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HIV-1 Nef impairs the dynamic of DC/NK crosstalk: different outcome of CD56^dim and CD56^bright NK cell subsets

Maria Giovanna Quaranta^*, Alfonso Napolitano^*, Massimo Sanchez, Luciana Giordani^*, Benedetta Mattioli^* and Marina Viora^*,1

^* Department of Drug Research and Evaluation,

Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy

¹Correspondence: Department of Drug Research and Evaluation, Istituto Superiore di Sanità; Viale Regina Elena, 299, 00161 Rome, Italy. E-mail: viora{at}iss.it

Dendritic cells (DCs) and natural killer (NK) cells are essential components of the innate immunity and play a critical role in the first phase of host defense against infection. Interactions between DCs and NK cells have been demonstrated in a variety of settings, with evidence emerging of complex bidirectional crosstalk between the two cell types. The accessory HIV-1 Nef protein is a crucial determinant for viral replication and pathogenesis. We previously demonstrated that Nef, hijacking DC functional activity, subverts the DC arm of immune response to escape the adaptive immune attack. Here, we monitor the effect of Nef on the outcome of the innate immune response, focusing on the impact of Nef on DC/NK crosstalk. We demonstrate that Nef up-regulates the ability of DCs to stimulate the immunoregulatory NK cells (CD56^bright) as assessed by the activated phenotype, up-regulation of their proliferative response and INF- release. On the other hand, Nef-pulsed DCs inhibit cytotoxic NK cells (CD56^dim), as assessed by the reduced HLA-DR surface expression, reduced proliferation and cytotoxic activity. Moreover, in the presence of Nef-pulsed DCs, we found a significant up-regulation of TNF- secretion and a significant reduction of IL-10, GM-CSF, MIP-1 and RANTES secretion. Our findings suggest that the Nef-induced dysregulation in the DC/NK cell crosstalk may represent a potential mechanism through which HIV escapes innate immune surveillance.—Quaranta, M.G., Napolitano, A., Sanchez, M., Giordani, L., Mattioli, B., Viora, M. HIV-1 Nef impairs the dynamic of DC/NK crosstalk: different outcome of CD56^dim and CD56^bright NK cell subsets.

Key Words: AIDS • innate immunity • immune evasion