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

Abstract

The mutational escape of HIV-1 from established CTL responses is becoming evident. However, it is not yet clear whether antigenic variations of HIV-1 may have an additional effect on the differential antiviral effectiveness of HIV-specific CTLs. Herein, we characterized HIV-specific CTL responses toward Pol, Env, and Nef optimal epitopes presented by HLA-B*35 during a chronic phase of HIV-1 infection. We found CTL escape variants within Pol and Nef epitopes that affected recognition by TCRs, although there was no mutation within the Env epitope. An analysis of peptide-HLA tetrameric complexes revealed that CD8 T cells exclusively specific for the Nef variant were generated following domination by the variant viruses. The variant-specific cells were capable of killing target cells and producing antiviral cytokines but showed impaired Ag-specific proliferation ex vivo, whereas wild-type specific cells had potent activities. Moreover, clonotypic CD8 T cells specific for the Pol variant showed diminished proliferation, whereas Env-specific ones had no functional heterogeneity. Taken together, our data indicate that antigenic variations that abolished TCR recognition not only resulted in escape from established CTL responses but also eventually generated another subset of variant-specific CTLs having decreased antiviral activity, causing an additional negative effect on antiviral immune responses during a chronic HIV infection.

Impact of Intrinsic Cooperative Thermodynamics of Peptide-MHC Complexes on Antiviral Activity of HIV-Specific CTL

“…Both VY8 and RY11 share anchor residues, proline at position 2 and tyrosine at the C terminus, which are optimal for binding with HLA-B*3501 (56,57); and both Ags are dominantly recognized in HLA-B*3501 ϩ individuals with an HIV-1 infection (6,10,58). Even in such a case, the improved thermostability of pMHC by an amino acid substitution within the epitopes, even other than a primary anchor residue, can substantially enhance the susceptibility to recognition by CTLs for killing target cells, suggesting that the altered peptide ligand strategy is capable of enhancing CTL-mediated immune responses against HIV-1 infection similar to that used for anti-cancer vaccines targeting self-Ags (34, 39).…”

“…However, significant differences exist not only in the antiviral activity of HIV-specific CTLs among specificities (4 -7) but also in CTL specificities between early and chronic phases of an HIV infection (8 -10). Changes in CTL specificity could lead to the accumulation of less effective antiviral CTLs in the late chronic phase of an infection (6,11,12). There are a number of different possibilities in the literature that potentially explain the heterogeneity in the antiviral activity of CTLs, such as: differences in functional avidity of CTLs toward exogenously pulsed synthetic peptides (7,13), TCR usage (14,15), cross-reactive capacity of CTLs toward variant Ags (14,16), kinetics and amplitude of immunogenic protein expression (9,(17)(18)(19), Ag processing and presentation pathways (20,21), and binding activity of an antigenic peptide to a given HLA class I molecule (22).…”

“…CTL clones were established as previously described (6,15) by using PBMC samples taken from HLA-B*3501 ϩ individuals (Pt-01, Pt-03, Pt-19, and Pt-33) in the chronic phase of an HIV-1 infection. Briefly, a bulk CTL culture, which had been established by stimulation of PBMC with a synthetic peptide for 1-2 wk, was further seeded at a density of 0.8 or 5 cells/well with a cloning mixture (irradiated allogeneic PBMC and C1R-B3501 cells pulsed with 1 M peptide in RPMI 1640 with 10% FCS and 100 U/ml recombinant IL-2).…”

Differential Clade-Specific HLA-B*3501 Association with HIV-1 Disease Outcome Is Linked to Immunogenicity of a Single Gag Epitope

“…In this way, HLA alleles such as HLA-B*57 or HLA-B*27, associated with immune control (4,46,59), restrict dominant Gag-specific responses, escape from which results in a substantial reduction in viral replicative capacity (13,15,46,53,65). In contrast, HLA alleles such as HLA-B*35, associated with rapid disease progression (12), restrict dominant epitopes in Nef, Env, and other non-Gag proteins (7,39,58,67,69,72,73).…”

Adoptive Transfer of Engineered Rhesus Simian Immunodeficiency Virus-Specific CD8+T Cells Reduces the Number of Transmitted/Founder Viruses Established in Rhesus Macaques

“…ϩ T cell plays an important role in control of AIDS viruses, i.e., human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) (1)(2)(3)(4)(5)(6)(7)(8)(9)(10). However, in most cases, CD8…”