Epitope-dependent effect of long-term cART on maintenance and recovery of HIV-1-specific CD8⁺ T cells

The frequency of HIV-1-specific T cells is reduced and their functional ability remains impaired in people living with HIV-1 (PLWH) under combined antiretroviral therapy (cART). However, no studies have yet reported on T-cell responses to large numbers of well-characterized HIV-1 epitopes before and under cART within the same individuals. Therefore, how cART affects the maintenance of HIV-1-specific CD8(+) T cells and which HIV-1-specific CD8(+) T cells would be useful for curative treatment remain unclear. We investigated T-cell responses to 63 HIV-1 epitopes at pre-cART and under cART in 90 PLWH who received long-term cART. The frequency of T-cell responses to HIV-1 epitopes under long-term cART varied from 0% to 100%, indicating an epitope-dependent effect of long-term cART on HIV-1-specific CD8(+) T cells. The magnitude of the responses under cART was 26.2% of that at pre-cART. The frequency of T-cell responses to protective epitopes under cART was higher than that to non-protective ones. T-cell responses to HIV-1 epitopes were detected at pre-cART in most non-AIDS HIV patients, whereas they were not detectable at pre-cART in half of the AIDS patients. Long-term cART enhanced the ability of HIV-1-specific T cells to proliferate in vitro in non-AIDS HIV patients, while it restored this ability of the T cells in AIDS patients. This study demonstrated that CD8(+) T cells specific for large numbers of HIV-1 epitopes were maintained in an epitope-dependent fashion under long-term cART and implied that some HIV-1-specific T cells are still candidates as effector cells for curative treatment. IMPORTANCE HIV-1-specific CD8(+) T cells are anticipated to become effector cells for curative treatment using the "shock and kill" approach in people living with HIV-1 (PLWH) under combined antiretroviral therapy (cART). Previous studies demonstrated that the frequency of HIV-1-specific CD8(+) T cells is reduced under cART and their functional ability remains impaired. These studies analyzed T-cell responses to a small number of HIV-1 epitopes or overlapping HIV-1 peptides. Therefore, the features of CD8(+) T cells specific for HIV-1 epitopes under cART remain only partially clarified. Here, we analyzed CD8(+) T cells specific for 63 well-characterized epitopes in 90 PLWH. We demonstrated that CD8(+) T cells specific for large numbers of HIV-1 epitopes were maintained in an epitope-dependent fashion under long-term cART and that long-term cART enhanced or restored the ability of HIV-1-specific T cells to proliferate in vitro. This study implies that some HIV-1-specific T cells would be useful as effector cells for curative treatment.