Kuse N, Akahoshi T, Gatanaga H, Ueno T, Oka S, Takiguchi M.
Selection of TI8-8V mutant associated with long-term control of HIV-1 by cross-reactive HLA-B*51:01-restricted cytotoxic T cells. J Immunol. 2014 Nov 15;193(10):4814-22.
- The 8V mutation of the TI8 epitope was found in all elite controllers of HIV-1-infected HLA-B*51:01+ Japanese hemophiliacs.
- The 8V was an escape mutant selected by cross-reactive CTLs carrying TCR that could discriminate this mutant from WT.
- Cross-reactive CTLs which evenly recognize both wild-type and the 8V viruses were elicited after emergence of the 8V virus.
- Two-types of cross-reactive CTLs may contribute to control HIV-1 for a long time such as 30 years.
Elite controllers of HIV-1-infected HLA-B*51:01(+) hemophiliacs, who remain disease free and have a very low plasma viral load for >30 y, had the 8V mutation at an immunodominant Pol283-8 (TI8) epitope, whereas the 8T mutant was predominantly selected in other HIV-1-infected HLA-B*51:01(+) hemophiliacs, suggesting an important role of the 8V mutant selection in long-term control of HIV-1. However, the mechanism of this selection and the long-term control in these elite controllers remains unknown. In this study, we investigated the mechanism of the 8V mutant selection in these controllers. TI8-specific CTLs from these individuals evenly recognized both TI8 peptide-pulsed and TI8-8V peptide-pulsed cells and effectively suppressed replication of wild-type (WT) and the 8V viruses. However, the results of a competitive viral suppression assay demonstrated that CTLs from the individual who had WT virus could discriminate WT virus from the 8V virus, whereas those from the individuals who had the 8V virus evenly recognized both viruses. The former CTLs carried TCRs with weaker affinity for the HLA-B*51:01-TI8-8V molecule than for the HLA-B*51:01-TI-8 one, whereas the latter ones carried TCRs with similar affinity for both molecules. The reconstruction of the TCRs from these CTLs in TCR-deficient cells confirmed the different recognition of the TCRs for these epitopes. The present study showed that the 8V mutant virus could be selected by cross-reactive CTLs carrying TCR that could discriminate a small difference between the two molecules. The selection of the 8V mutant and elicitation of these two cross-reactive CTLs may contribute to the long-term control of HIV-1.