4th International AIDS Society Conference on HIV Pathogenesis and Treatment Sydney, Australia - July 22 - 25, 2007

HIV-1 NEF IS A CRITICAL REGULATOR OF PD-1 UPREGULATION DURING HIV-1 INFECTION

IAS Conf HIV Pathog Treat 2007 Jul 22-25;4th: Abstract No. MOAA103

Muthumani K.¹, Choo A.Y.², Sundaram S.G.¹, Laddy D.J.¹, Hokey D.A.¹, Kutzler M.A.¹, Weiner D.B.^1
1University of Pennsylvania School of Medicine, Pathology and Lab. Medicine, Philadelphia, PA, United States, ²Harvard Medical School, Department of Cell Biology, Boston, United States

Chronic viral infection is characterized by the functional impairment of virus-specific T cell responses. Accordingly, recent evidences have suggested that the inhibitory receptor programmed death 1 (PD-1), is specifically upregulated on antigen-specific T cells during various chronic viral infections. Indeed, it has been shown that HIV specific CD4+ and CD8+ T cells both express elevated levels of PD-1 and correlates with viral load and inversely with CD4+ T cells counts. More importantly, in vitro blockade of the PD-1/PD-1L pathway was sufficient to both increase and stimulate viral specific proliferation and cytokine production. However, the mechanism that mediates the HIV-induced PD-1 upregulation is not known. Here, we provide evidence that the HIV-1 accessory protein Nef is both necessary and sufficient to transcriptionally induce the expression of PD-1 during HIV infection in both CD4+ and CD8+ T cells. Nef-induced PD-1 upregulation requires its proline rich motif and the activation of the downstream kinase p38. Furthermore, we show that Nef also stimulates the expression of PD-1 in noninfected CD8+ T cells via a non-cell-autonomous mechanism that requires the release of Nef from infected CD4+ T cells into infection-free CD8+ T cells. Lastly in HIV-1 patients, there is a direct correlation between serum levels of Nef and PD-1 expression on HIV-specific CD8+ T cells. These PD-1 expressing cells also exhibit increased levels of activated p38 and the inhibition of this kinase dramatically attenuates the expression of PD-1.

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2007-07-22
MOAA103
Immune Activation in HIV Pathogenesis

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