Cutting Edge: Epitope-Dependent Effect of Nef-Mediated HLA Class I Down-Regulation on Ability of HIV-1-Specific CTLs to Suppress HIV-1 Replication

Abstract

It is believed that Nef-mediated HLA class I down-regulation is one of the mechanisms that allow HIV-1-infected cells to escape from being killed by HIV-1-specific human CTLs. In this study, we show that the effect of Nef-mediated HLA class I down-regulation on the ability of HIV-1-specific CTLs to suppress HIV-1 replication is epitope dependent. The CTLs specific for two Pol epitopes presented by HLA-B*5101, one of the HLA alleles associated with slow progression to AIDS, effectively killed HIV-1-infected CD4+ T cells and suppressed HIV-1 replication. In contrast, those specific for the other four epitopes failed to kill HIV-1-infected CD4+ T cells and partially or hardly suppressed HIV-1 replication. The difference of the ability between these two types of CTLs may result from the difference of the number of HLA class I epitope complex on the surface of NL-432-infected CD4+ T cells.

Pol-Specific CD8 + T Cells Recognize Simian Immunodeficiency Virus-Infected Cells Prior to Nef-Mediated Major Histocompatibility Complex Class I Downregulation

“…These results are interesting in light of a recent study investigating the effect of Nef-mediated MHC-I downregulation on the ability of HIV-specific CD8 ϩ T cells to suppress viral replication (41). Intriguingly, Pol-specific CD8 ϩ T cells effectively eliminated HIV-infected cells, even in the presence of effective MHC-I down modulation.…”

Improved Vaccine Protection from Simian AIDS by the Addition of Nonstructural Simian Immunodeficiency Virus Genes

“…CTL recognition of Nef, Rev, and Tat epitopes on cells in the early stage of infection results in their elimination before progeny virus is released (17,21). In a series of elegant experiments, van Baalen et al (22) have shown that CTL recognition of early, rather than late, Ags resulted in a Ն2-to 3-log 10 reduction of virus production by similar numbers of effector cells in 10 days of culture.…”

“…Indeed, cytotoxic responses to epitopes encoded by these open reading frames are frequently detected in primary HIV infection (15,16). Immune response to early regulatory genes may be particularly important to viral containment, because their recognition by cytotoxic CD8 ϩ T cells may occur before Nef-mediated down-modulation of MHC class I molecules on the surface of infected cells, resulting in the elimination of infected cells before the release of virions (17)(18)(19)(20)(21)(22). The ability of early regulatory protein-specific CTLs to exert immunological pressure has been inferred by the selection for viral immune escape variants in Tat (23) and Nef (24,25) during primary SIV infection.…”

Selection of TI8-8V Mutant Associated with Long-Term Control of HIV-1 by Cross-Reactive HLA-B*51:01–Restricted Cytotoxic T Cells

“…The cytotoxic activity of TI8-specific CTL clones was determined by the standard 51 Cr release assay described previously (36). Briefly, C1R-B*51:01 cells were incubated with 100 mCi Na 2…”

“…The 8T mutation is predominantly found in HIV-1-infected HLA-B*51:01 + donors. TI8-specific CTLs have a strong ability to suppress the replication of wild-type (WT) and the 8V mutant viruses in vitro but fail to suppress that of the 8T, 8L, and 8R mutant viruses (35,36). A study using a Japanese hemophiliac cohort showed that the 8V mutation is found in only HLA-B*B51:01 + elite controllers (34), suggesting that the selection of the 8V mutant virus is a critical factor for long-term control of HIV-1 in Japanese hemophiliacs.…”