HIV-1 gp41 fusogenic function triggers autophagy in uninfected cells

HIV-1 gp41 fusogenic function triggers autophagy in uninfected cells

Fecha de publicación online: 16/11/2008

Abstract:

Cell-expressed HIV-1 envelope glycoproteins (gp120 and
gp41, called Env) induce autophagy in uninfected CD4 T cells,
leading to their apoptosis, a mechanism most likely contributing
to immunodeficiency. The presence of CD4 and CXCR4
on target cells is required for this process, but Env-induced
autophagy is independent of CD4 signaling. Here we demonstrate
that CXCR4-mediated signaling pathways are not directly
involved in autophagy and cell death triggering. Indeed, cells
stably expressing mutated forms of CXCR4, unable to transduce
different Gi-dependent and -independent signals, still undergo
autophagy and cell death after coculture with effector cells
expressing Env. After gp120 binding to CD4 and CXCR4, the N
terminus fusion peptide (FP) of gp41 is inserted into the target
membrane, and gp41 adopts a trimeric extended pre-hairpin
intermediate conformation, target of HIV fusion inhibitors such
as T20 and C34, before formation of a stable six-helix bundle
structure and cell-to-cell fusion. Interestingly, Env-mediated
autophagy is triggered in both single cells (hemifusion) and
syncytia (complete fusion), and prevented by T20 and C34. The
gp41 fusion activity is responsible for Env-mediated autophagy
since the Val2Glu mutation in the gp41 FP totally blocks this
process. On the contrary, deletion of the C-terminal part of gp41
enhances Env-induced autophagy. These results underline the
major role of gp41 in inducing autophagy in the uninfected cells
and indicate that the entire process leading to HIV entry into
target cells through binding of Env to its receptors, CD4 and
CXCR4, is responsible for autophagy and death in the uninfected,
bystander cells.

Autores: M. Denizot, M. Varbanov, L. Espert, V. Robert-Hebmann, S. Sagnier, E. Garcia, M. Curriu, R. Mamoun, J. Blanco, M. Biard-Piechaczyk.
  • Código Doi: Autophagy, 4 (8) : 998-1008

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Irsi Caixa

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