Longitudinal Changes in CD4+, CD8+ T Cell Phenotype and Activation Marker Expression Following Antiretroviral Therapy Initiation among Patients with Cryptococcal Meningitis

Abstract

Despite improvement in the prognosis of HIV/AIDS (human immunodeficiency virus/acquired immune deficiency syndrome) patients on antiretroviral therapy (ART), cryptococcal meningitis (CM) still causes 10–15% mortality among HIV-infected patients. The immunological impact of ART on the CD4+ and CD8+ T cell repertoire during cryptococcal co-infection is unclear. We determined longitudinal phenotypic changes in T cell subsets among patients with CM after they initiated ART. We hypothesized that ART alters the clonotypic phenotype and structural composition of CD4+ and CD8+ T cells during CM co-infection. For this substudy, peripheral blood mononuclear cells (PBMC) were isolated at four time points from CM patients following ART initiation during the parent study (ClinicalTrials.gov number, NCT01075152). Phenotypic characterization of CD4+ and CD8+ T cells was done using T cell surface marker monoclonal antibodies by flow cytometry. There was variation in the expression of immunophenotypic markers defining central memory (CD27+CD45R0+), effector memory (CD45R0+CD27–), immune activation (CD38+ and Human Leucocyte Antigen DR (HLA-DR+), and exhaustion (Programmed cell death protein one (PD-1) in the CD4+ T cell subset. In comparison to the CD4+ T cell population, the CD8+ central memory subset declined gradually with minimal increase in the effector memory subset. Both CD4+ and CD8+ T cell immune exhaustion and activation markers remained elevated over 12 weeks. The relative surge and decline in the expression of T cell surface markers outlines a variation in the differentiation of CD4+ T cells during ART treatment during CM co-infection.

Landmark clinical observations and immunopathogenesis pathways linked to HIV and Cryptococcus fatal central nervous system co‐infection

“…24 Another study at the same timing reported PD-1 expression on T cells at 60% of CD4 + T cells and 30% of CD8 + T cells with persistant high PD-1 expression on circulating T cells beyond 12 weeks of follow-up. 99 In this case, it is not clear whether sustained PD-1 expression in cryptococcosis is due to persistent activation or another mechanism. But, whether PD-1 or its ligand expression is different with infecting Cryptococcus species is yet to the investigated.…”

“…One study at cryptococcal meningitis diagnosis reported the PD‐1 expression on circulating cellular lineages at 2% of B cells (CD19 + lymphocytes), 25% of T cells and 1% of monocytes 24 . Another study at the same timing reported PD‐1 expression on T cells at 60% of CD4 + T cells and 30% of CD8 + T cells with persistant high PD‐1 expression on circulating T cells beyond 12 weeks of follow‐up 99 . In this case, it is not clear whether sustained PD‐1 expression in cryptococcosis is due to persistent activation or another mechanism.…”

Prediction of Hospital Discharge Outcome From Changes in Albumin Quotient and Cerebrospinal Fluid Lactate Dehydrogenase in Patients With Cryptococcal Meningitis

“…The dominant mechanism for HIV-induced immunode ciency is depletion and distortion of CD4 + T cells, and further lymphocyte defects [31,32]. Therefore, dynamic monitoring of CD4 + T cell counts is critical for HIV-positive patients [34]. In our cohort, there was no signi cant difference in baseline CD4 + T cell counts at admission between favorable outcome group and unfavorable outcome group.…”