Massive secretion by T cells is caused by HIV Nef in infected cells and by Nef transfer to bystander cells.
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.
Muratori
Claudia
C
Department of Microbiology and Immunology, University of Miami, Miller School of Medicine, Miami, FL 33136, USA.
Cavallin
Lucas E
LE
Krätzel
Kirsten
K
Tinari
Antonella
A
De Milito
Angelo
A
Fais
Stefano
S
D'Aloja
Paola
P
Federico
Maurizio
M
Vullo
Vincenzo
V
Fomina
Alla
A
Mesri
Enrique A
EA
Superti
Fabiana
F
Baur
Andreas S
AS
D024201:Bystander Effect; D002478:Cells, Cultured; D004705:Endocytosis; D005089:Exocytosis; D015658:HIV Infections / Q000276:immunology / Q000378:metabolism*; D015497:HIV-1 / Q000378:metabolism*; D054884:Host-Pathogen Interactions; D006801:Humans; D008213:Lymphocyte Activation; D021381:Protein Transport; D055571:Secretory Pathway; D022142:Secretory Vesicles / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism*; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*
D054311:nef Gene Products, Human Immunodeficiency Virus