Exhaustion of Activated CD8 T Cells Predicts Disease Progression in Primary HIV-1 Infection

Abstract

The rate at which HIV-1 infected individuals progress to AIDS is highly variable and impacted by T cell immunity. CD8 T cell inhibitory molecules are up-regulated in HIV-1 infection and associate with immune dysfunction. We evaluated participants (n = 122) recruited to the SPARTAC randomised clinical trial to determine whether CD8 T cell exhaustion markers PD-1, Lag-3 and Tim-3 were associated with immune activation and disease progression. Expression of PD-1, Tim-3, Lag-3 and CD38 on CD8 T cells from the closest pre-therapy time-point to seroconversion was measured by flow cytometry, and correlated with surrogate markers of HIV-1 disease (HIV-1 plasma viral load (pVL) and CD4 T cell count) and the trial endpoint (time to CD4 count <350 cells/μl or initiation of antiretroviral therapy). To explore the functional significance of these markers, co-expression of Eomes, T-bet and CD39 was assessed. Expression of PD-1 on CD8 and CD38 CD8 T cells correlated with pVL and CD4 count at baseline, and predicted time to the trial endpoint. Lag-3 expression was associated with pVL but not CD4 count. For all exhaustion markers, expression of CD38 on CD8 T cells increased the strength of associations. In Cox models, progression to the trial endpoint was most marked for PD-1/CD38 co-expressing cells, with evidence for a stronger effect within 12 weeks from confirmed diagnosis of PHI. The effect of PD-1 and Lag-3 expression on CD8 T cells retained statistical significance in Cox proportional hazards models including antiretroviral therapy and CD4 count, but not pVL as co-variants. Expression of ‘exhaustion’ or ‘immune checkpoint’ markers in early HIV-1 infection is associated with clinical progression and is impacted by immune activation and the duration of infection. New markers to identify exhausted T cells and novel interventions to reverse exhaustion may inform the development of novel immunotherapeutic approaches.

Immunosenescence and hurdles in the clinical management of older HIV-patients

“…PD-1 has a central role in virus-specific CD8 T-cell exhaustion, it is upregulated in most CD8 T-cell populations during HIV infection and correlates with the level of CD8 T-cell exhaustion and with disease progression. [172][173] Several studies on animal models showed how PD-1 blockade was able to enhance proliferation of CD4 and CD8 T-cells, especially HIV-specific clones; moreover, an increased proliferation of resting memory B-cells and a reduction in microbial translocation were also demonstrated in animals treated with anti-PD-1 antibodies. 174 Other potential immune checkpoints target for immune intervention may be CTLA-4, Lag-3, Tim-3 and TIGIT and several investigators are exploring therapeutic options directed at these molecules.…”

Immune checkpoint blockade in infectious diseases

“…In the absence of ART, increased expression of PD-1 was associated with accelerated decline in CD4 + T cells following acute infection 48 and untreated chronic infection 36 . Following ART, PD-1 expression on CD8 + T cells has been associated with impaired CD4 + T cell immune reconstitution 49 microvascular disease 50 , elevated oxidised high and low density lipoproteins 51 and a shorter time to viral rebound once ART was stopped 52 .…”

PD-1 Blockade Promotes Epitope Spreading in Anticancer CD8+ T Cell Responses by Preventing Fratricidal Death of Subdominant Clones To Relieve Immunodomination

“…However, when the immune system fails to eradicate cancer or clear stubborn infections, prolonged antigenic stimulation may lead to T CD8 functional impairments, including exhaustion and anergy (1–4). Exhausted or anergic T CD8 are often unable to secrete effector cytokines or launch optimal proliferative and cytotoxic responses to cognate Ags, which may compromise host defense mechanisms, positive clinical outcomes or even survival (5–7). …”