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Background: HIV infection occurs predominantly in the mucosal surfaces of the gastrointestinal tract and is associated with compromised intestinal barrier integrity and dysbiosis that is not reversed by current antiretroviral therapy (ART). Innate lymphoid cells (ILCs) orchestrate mucosal barrier defences and are involved in the regulation of tissue homeostasis. However, the impact of HIV-1 infection on ILCs in the human intestinal mucosa and gut draining lymphoid tissue is unknown. Methods: Here, we present a large cohort of patients from a gastrointestinal clinic in KwaZulu-Natal, South Africa recruited within extremely high HIV endemic areas. Human gut draining lymph nodes and intestinal biopsies were collected during surgical procedures. Phenotypic characterization of ILCs was done using flow cytometry and immunohistochemistry. Moreover, we employed single-cell transcriptomics of pre-sorted ILCs to examine the gene expression profile and ex vivo response to HIV infection. Results: Total ILC levels in the gut of HIV uninfected individuals were comparable. However, we found ILC subtype-specific and regional changes between the small and large intestine. Intraepithelial ILC1 (p < 0.0001) and NK cells (p < 0.0001) were significantly enriched in the duodenum compared to the colon, whereas ILC3s were significantly expanded in the colon compared to the duodenum (p < 0.0001) in HIV uninfected individuals. In HIV infected participants, we observed expansion of duodenal ILC3s (p = 0.03) that was not found within the colon compared to HIV uninfected participants. The gut compartment-specific difference in ILC3 levels was independent of CD4 T-cell depletion observed in both compartments (p < 0.0001). We found modest changes in ILC3 levels within gut lymph nodes in HIV infected and uninfected individuals. Single-cell RNAseq of presorted ILCs from lymph nodes reveals tissue-specific transcriptional profiles between NK, ILC1 and ILC3 subsets with pending analysis of their response to HIV infection ex vivo. Conclusions: Compartment-specific differences in ILC subsets suggest distinct roles for these cells throughout the small and large intestine. Strikingly, ILC subset change in response to HIV infection within the small intestine with enriched ILC3s in HIV infected duodenal biopsies, irrespective of CD4 T cell depletion, suggests that ILC3s may play important roles in intestinal epithelial homeostasis that should be explored further for therapeutic potentials during chronic HIV-1 infection., OA05.03 O.E. Asowata (1); R. Fardoos (2); A. Singh (1); Y. Zungu (1); A. Ngoepe (1); F. Nene (1); A. Ntuli (1); F. Karim (1); A. Shalek (3); F. Anderson [...]

Background: HIV 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., Methods: We 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., Results: This 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 centre (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 naïve 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., Conclusions: Despite 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., Funding: This 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., Competing Interests: RK, JS, HS, DM, FK, YG, AN, YZ, IG, MB, KK, MM, NM, DR, OL, JJ, DS, IW, AS, HK, TN, AL No competing interests declared, WH Reviewing editor, eLife, (© 2022, Krause et al.)

HIV infection in the human gastrointestinal (GI) tract is thought to be central to HIV progression, but knowledge of this interaction is primarily limited to cohorts within Westernized countries. Here, we present a large cohort recruited from high HIV endemic areas in South Africa and found that people living with HIV (PLWH) presented at a younger age for investigation in the GI clinic. We identified severe CD4+ T cell depletion in the GI tract, which was greater in the small intestine than in the large intestine and not correlated with years on antiretroviral treatment (ART) or plasma viremia. HIV-p24 staining showed persistent viral expression, particularly in the colon, despite full suppression of plasma viremia. Quantification of mucosal antiretroviral (ARV) drugs revealed no differences in drug penetration between the duodenum and colon. Plasma markers of gut barrier breakdown and immune activation were elevated irrespective of HIV, but peripheral T cell activation was inversely correlated with loss of gut CD4+ T cells in PLWH alone. T cell activation is a strong predictor of HIV progression and independent of plasma viral load, implying that the irreversible loss of GI CD4+ T cells is a key event in the HIV pathogenesis of PLWH in South Africa, yet the underlying mechanisms remain unknown.

There are conflicting reports on the effects of HIV on COVID-19. Here, we analyzed disease severity and immune cell changes during and after SARS-CoV-2 infection in 236 participants from South Africa, of which 39% were people living with HIV (PLWH), during the first and second (Beta dominated) infection waves. The second wave had more PLWH requiring supplemental oxygen relative to HIV-negative participants. Higher disease severity was associated with low CD4 T cell counts and higher neutrophil to lymphocyte ratios (NLR). Yet, CD4 counts recovered and NLR stabilized after SARS-CoV-2 clearance in wave 2 infected PLWH, arguing for an interaction between SARS-CoV-2 and HIV infection leading to low CD4 and high NLR. The first infection wave, where severity in HIV negative and PLWH was similar, still showed some HIV modulation of SARS-CoV-2 immune responses. Therefore, HIV infection can synergize with the SARS-CoV-2 variant to change COVID-19 outcomes., Competing Interests: FK, IG, SC, YZ, RK, MB, KK, YG, HR, NM, MM, DM, DR, TN, WH, BG, RL, EW, Td, MM, GL, AL, HK, AS No competing interests declared, (© 2021, Karim et al.)

SARS-CoV-2 infects epithelial cells of the human gastrointestinal (GI) tract and causes related symptoms. HIV infection impairs gut homeostasis and is associated with an increased risk of COVID-19 fatality. To investigate the potential link between these observations, we analyzed single-cell transcriptional profiles and SARS-CoV-2 entry receptor expression across lymphoid and mucosal human tissue from chronically HIV-infected individuals and uninfected controls. Absorptive gut enterocytes displayed the highest coexpression of SARS-CoV-2 receptors ACE2, TMPRSS2, and TMPRSS4, of which ACE2 expression was associated with canonical interferon response and antiviral genes. Chronic treated HIV infection was associated with a clear antiviral response in gut enterocytes and, unexpectedly, with a substantial reduction of ACE2 and TMPRSS2 target cells. Gut tissue from SARS-CoV-2-infected individuals, however, showed abundant SARS-CoV-2 nucleocapsid protein in both the large and small intestine, including an HIV-coinfected individual. Thus, upregulation of antiviral response genes and downregulation of ACE2 and TMPRSS2 in the GI tract of HIV-infected individuals does not prevent SARS-CoV-2 infection in this compartment. The impact of these HIV-associated intestinal mucosal changes on SARS-CoV-2 infection dynamics, disease severity, and vaccine responses remains unclear and requires further investigation.