Serological correlates of survival in HIV-associated cryptococcal meningitis

ABSTRACT Cryptococcal meningitis (CM), a devastating disease of the central nervous system (CNS) caused by the encapsulated fungus Cryptococcus neoformans (Cn), occurs mainly in people with HIV (PWH) with profound CD4T (CD4) cell loss. In a 2020 analysis, globally, there were 152,000 CM cases accounting for 19% of AIDS- related mortality. While cryptococcal antigen (CrAg) screening, antiretroviral therapy (ART), and potent antifungal drugs have led to earlier diagnosis and improved outcomes, mortality remains inexplicably high. The landmark >800 participant phase III randomized controlled AMBIsome Therapy Induction OptimizatiON-cryptococcal meningitis trial (AMBITION, heretofore ‘Ambition’) in African PWH with CM comparing a single dose of Liposomal Amphotericin B (L-Amb) to WHO-recommended first-line induction with Amphotericin B deoxycholate found L- AmB was noninferior, but mortality was high, 25% L-AmB, 29%, WHO, and highest (37%) in recent ART initiators. Although there were fewer adverse events with L-AmB, leading WHO to recommend a practice change to the L- AmB regimen, there are no correlates of survival or treatment response for PWH with CM. This is a major roadblock to improving CM outcomes as clinicians lack tools to make management decisions for those who do not improve, such as when and in whom to use corticosteroids or intensify antifungals. The hypothesis of this application is that certain plasma immunoglobulin (Ig) measures are associated with survival and treatment response in PWH with CM. The project builds on our extensive data showing that 1) Cn elicits distinct antibody responses in PWH with asymptomatic latency (CrAg-/CM-) and antigenemia (CrAg+) and those with disease (CM); 2) Cn capsular polysaccharide glucuronoxylomannan (GXM)-IgG levels were associated with survival in PWH with antigenemia and trended so in CM; 3) human Cn-binding Igs promote Fc receptor (FcR)-mediated antifungal activity; and 4) normal human Igs bind and alter Cn virulence features. Leveraging these data and our deep knowledge of human Cn immunity and antibody responses, we propose three aims to identify serological correlates of survival and treatment response in existing de-identified plasma samples from the full 844 participant Ambition cohort provided by principal investigator, Joe Jarvis. Aim 1: To identify associations between survival and plasma isotype/subclass and Cn binding-Ig levels in Ambition participants. Aim 2: To compare survival, Ig FcγR functional activity and FcγR polymorphisms of Ambition participants on ART ≤2wks prior to randomization matched 1:1 to those not on ART. Aim 3: To use systems serology and computational platforms to identify signatures of survival and treatment response in Ambition participants, integrating Ig features with survival status, clinical, microbiologic, and laboratory data. Clinicians urgently need correlates of CM survival and treatment response to guide management to improve outcomes and reduce mortality. Data generated in this project will be poised for validation in ongoing and prospective cohorts of PWH with CM and other high-risk groups to inform treatment guidance and development of adjunctive antibody therapies to improve CM outcomes.