Logo image
Back
Type I Interferon Upregulates Bak and Contributes to T Cell Loss during Human Immunodeficiency Virus (HIV) Infection
Journal article   Open access

Type I Interferon Upregulates Bak and Contributes to T Cell Loss during Human Immunodeficiency Virus (HIV) Infection

Joseph A. Fraietta, Yvonne M. Mueller, Guibin Yang, Alina C. Boesteanu, Donald T. Gracias, Duc H. Do, Jennifer L. Hope, Noshin Kathuria, Shannon E. McGettigan, Mark G. Lewis, …
PLoS pathogens, v 9(10), pp e1003658-e1003658
01 Oct 2013
DOI: https://doi.org/10.1371/journal.ppat.1003658
PMID: 24130482
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://doi.org/10.1371/journal.ppat.1003658View
Published, Version of Record (VoR)CC BY V4.0,  Open

Abstract

Life Sciences & Biomedicine Microbiology Parasitology Science & Technology Virology
The role of Type I interferon (IFN) during pathogenic HIV and SIV infections remains unclear, with conflicting observations suggesting protective versus immunopathological effects. We therefore examined the effect of IFN alpha/beta on T cell death and viremia in HIV infection. Ex vivo analysis of eight pro-and anti-apoptotic molecules in chronic HIV-1 infection revealed that pro-apoptotic Bak was increased in CD4+ T cells and correlated directly with sensitivity to CD95/Fas-mediated apoptosis and inversely with CD4+ T cell counts. Apoptosis sensitivity and Bak expression were primarily increased in effector memory T cells. Knockdown of Bak by RNA interference inhibited CD95/Fas-induced death of T cells from HIV-1-infected individuals. In HIV-1-infected patients, IFN alpha-stimulated gene expression correlated positively with ex vivo T cell Bak levels, CD95/Fas-mediated apoptosis and viremia and negatively with CD4+ T cell counts. In vitro IFN alpha/beta stimulation enhanced Bak expression, CD95/Fas expression and CD95/Fas-mediated apoptosis in healthy donor T cells and induced death of HIV-specific CD8+ T cells from HIV-1-infected patients. HIV-1 in vitro sensitized T cells to CD95/Fas-induced apoptosis and this was Toll-like receptor (TLR) 7/9- and Type I IFN-dependent. This sensitization by HIV-1 was due to an indirect effect on T cells, as it occurred in peripheral blood mononuclear cell cultures but not purified CD4+ T cells. Finally, peak IFN alpha levels and viral loads correlated negatively during acute SIV infection suggesting a potential antiviral effect, but positively during chronic SIV infection indicating that either the virus drives IFN alpha production or IFN alpha may facilitate loss of viral control. The above findings indicate stage-specific opposing effects of Type I IFNs during HIV-1 infection and suggest a novel mechanism by which these cytokines contribute to T cell depletion, dysregulation of cellular immunity and disease progression.

Metrics

16 Record Views
82 citations in Web of Science
71 citations in Scopus

Details

UN Sustainable Development Goals (SDGs)

This publication has contributed to the advancement of the following goals:

#3 Good Health and Well-Being

InCites Highlights

Data related to this publication, from InCites Benchmarking & Analytics tool:

Collaboration types
Industry collaboration
Domestic collaboration
Web of Science research areas
Microbiology
Parasitology
Virology
Logo image