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Functional Synergy between CD40 Ligand and HIV-1 Tat Contributes to Inflammation: Implications in HIV Type 1 Dementia¹

Ziye Sui^*, Lynn F. Sniderhan, Giovanni Schifitto^¶, Richard P. Phipps^,, Harris A. Gelbard^*,,,¶,||, Stephen Dewhurst^*,,# and Sanjay B. Maggirwar^2,*,

^* Interdepartmental Program in Neuroscience, Department of Microbiology and Immunology, Department of Environmental Medicine, Center for Aging and Development, ^¶ Department of Neurology, ^|| Department of Pediatrics, and ^# James P. Wilmot Cancer Center, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642

HIV type 1 (HIV-1)-associated dementia (HAD) is believed to occur due to aberrant activation of monocyte-derived macrophages and brain-resident microglial cells by viral proteins as well as by the proinflammatory mediators released by infected cells. To investigate the inflammatory aspects of the disease, we examined the levels of soluble CD40L (sCD40L) in paired samples of plasma and cerebrospinal fluid obtained from 25 HIV-infected individuals. A significantly higher level of sCD40L was detected in both cerebrospinal fluid and plasma from HIV-infected patients with cognitive impairment, compared with their nonimpaired counterparts. The contribution of sCD40L to the pathogenesis of HAD was then examined by in vitro experiments. rCD40L synergized with HIV-1 Tat to increase TNF- release from primary human monocytes and microglia, in an NF-B-dependent manner. The mechanistic basis for this synergism was attributed to a Tat-mediated up-regulation of CD40 in monocytes and microglia. Finally, the CD40L-mediated increase in TNF- production by monocytes was shown to be biologically important; immunodepletion experiments revealed that TNF- was essential for the neurotoxic effects of conditioned medium recovered from Tat/CD40L-treated monocytes. Taken together, our results show that CD40 signaling in microglia and monocytes can synergize with the effects of Tat, further amplifying inflammatory processes within the CNS and influencing neuronal survival.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the following National Institutes of Health Grants: RO1 NS054578 (to S.B.M., H.A.G., and R.P.P.); P01 MH64570 (to H.A.G., S.D., G.S., and S.B.M.); RO1 MH56838 (to H.A.G. and S.B.M.); RO1 DE011390 (to R.P.P. and S.B.M.); RO1 HL078603, RO1 ES01247 (to R.P.P.); RO1 MH64409, RO1 NS049465, MO1 RR00044 (to G.S.); T32 AI49105 (to L.F.S.).

² Address correspondence and reprint requests to Dr. Sanjay B. Maggirwar, Department of Microbiology and Immunology, University of Rochester Medical Center, 601 Elmwood Avenue, Box 672, Rochester, NY 14642. E-mail address: sanjay_maggirwar{at}urmc.rochester.edu

³ Abbreviations used in this paper: HIV-1, HIV type 1; HAD, HIV-associated dementia; HAART, highly active antiretroviral therapy; PAF, platelet-activating factor; cPAF, carbamyl-PAF; CeSF, cerebrospinal fluid; sCD40L, soluble CD40L; CM, conditioned medium; CGN, cerebellar granule neuron; FPBS, PBS supplemented with 1% FBS; RT, room temperature.