Massive Secretion by T Cells Is Caused by HIV Nef in Infected Cells and by Nef Transfer to Bystander Cells

Claudia Muratori^1, 2, Lucas E. Cavallin¹, Kirsten Krätzel⁵, Antonella Tinari³, Angelo De Milito⁴, Stefano Fais⁴, Paola D'Aloja², Maurizio Federico², Vincenzo Vullo⁶, Alla Fomina⁷, Enrique A. Mesri¹, Fabiana Superti³ and Andreas S. Baur^1, 5, ,  

¹ Department of Microbiology and Immunology, University of Miami, Miller School of Medicine, Miami, FL 33136, USA
² National AIDS Centre, Istituto Superiore di Sanità, 00161 Rome, Italy
³ Department of Technology and Health, Istituto Superiore di Sanità, 00161 Rome, Italy
⁴ Department of Therapeutic Research and Medicines Evaluation, Unit of Antitumor Drugs, Istituto Superiore di Sanità, 00161 Rome, Italy
⁵ Department of Dermatology, University of Erlangen/Nürnberg, 91054 Erlangen, Germany
⁶ Department of Infectious and Tropical Diseases, La Sapienza University, Rome, Italy
⁷ Department of Physiology and Membrane Biology, University of California, Davis, CA 95616, USA

Summary

The HIV Nef protein mediates endocytosis of surface receptors that correlates with disease progression, but the link between this Nef function and HIV pathogenesis is not clear. Here, we report that Nef-mediated activation of membrane trafficking is bidirectional, connecting endocytosis with exocytosis as occurs in activated T cells. Nef expression induced an extensive secretory activity in infected and, surprisingly, also in noninfected T cells, leading to the massive release of microvesicle clusters, a phenotype observed in vitro and in 36%87% of primary CD4 T cells from HIV-infected individuals. Consistent with exocytosis in noninfected cells, Nef is transferred to bystander cells upon cell-to-cell contact and subsequently induces secretion in an Erk1/2-dependent manner. Thus, HIV Nef alters membrane dynamics, mimicking those of activated T cells and causing a transfer of infected cell signaling (TOS) to bystander cells. This mechanism may help explain the detrimental effect on bystander cells seen in HIV infection.