Noncytolytic inhibition of X4 virus by bulk CD8(+) cells from human immunodeficiency virus type 1 (HIV-1)-Infected persons and HIV-1-Specific cytotoxic T lymphocytes is not mediated by beta-chemokines

Human immunodeficiency virus (HIV)-specific cytotoxic T lymphocytes (CTL) m ediate immunologic selection pressure by both cytolytic and noncytolytic me chanisms. Non cytolytic mechanisms include the release of beta -chemokines blocking entry of R5 HIV-1 strains. In addition, CD8(+) cells inhibit X4 vi rus isolates via release of as yet poorly characterized soluble factors. To further characterize these factors, we performed detailed analysis of CTL as well as bulk CD8+ T lymphocytes from six HIV-1-infected individuals and from six HIV-1-seronegative individuals. Kinetic studies revealed that secr eted suppressive activities of HIV-1-specific CTL and bulk CD8(+) T lymphoc ytes from all HIV-1-infected persons are significantly higher than that of supernatants from seronegative controls. The suppressive activity could be blocked by monensin and brefeldin A, was heat labile, and appeared in a pat tern different from that of secretion of chemokines (MDC, I-309, MIP-1 alph a, MIP-1 beta, and RANTES), cytokines (gamma interferon, tumor necrosis fac tor alpha, and granulocytemacrophage colony-stimulating factor), and interl eukins (interleukin-13 and interleukin-16). This suppression activity was c haracterized by molecular size exclusion centrifugation and involves a supp ressive activity of > 50 kDa which could be bound to heparin and a nonbindi ng inhibitory activity of < 50 kDa. Our data provide a functional link betw een CD8(+) cells and CTL in the noncytolytic inhibition of HIV-1 and sugges t that suppression of X4 virus is mediated through proteins. The sizes of t he proteins, their affinity for heparin, and the pattern of release indicat e that these molecules are not chemokines.