Identification of multiple HIV-1 CTL epitopes presented by HLA-B∗5101 molecules

et al. 2004

J Virol

Self Cite

118

Investigating escape mechanisms of human immunodeficiency virus type 1 (HIV-1) from cytotoxic T lymphocytes (CTLs) is essential for understanding the pathogenesis of HIV-1 infection and developing effective vaccines. To study the processing and presentation of known CTL epitopes, we prepared Epstein-Barr virustransformed B cells that endogenously express the gag gene of six field isolates by adopting an env/nef-deletion HIV-1 vector pseudotyped with vesicular stomatitis virus G protein and then tested them for the recognition by Gag epitope-specific CTL lines or clones. We observed that two field variants, SLFNTVAVL and SVYNTV ATL, of an A‫-1020ء‬restricted Gag CTL epitope SLYNTVATL, and three field variants, KYRLKHLVW, QYRLKHIVW, and RYRLKHLVW, of an A24-restricted Gag CTL epitope KYKLKHIVW escaped from being killed by the CTL lines, despite the fact that they were recognized when the synthetic peptides corresponding to these variant sequences were exogenously loaded onto the target cells. Thus, their escape is likely due to the changes that occur during the processing and presentation of epitopes in the infected cells. Mutations responsible for this mode of escape were located within the epitope regions rather than the flanking regions, and such mutations did not influence the virus replication. The results suggest that the impaired antigen processing and presentation often occur in HIV-1 field isolates and thus are one of the major mechanisms that enable HIV-1 to escape from CTL recognition. We emphasize the importance of testing HIV-1 variants in an endogenous expression system.

Section: Resultsmentioning

confidence: 99%

“…Conventionally, the intracellular HIV-1 antigen processing and presentation has been studied with recombinant vaccinia viruses expressing an HIV-1 gene (3,4,11,20,26). Several studies have addressed this issue in the context of HIV-infected T cells (4,29,32,33).…”

mentioning

confidence: 99%

Impaired Processing and Presentation of Cytotoxic-T-Lymphocyte (CTL) Epitopes Are Major Escape Mechanisms from CTL Immune Pressure in Human Immunodeficiency Virus Type 1 Infection

Yokomaku

Miura

et al. 2004

J Virol

Self Cite

118

“…Binding of HIV-1 epitope peptides to HLA-B*5101 was examined by a peptide stabilization assay using RMA-S-B*5101 cells as previously described (10).…”

Section: Peptide Binding Assaymentioning

confidence: 99%

“…HLA-B57 and -B27 alleles are well-known factors associated with slow progression to AIDS (10). A recent study revealed that HIV-1-specific CD8 ϩ T cells have a high proliferation capacity that is coupled to perforin expression in HLA-B*5701 ϩ LTNPs but not in HLA-B*5701 ϩ or HLA-B*5701 Ϫ progressors (15), suggesting that HIV-1-specific CD8 ϩ T cells, which have a high proliferation capacity and effector function, control HIV-1 replication in HLA-B*5701 ϩ LTNPs.…”

Section: Ability Of Four Hla-b*5101-restricted Ctls To Recognize Hiv-mentioning

confidence: 99%

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

The Journal of Immunology

Fujiwara

Oka

et al. 2005

Self Cite

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.

“…Two HIV-1-specific, HLA-B*3501-restricted CTL clones (SF2-33-135 and SF2-4-2), an HLA-A*2402-restricted CTL clone (SF2-Env379-9-3), and an HLA-B*5101-restricted CTL clone (SF2-pol283-8-54) were previously generated (18,41,42). The HIV-1-specific, HLA-A*3303-restricted CTL clone SF2-pol594-9-1 was recently established (unpublished data).…”

Section: Purification Of Cd4mentioning

confidence: 99%

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

Akari

Adachi

et al. 2002

J Virol

Self Cite

105

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.