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

Abstract

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.

Altering Effects of Antigenic Variations in HIV-1 on Antiviral Effectiveness of HIV-Specific CTLs

“…Recent studies have demonstrated that mutational escape from HIV-specific CTL is caused by interference with the intracellular processing of virus-derived proteins (15,16). We also found HLA-B*35-associated mutations flanking the epitopic regions in Env and Nef.…”

“…CTL escape mutations occur at critical sites in the CTL epitopes in the viral genome or in the flanking sequences encoding these epitopes, leading to altered Ag processing (15,16), loss of peptide-HLA binding, or loss of TCR recognition. The two former consequences of these mutations result in the ultimate loss of epitopes to be presented on the surface of virus-infected cells for recognition by CTLs.…”

Quantifiable cytotoxic T lymphocyte responses and HLA-related risk of progression to AIDS

“…A hallmark of HIV infection is its ability to generate immune escape mutations in epitopes (14)(15)(16)(17) and their flanking regions (18,19). CTL escape mutants have been found in population studies, in which they correlate with higher viral loads (20), and they can be transmitted from mother to child (21,22) as well as between sexual partners (ref.…”

Degeneracy and Repertoire of the Human HIV-1 Gag p1777–85 CTL Response

“…N is rarely substituted (1 of 371), and the C-terminal flanking sequences, important for processing (28), are also highly conserved (9,23,29). Only two intraepitopic substitutions that affect processing have been reported by one group (30), suggesting that this may not be a common escape mechanism for SL9. The T cell repertoire for SL9 is broad and sustainable, because large numbers of circulating SL9-T cells are found in 75% of chronically infected patients (10 -12) and can remain elevated for years (17).…”