T cells with high PD-1 expression are associated with lower HIV-specific immune responses despite long-term antiretroviral therapy

Abstract

Objective: We evaluated frequencies of T cells with high PD-1 expression (PD-1) before and after long-term effective antiretroviral therapy (ART), and determined if frequencies on-ART correlated positively with measures of HIV persistence and negatively with HIV-specific responses.

Methods: We enrolled individuals who started ART during chronic infection and had durable suppression of viremia for at least 4 years (N = 99). We assessed PD-1 T-cell frequencies at timepoints pre-ART and on-ART using flow cytometry, and evaluated how frequencies on-ART are associated with measures of HIV persistence, HIV-specific immune responses, and immune activation levels.

Results: Pre-ART, PD-1 CD4 T cells correlated positively with viremia and negatively with CD4 T-cell count. At year 1 on-ART, %PD-1 CD4 T cells decreased but then remained stable at 4 and 6-15 years on-ART, whereas %PD-1 CD8 T cells on-ART remained similar to pre-ART. PD-1 CD4 T cells correlated positively with HIV DNA pre-ART and on-ART, and with CD4 T-cell activation on-ART. PD-1 CD4 T cells negatively correlated with HIV Gag-specific and Env-specific T-cell responses but not with CMV-specific or EBV-specific responses. PD-1 CD8 T cells trended towards a negative correlation with responses to Gag and Env, but not to CMV and EBV.

Conclusion: PD-1 T cells persist in blood despite prolonged suppression on ART, correlate with HIV DNA levels, and are associated with lower HIV-specific T-cell responses but not CMV-specific or EBV-specific responses, suggesting that these cells are HIV-specific. The findings support evaluating PD-1 blockade strategies for their effect on HIV persistence and HIV-specific immunity.

Figure 1.. (A) PD-1^HI and (B) PD-1⁺ T cell frequencies following antiretroviral therapy (ART) initiation.

Figure shows the frequencies of PD-1^HI and total PD-1⁺ CD4⁺ and CD8⁺ T cells prior to ART (0) and at 1, 4, and 6-15 years following ART initiation. P values are for the change in frequencies between pre-ART (year 0) and year 1 on-ART.

Figure 1.. (A) PD-1^HI and (B) PD-1⁺ T cell frequencies following antiretroviral therapy (ART) initiation.

Figure shows the frequencies of PD-1^HI and total PD-1⁺ CD4⁺ and CD8⁺ T cells prior to ART (0) and at 1, 4, and 6-15 years following ART initiation. P values are for the change in frequencies between pre-ART (year 0) and year 1 on-ART.

Figure 2.

Correlations of on-ART (A) PD-1^HI and (B) total PD-1⁺ T cell frequencies with pre-ART percentages.

Figure 2.

Correlations of on-ART (A) PD-1^HI and (B) total PD-1⁺ T cell frequencies with pre-ART percentages.

Figure 3.

Association between PD-1^HI (A) CD4⁺ and (B) CD8⁺ T cell frequencies with levels of HIV-1 DNA pre- and on-ART and with interferon gamma ELISPOT responses to (C) Gag and (D) Env peptide pools.

Figure 3.

Association between PD-1^HI (A) CD4⁺ and (B) CD8⁺ T cell frequencies with levels of HIV-1 DNA pre- and on-ART and with interferon gamma ELISPOT responses to (C) Gag and (D) Env peptide pools.

Figure 3.

Association between PD-1^HI (A) CD4⁺ and (B) CD8⁺ T cell frequencies with levels of HIV-1 DNA pre- and on-ART and with interferon gamma ELISPOT responses to (C) Gag and (D) Env peptide pools.

Figure 3.

Association between PD-1^HI (A) CD4⁺ and (B) CD8⁺ T cell frequencies with levels of HIV-1 DNA pre- and on-ART and with interferon gamma ELISPOT responses to (C) Gag and (D) Env peptide pools.