Intracellular Casp8p41 content is inversely associated with CD4 T cell count

Abstract

Casp8p41 is a protein fragment generated by cleavage of procaspase 8 by human immunodeficiency virus (HIV) protease. We measured Casp8p41 content in memory CD4 T cells and analyzed the association of Casp8p41 content with CD4 T cell count, cross-sectionally and longitudinally. Casp8p41 content was inversely correlated with CD4 T cell count, and change in Casp8p41 content was associated with absolute CD4 T cell count with change over time. Casp8p41 change was a better predictor of CD4 T cell count change than activated CD8 T cell percentage or viral load and was comparable to bacterial 16s DNA levels. This suggests that Casp8p41 is a relevant mediator of CD4 T cell death during HIV infection.

Figure 1

A, Diagram of the generation and effects of Casp8p41 in human immunodeficiency virus (HIV)–infected cells. B, Representative dot plots demonstrating the gating strategy for quantification of the percentage of memory CD4 T cells positive for Casp8p41 by flow cytometry. In total, 1.5 to 2 million events per patient were analyzed. C, Casp8p41 colocalizes with HIV p24 antigen in HIV-infected patients. D, Casp8p41 content was measured and compared in 13 HIV-uninfected and 67 HIV-infected individuals. *P < .002, Mann-Whitney test.

Figure 2

Cross-sectional analysis of the correlation between (A) percent memory CD4 T cells positive for Casp8p41 and absolute CD4 T cell counts (r = −0.31, P = .03) or (B) between human immunodeficiency virus level and absolute CD4 T cell counts (r = 0.006, P = .97) in 53 HIV-infected patients with active viral replication. Correlation coefficients calculated by Spearman Rank test. *P < .05 was considered statistically significant. Casp8p41 content was measured longitudinally in previously antiretroviral naive HIV-infected patients who started antiretroviral therapy and compared with the CD4 T cell count. Representative plots of the percentage memory CD4 T cells positive for Casp8p41 (circles) and CD4 T cell counts (squares) a patient with consistently decreasing Casp8p41 content (C), or a patient with increasing Casp8p41 content (D).