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Journal article
Nef promotes evasion of human immunodeficiency virus type 1-infected cells from the CTLA-4-mediated inhibition of T-cell activation
Journal of general virology, v 96(Pt 6), pp 1463-77
01 Jun 2015
PMID: 25626682
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
CTLA-4 is a negative regulator of T-cell receptor-mediated CD4(+) T-cell activation and function. Upregulation of CTLA-4 during human immunodeficiency virus type 1 (HIV-1) infection on activated T cells, particularly on HIV-specific CD4(+) T cells, correlates with immune dysfunction and disease progression. As HIV-1 infects and replicates in activated CD4(+) T cells, we investigated mechanisms by which HIV-1 modulates CTLA-4 expression to establish productive viral infection in these cells. Here, we demonstrate that HIV-1 infection in activated CD4(+) T cells was followed by Nef-mediated downregulation of CTLA-4. This was associated with a decreased T-cell activation threshold and significant resistance to CTLA-4 triggering. In line with these in vitro results, quantification of pro-viral HIV DNA from treatment-naive HIV-infected subjects demonstrated a preferential infection of memory CD4(+)CTLA-4(+) T cells, thus identifying CTLA-4 as a biomarker for HIV-infected cells in vivo. As transcriptionally active HIV-1 and Nef expression in vivo were previously shown to take place mainly in the CD3(+)CD4(-)CD8(-) [double-negative (DN)] cells, we further quantified HIV DNA in the CTLA-4(+) and CTLA-4(-) subpopulations of these cells. Our results showed that DN T cells lacking CTLA-4 expression were enriched in HIV DNA compared with DN CTLA-4(+) cells. Together, these results suggested that HIV-1 preferential infection of CD4(+)CTLA-4(+) T cells in vivo was followed by Nef-mediated concomitant downregulation of both CD4 and CTLA-4 upon transition to productive infection. This also highlights the propensity of HIV-1 to evade restriction of the key negative immune regulator CTLA-4 on cell activation and viral replication, and therefore contributes to the overall HIV-1 pathogenesis.
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Details
- Title
- Nef promotes evasion of human immunodeficiency virus type 1-infected cells from the CTLA-4-mediated inhibition of T-cell activation
- Creators
- Mohamed El-Far - Université de MontréalPetronela Ancuta - Université de MontréalJean-Pierre Routy - McGill University Health CentreYuwei Zhang - Université de MontréalWendy Bakeman - Vaccine & Gene Therapy Institute of FloridaRebeka Bordi - Centre Hospitalier de l’Université de MontréalSandrina Dafonseca - Université de MontréalElias A Said - Université de MontréalAnnie Gosselin - Centre Hospitalier de l’Université de MontréalTévy-Suzy Tep - Université de MontréalQuentin Eichbaum - Vanderbilt UniversityJulien van Grevenynghe - Université de MontréalOlivier Schwartz - Institut PasteurGordon J Freeman - Dana-Farber Cancer InstituteElias K Haddad - Centre de rechercheNicolas Chomont - Université de MontréalRafick-Pierre Sékaly - Vaccine & Gene Therapy Institute of Florida
- Publication Details
- Journal of general virology, v 96(Pt 6), pp 1463-77
- Publisher
- Microbiology Society
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- College of Medicine; Infectious Diseases (and HIV Medicine); Drexel University
- Web of Science ID
- WOS:000358189000027
- Scopus ID
- 2-s2.0-84937622269
- Other Identifier
- 991020100057304721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Biotechnology & Applied Microbiology
- Virology