B cell responses, immune modulation, and survival among patients with HIV-associated cryptococcal meningitis.

Abstract

ABSTRACT Introduction: A clear mechanism to advance treatment that would improve survival after HIV-associated cryptococcal meningitis despite antifungal therapy in sub-Saharan Africa remains elusive. We hypothesized that host survival differs by the levels of immune-modulated response at diagnosis. Methodology: By univariate and multivariate methods, we performed in-depth interrogation of the cryptococcal host biologic gender, clinical features, microbiologic factors, and immunologic-specific factors at baseline, focusing on B cells in the blood and CSF (objective 1) or representative Th1, Th2, Th17, Tfh cytokine and chemokine responses in CSF (objectives 2 and 3) from a longitudinal cohort of consenting adults with HIV-associated cryptococcal meningitis who died or survived on antifungal treatment. Results 1. Objective 1- Elevation of blood PD-1 expression on plasmablasts/plasma cells correlated with better survival (Chapter 4). 2. Objective 2 - Survival was lower among females at 47% compared to males at 60% and overall at 54%. By gender, female survival correlated with levels of Myeloid CCL11/Eotaxin chemokine and Lymphoid CXCL10/IP-10 chemokine modulatory responses, while male survival correlated with IL-10 and PD-L1/B7-H1 distinctive immune correlates of IL-8 and IL-15 balance (Chapter 5). 3. Objective 3 - Severe immune exhaustion, typical of the poorest immune response correlated with high CSF cryptococcal fungal burden and greatest risk of poor survival. Specific correlates of survival included peripheral CD4/CD8 T cells counts, level of CSF white cell counts, level of CSF Th1 - Lymphoid CXCL10/IP-10 underlying Th1 (IL-2, IFN-γ, TNF-α, and PD-L/B7-H1) The Myeloid CCL11/Eotaxin associated Th17 (IL-17) Th-2 (IL-13) innate (IL-15) and immune regulatory (IL-10) distinctively correlate with host survival among a group of subjects with 5-20 CSF white cells counts/μL (Chapter 6). Conclusion: The immune modulators of 1) PD-1 on plasmablasts/plasma cells, 2) Lymphoid CXCL10/IP-10 Th1, and 3) Myeloid CCL11/Eotaxin underlay an antibody and Th1 mediated mechanisms of immune-based antifungal treatment improvement to improve host survival.