Prediction of PD-L1 inhibition effects for HIV-infected individuals

• Published in: PLoS computational biology Vol. 15; no. 11; p. e1007401
• Main Authors: Zheltkova, Valerya, Argilaguet, Jordi, Peligero, Cristina, Bocharov, Gennady, Meyerhans, Andreas
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.11.2019; Public Library of Science (PLoS)
• Subjects: Analysis; Antibodies; Antigens; Apoptosis; B cells; B7-H1 Antigen - metabolism; B7-H1 Antigen - physiology; Biology; Biology and Life Sciences; Cancer therapies; CD4 antigen; CD4-Positive T-Lymphocytes - immunology; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - physiology; Cell activation; Cell cycle; Cell cycle and cell division; Cell Division; Cell growth; Cell number; Cell Proliferation; Computational mathematics; Cytotoxic T cells; Cytotoxicity; Decomposition; Gag protein; Health aspects; Health sciences; Histograms; HIV; HIV infections; HIV Infections - immunology; HIV Infections - therapy; HIV patients; HIV-1 - immunology; Human immunodeficiency virus; Humans; Immune checkpoint inhibitors; Infection; Infections; Laboratories; Lymphocyte Activation - immunology; Lymphocytes; Lymphocytes B; Lymphocytes T; Mathematical models; Medical research; Medicine and Health Sciences; Models, Theoretical; Parameter estimation; PD-1 protein; PD-L1 protein; Peptides; Phenotypes; Population; Predictions; Questions; Restoration; Subgroups; T cells; T helper cells; T-Lymphocytes, Cytotoxic - immunology; Viral Load; Virus diseases; Viruses; Russia; Spain
• ISSN: 1553-7358; 1553-734X; 1553-7358
• DOI: 10.1371/journal.pcbi.1007401

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.