Abstract
The novel therapies with immune checkpoint inhibitors hold great promises for patients with chronic virus infections and cancers. This is based mainly on the partial reversal of the exhausted phenotype of antigen-specific cytotoxic CD8 T cells (CTL). Recently, we have shown that the restoration of HIV-specific T cell function depends on the HIV infection stage of an infected individual. Here we aimed to answer two fundamental questions: (i) Can one estimate growth parameters for the HIV-specific proliferative responsiveness upon PD-L1 blockade ex vivo? (ii) Can one use these parameter estimates to predict clinical benefit for HIV-infected individuals displaying diverse infection phenotypes? To answer these questions, we first analyzed HIV-1 Gag-specific CD8 T cell proliferation by time-resolved CFSE assays and estimated the effect of PD-L1 blockade on division and death rates, and specific precursor frequencies. These values were then incorporated into a model for CTL-mediated HIV control and the effects on CTL frequencies, viral loads and CD4 T cell counts were predicted for different infection phenotypes. The biggest absolute increase in CD4 T cell counts was in the group of slow progressors while the strongest reduction in virus loads was observed in progressor patients. These results suggest a significant clinical benefit only for a subgroup of HIV-infected individuals. However, as PD1 is a marker of lymphocyte activation and expressed on several lymphocyte subsets including also CD4 T cells and B cells, we subsequently examined the multiple effects of anti-PD-L1 blockade beyond those on CD8 T cells. This extended model then predicts that the net effect on HIV load and CD4 T cell number depends on the interplay between positive and negative effects of lymphocyte subset activation. For a physiologically relevant range of affected model parameters, PD-L1 blockade is likely to be overall beneficial for HIV-infected individuals.
Highlights
A hallmark of chronic virus infections with persisting antigen and cancer growth is the downregulation of immune effector mechanisms [1,2,3]
Based on the hypothesis that gain in the proliferation of CTL by such interventions may positively influence HIV-1 disease progression, we developed a general framework of how to quantify the proliferative CTL responsiveness after PD-L1 blockade, and translate it to patient outcome predictions
PD-L1 blockade activates (i) exhausted CD4 T cells generating additional HIV target cells for virus expansion as well as (ii) exhausted B cells producing increasing antibody levels that potentially inhibit HIV spread. To assess these virus-specific effects of a PD-L1 blockade, we extended our basic model and incorporated experimentally determined CD4 T cell proliferation gains and estimates on HIVspecific antibody increases
Summary
A hallmark of chronic virus infections with persisting antigen and cancer growth is the downregulation of immune effector mechanisms [1,2,3]. Amongst these are T cell exhaustion by deletion [4] and functional impairment [5]. T cell exhaustion is partly reversible by antibodies that inhibit the interaction of the inhibitory receptors with their ligands [2] This exhausted T cell (Tex) revitalization, albeit transient, can lead to a reduction of virus titers and cancer growth [7]. A search for reliable predictive biomarker that could identify therapy-responsive patients is presently pursued with intensity
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