The anti-caspase inhibitor Q-VD-OPH prevents AIDS disease progression in SIV-infected rhesus macaques.

Abstract

Apoptosis has been proposed as a key mechanism responsible for CD4+ T cell depletion and immune dysfunction during HIV infection. We demonstrated that Q-VD-OPH, a caspase inhibitor, inhibits spontaneous and activation-induced death of T cells from SIV-infected rhesus macaques (RMs). When administered during the acute phase of infection, Q-VD-OPH was associated with (a) reduced levels of T cell death, (b) preservation of CD4+/CD8+ T cell ratio in lymphoid organs and in the gut, (c) maintenance of memory CD4+ T cells, and (d) increased specific CD4+ T cell response associated with the expression of cytotoxic molecules. Although therapy was limited to the acute phase of infection, Q-VD-OPH-treated RMs showed lower levels of both viral load and cell-associated SIV DNA as compared with control SIV-infected RMs throughout the chronic phase of infection, and prevented the development of AIDS. Overall, our data demonstrate that Q-VD-OPH injection in SIV-infected RMs may represent an adjunctive therapeutic agent to control HIV infection and delaying disease progression to AIDS.

• Authors: Mireille Laforge, Ricardo Silvestre, Vasco Rodrigues, Julie Garibal, Laure Campillo-Gimenez, Shahul Mouhamad, Valérie Monceaux, Marie-Christine Cumont, Henintsoa Rabezanahary, Alain Pruvost, Anabela Cordeiro-da-Silva, Bruno Hurtrel, Guido Silvestri, Anna Senik, Jérôme Estaquier
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 128 Issue 4 Pg. 1627-1640 (04 02 2018) ISSN: 1558-8238 [Electronic] United States
• PMID: 29553486 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amino Acid Chloromethyl Ketones
• Caspase Inhibitors
• Quinolines
• quinoline-val-asp(OMe)-CH2-OPH

Topics

• Acquired Immunodeficiency Syndrome (drug therapy, enzymology, pathology)
• Amino Acid Chloromethyl Ketones (pharmacology)
• Animals
• CD4-CD8 Ratio
• CD4-Positive T-Lymphocytes (enzymology, pathology)
• Caspase Inhibitors (pharmacology)
• Disease Progression
• Female
• Lymphocyte Depletion
• Macaca mulatta
• Quinolines (pharmacology)
• Simian Acquired Immunodeficiency Syndrome (drug therapy, enzymology, pathology)
• Simian Immunodeficiency Virus (metabolism)