4-UTILIZING HIV-1 STRAINS ACTIVATE INNATE IMMUNITY VIA CD14 AND TOLL-LIKE RECEPTOR 2

Int Conf AIDS. 2006 Aug 13-18;16 Abstract No. ThLB0303

H. Zhu¹, R.C. Huard¹, M. Nociari¹, T. He², K. Zerria¹, Z. Chen², D. Golenbock³, J.L. Ho¹, AIDS pathogenesis, Immunology, innate immunity.
¹Joan and Sanford I. Weill Medical College of Cornell University, Medicine, Div International Medicine & Infectious Diseases, New York, NY, United States, ²Aaron Diamond AIDS Research Center, The Rockefeller University, New York, NY, United States, ³University of Massachusetts Medical School, Medicine, Div Infectious Diseases, Worcester, MA, United States

BACKGROUND: Exactly how HIV-1 infection leads to AIDS remains a fundamental poorly answered scientific question. Since generalized immune hyperactivation and rising serum proinflammatory cytokine levels predict HIV-1 disease progression to AIDS, and Toll-like receptors (TLRs) mediate innate immune inflammatory responses, studies were conducted to evaluate HIV-1 interactions with TLRs. We report novel findings and a previously undiscovered potential mechanism for AIDS pathogenesis in that late-stage CXCR4-utilizing HIV-1 strains activate innate immune cells via Toll-like receptor (TLR)-2.

METHODS AND RESULTS: TLR-expressing reporter cell lines were used to show that late-stage CXCR4 (X4)-utilizing HIV-1 strains transduce intracellular signals via human TLR2. X4 HIV-1 also stimulated pro- and anti-inflammatory cytokine production from human monocytes and/or macrophage-like cell lines in a CD14- and TLR2-dependent manner and did not require CD4 or CXCR4 chemokine receptor interaction. These effects were seen not only with laboratory cloned HIV-1 but also with clinical isolates of B and C clades. However, monocyte and TLR2 reporter cell line activation was not seen when CCR5 monotropic HIV-1 strains were evaluated. These effects were mediated by intact HIV-1 particles as shown by studies using several antibodies. Moreover, experiments with several HIV-1 molecular constructs indicated that a critical component mediating TLR2 activation is genetically encoded by the virus, but is an element(s) other than the gp120 envelope glycoprotein. At present, the viral encoded or viral associated ligand(s) responsible for TLR2 mediated innate immune cell activation remains to be identified.

CONCLUSIONS: Overall, these data uncover a new mechanism through which HIV-1 may disturb normal immune function and prompt the immune collapse and other associated clinical pathologies of AIDS. The lack of TLR2 activation by CCR5-utilizing HIV-1 strain and failure to trigger a pro-inflammatory response may also be a measure of immune evasion in early-stage viruses allowing infection by these strains via the mucosal route.

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2006-08-13
ThLB0303

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