Kloverpris, H. | bioRxiv Science

bioRxiv2023

Colon resident CD8+ T cells from people with HIV on antiretroviral therapy exhibit mitochondrial dysfunction and impaired responses

CD8+ tissue-resident memory T cells (CD8+ TRM) play an important role in mediating immune responses against HIV in the gastrointestinal (GI) mucosa. Antiretroviral therapy (ART) successfully supresses HIV replication in the blood, but fails to restore GI homeostasis, particularly within gut associated lymphoid tissue (GALT). The importance of cellular metabolism in shaping CD8+ TRM antiviral function has emerged as a crucial aspect of general immunoregulation. To gain better insight into the immunoregulation of CD8+ TRM during HIV, we characterized the function of blood and colon CD8+ T cells in people with HIV (PWH) on ART and HIV-uninfected individuals. We show that a higher proportion of activated CD8+ TRM persisted in the colon of PWH on ART, and these cells exhibited weaker immune response and compromised mitochondrial function compared to their peripheral counterparts. We also observed decreased mitochondrial function in CD8+ T cell in the colon compared to peripheral blood in PWH on ART. The study indicates that mitochondrial bioenergetic properties may be an indicator of colonic CD8+ TRM dysfunction in PWH on ART and highlights the importance of understanding cellular metabolism in shaping CD8+ TRM function to develop targeted immunotherapies for PWH.

immunology↗

bioRxiv2022

HIV skews the SARS-CoV-2 B cell response toward an extrafollicular maturation pathway

BackgroundHIV infection dysregulates the B cell compartment, affecting memory B cell formation and the antibody response to infection and vaccination. Understanding the B cell response to SARS-CoV-2 in people living with HIV (PLWH) may explain the increased morbidity, reduced vaccine efficacy, reduced clearance, and intra-host evolution of SARS-CoV-2 observed in some HIV-1 coinfections. MethodsWe compared B cell responses to COVID-19 in PLWH and HIV negative (HIV-ve) patients in a cohort recruited in Durban, South Africa, during the first pandemic wave in July 2020 using detailed flow cytometry phenotyping of longitudinal samples with markers of B cell maturation, homing and regulatory features. ResultsThis revealed a coordinated B cell response to COVID-19 that differed significantly between HIV-ve and PLWH. Memory B cells in PLWH displayed evidence of reduced germinal center (GC) activity, homing capacity and class-switching responses, with increased PD-L1 expression, and decreased Tfh frequency. This was mirrored by increased extrafollicular (EF) activity, with dynamic changes in activated double negative (DN2) and activated naive B cells, which correlated with anti-RBD-titres in these individuals. An elevated SARS-CoV-2 specific EF response in PLWH was confirmed using viral spike and RBD bait proteins. ConclusionsDespite similar disease severity, these trends were highest in participants with uncontrolled HIV, implicating HIV in driving these changes. EF B cell responses are rapid but give rise to lower affinity antibodies, less durable long-term memory, and reduced capacity to adapt to new variants. Further work is needed to determine the long-term effects of HIV on SARS-CoV-2 immunity, particularly as new variants emerge. FundingThis work was supported by a grant from the Wellcome Trust to the Africa Health Research Institute (Wellcome Trust Strategic Core Award [grant number 201433/Z/16/Z]). Additional funding was received from the South African Department of Science and Innovation through the National Research Foundation (South African Research Chairs Initiative, [grant number 64809]), and the Victor Daitz Foundation.

immunology↗