Different Effects of Nef-Mediated HLA Class I Down-Regulation on Human Immunodeficiency Virus Type 1-Specific CD8 + T-Cell Cytolytic Activity and Cytokine Production

Abstract

ABSTRACT A previous study using a Nef-defective human immunodeficiency virus type 1 (HIV-1) mutant suggested that Nef-mediated down-regulation of HLA class I on the infected cell surface affects the cytolytic activity of HIV-1-specific cytotoxic T-lymphocyte (CTL) clones for HIV-1-infected primary CD4 + T cells. We confirmed this effect by using a nef- mutant HIV-1 strain (NL-M20A) that expresses a Nef protein which does not induce down-regulation of HLA class I molecules but is otherwise functional. HIV-1-specific CTL clones were not able to kill primary CD4 + T cells infected with a Nef-positive HIV-1 strain (NL-432) but efficiently lysed CD4 + T cells infected with NL-M20A. Interestingly, CTL clones stimulated with NL-432-infected CD4 + T cells were able to produce cytokines, albeit at a lower level than when stimulated with NL-M20A-infected CD4 + T cells. This indicates that Nef - mediated HLA class I down-regulation affects CTL cytokine production to a lesser extent than cytolytic activity. Replication of NL-432 was partially suppressed in a coculture of HIV-1-infected CD4 + T cells and HIV-1-specific CTL clones, while replication of NL-M20A was completely suppressed. These results suggest that HIV-1-specific CD8 + T cells are able to partially suppress the replication of HIV-1 through production of soluble HIV-1-suppressive factors such as chemokines and gamma interferon. These findings may account for the mechanism whereby HIV-1-specific CD8 + T cells are able to partially but not completely control HIV-1 replication in vivo.