NDLI: Cytotoxic Lymphocytes Target HIV-1 Gag Through Granzyme M-Mediated Cleavage

Content Provider	Directory of Open Access Journals (DOAJ)
Author	Elisa Saccon Flora Mikaeloff Pol Figueras Ivern Ákos Végvári Anders Sönnerborg Ujjwal Neogi Robert van Domselaar
Abstract	Untreated HIV-1 infection leads to a slow decrease in CD4+ T cell lymphocytes over time resulting in increased susceptibility to opportunistic infections (acquired immunodeficiency syndrome, AIDS) and ultimately death of the infected individual. Initially, the host's immune response controls the infection, but cannot eliminate the HIV-1 from the host. Cytotoxic lymphocytes are the key effector cells in this response and can mediate crucial antiviral responses through the release of a set of proteases called granzymes towards HIV-1-infected cells. However, little is known about the immunological molecular mechanisms by which granzymes could control HIV-1. Since we noted that HIV-1 subtype C (HIV-1C) Gag with the tetrapeptide insertion PYKE contains a putative granzyme M (GrM) cleavage site (KEPL) that overlaps with the PYKE insertion, we analyzed the proteolytic activity of GrM towards Gag. Immunoblot analysis showed that GrM could cleave Gag proteins from HIV-1B and variants from HIV-1C of which the Gag-PYKE variant was cleaved with extremely high efficiency. The main cleavage site was directly after the insertion after leucine residue 483. GrM-mediated cleavage of Gag was also observed in co-cultures using cytotoxic lymphocytes as effector cells and this cleavage could be inhibited by a GrM inhibitor peptide. Altogether, our data indicate towards a noncytotoxic immunological mechanism by which GrM-positive cytotoxic lymphocytes target the HIV-1 Gag protein within infected cells to potentially control HIV-1 infection. This mechanism could be exploited in new therapeutic strategies to treat HIV-1-infected patients to improve immunological control of the infection.
e-ISSN	16643224
DOI	10.3389/fimmu.2021.669347
Journal	Frontiers in Immunology
Volume Number	12
Language	English
Publisher	Frontiers Media S.A.
Publisher Date	2021-04-01
Publisher Place	Switzerland
Access Restriction	Open
Subject Keyword	Immunologic Diseases. Allergy Cytotoxic Lymphocyte Granzyme M Gag (hiv-1) Hiv-1 Immune Control
Content Type	Text
Resource Type	Article

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