title: The CD8+ cell noncytotoxic anti-HIV response can be blocked by protease inhibitors.
abstract: CD8+ cells from healthy HIV-infected individuals can suppress HIV replication in infected CD4(+) cells without killing the cells. This CD8+ cell noncytotoxic antiviral response (CNAR), observed by coculture of CD8+ cells with infected CD4+ cells, is associated with secretion of a CD8+ cell antiviral factor (CAF). In attempts to identify CAF, we discovered that certain protease inhibitors, particularly leupeptin, can block, by up to 95%, the anti-HIV activity in CD8+ cell culture fluids as well as inhibit CNAR. The effect is dose-dependent and is observed in up to 70% of the CAF and CNAR assays by using fluids and cells from several different subjects. Pretreatment of CD8+ cells with leupeptin reduces CNAR, further supporting an inhibitory effect on a CD8+ cell product. This inhibitory activity of protease inhibitors does not affect cell growth, expression of activation antigens, or viability of either CD8+ cells or the infected CD4+ cells. The results suggest that a part of the CD8+ cell noncytotoxic response involves the activity of a protease or a protein that interacts with protease inhibitors. Proteolysis of a CD8+ cell product(s) may be involved. This observation offers a promising approach for identifying the mechanism of CNARCAF activity.
authors.affiliation: Department of Medicine, University of California School of Medicine, San Francisco, CA 94143-1270, USA.
authors.forename: Carl E
authors.initials: CE
authors.lastname: Mackewicz
authors.forename: Charles S
authors.initials: CS
authors.lastname: Craik
authors.forename: Jay A
authors.initials: JA
authors.lastname: Levy
mesh_terms: D000998:Antiviral Agents / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology*; D006678:HIV / Q000276:immunology* / Q000502:physiology; D015658:HIV Infections / Q000276:immunology / Q000821:virology; D006801:Humans; D066298:In Vitro Techniques; D007976:Leupeptins / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology*; D014779:Virus Replication
chemical_list: D000998:Antiviral Agents; D007976:Leupeptins; D011480:Protease Inhibitors; C032854:leupeptin