CROI 2025 Abstract eBook

Abstract eBook

Poster Abstracts

365

Occult CMV Replication Is a Persistent Driver of Effector T-Cell Expansion in PWH on Effective ART Nived Collercandy 1 , Camille Vellas 1 , Manon Nayrac 2 , Mary Requena 1 , Thomas Richarme 3 , Justine Latour 1 , Karl Barange 1 , Laurent Alric 1 , Guillaume Martin Blondel 1 , Jacques Izopet 1 , Pierre Delobel 1 1 Toulouse University Hospital, Toulouse, France, 2 Centre de Recherche du CHUM, Montreal, Canada, 3 Université Paul Sabatier, Toulouse, France Background: CMV infection is a driver of immune activation and senescence, with greater impact in the setting of HIV-1 co-infection, where it contributes to CD8 T cell expansion and low CD4/CD8 T cell ratios. CMV replication occurs primarily in people with HIV-1 (PWH) with low blood CD4 + T cell counts, but occult CMV replication may persist in some tissues due to incomplete CD4 + T cell reconstitution on antiretroviral therapy (ART), particularly in the gut, dissociated from restored blood CD4 + T cell counts. This occult CMV replication may drive CMV-specific antibodies and effector T cells even in PWH on successful ART. Methods: In a sub-study of ANRS EP61 GALT, 15 PWH who were also CMV seropositive (CMV + ), 15 controls without HIV but CMV + , 12 PWH without CMV (CMV - ) and 12 double-negative controls were included for FACS immunophenotyping of circulating T cells. CMV viremia was assessed by PCR. Anti-CMV IgG titers were measured as a marker of immune stimulation by CMV. Results: CMV viremia was negative in all CMV + subjects. However, CMV + PWH had significantly higher anti-CMV IgG titers than CMV + HIV-negative controls (median 553 [277-933] vs 163 [122-245], P <0.01). While an inverted Vδ 1 /Vδ 2 ratio among γδ T cells has been described as a hallmark of PWH, it was found only in CMV + PWH. γδ T cell counts are increased in PWH, with the highest levels in CMV + PWH compared to CMV - PWH and CMV - controls ( P =0.0.1 and P <0.001, respectively) (Figure). Vδ 1 subset counts and proportions were significantly increased in CMV + PWH compared to other groups. The Vδ 2 subset was not significantly changed in number, but was reduced in proportion. The effector cell receptor CX3CR1 was highly expressed on Vδ 1 T cells, with the highest expression in CMV+ PWH. Conventional T cells showed the same results, with an expansion of CX3CR1 + TEMRA T cells in the same groups. CMV IgG titers correlated with CX3CR1 + CD8 and CD8 TEMRA, total CD8 count, and with the duration of HIV virological suppression. Conclusions: Occult CMV replication during HIV-1 infection is involved in the expansion of several circulating T cell populations, particularly Vδ 1 T cells, even in PWH on effective ART with restored circulating CD4 T cell counts and undetectable CMV DNA in their blood. CX3CR1 expression on T cells is associated with CMV status and is likely driven by occult CMV replication. CMV IgG titers may be used as a surrogate for occult CMV replication.

versus 27.6-48.0% of PLWH (Fig 1). Intriguingly, no individuals with detectable anti-IFNα auto-Abs demonstrated IFN neutralisation in vitro . Median auto-Ab levels were significantly higher (***p<0.001) in viraemic individuals compared to those with undetectable viral loads (<50 copies/ml), respectively, across IFNα2A (9.9, 95%CI 9.2-16.9 versus 5.4, 95%CI 5.2-7.8), IFNω (5.0, 95%CI 4.8-6.4 versus 8.4, 95%CI 7.6-13.8), IFNγ (4.8, 95%CI 4.6-7.0 versus 10.3, 95%CI 9.0-16.0), IFNλ1 (5.2, 95%CI 5.0-6.9 versus 10.8, 95%CI 9.0-15.9). Auto-Ab levels fell in longitudinal samples after initiation of anti-retroviral therapy (ART) in PLWH. Conclusions: We detected high levels of non-neutralising anti-IFN auto-Abs in PLWH. Auto-Ab levels associated with HIV viraemia and were responsive to ART. Population-level longitudinal studies are needed to determine the impact of these auto-Abs on long-term HIV outcomes. The underlying immunopathogenesis of anti-IFN auto-Abs remains unknown and chronic virus infection provides opportunity for mechanistic studies. Secreted ORF8 Reprograms Macrophages to Enhance Lung Epithelial Cell Infection by SARS-CoV-2 Yusuke Matsui 1 , Rahul K. Suryawanshi 1 , Mauricio Montano 1 , Taha Y. Taha 1 , Mir M. Khalid 1 , Kanika Khanna 1 , Jin Tang 1 , Yuan Zhou 1 , Xiaohui Fang 2 , Mazharul Maishan 2 , Robyn M. Kaake 1 , Michael A. Matthay 2 , Nevan J. Krogan 1 , Melanie Ott 1 1 Gladstone Institutes, San Francisco, CA, USA, 2 University of California San Francisco, San Francisco, CA, USA Background: ORF8 is an accessory protein encoded by SARS-CoV-2, containing an immunoglobulin-like domain of approximately 20 kDa, and is secreted extracellularly by infected cells. Serum levels of ORF8 have been shown to correlate with disease severity in COVID-19 patients, though its exact function and target cells remain unknown. We hypothesized that extracellular ORF8 influences COVID-19 pathogenesis through its effects on immune cells and investigated this mechanism. Methods: We demonstrated that secreted ORF8 targets macrophages and alters their identity, inflammatory profile, and susceptibility to SARS-CoV-2 infection, thereby enhancing lung epithelial cell infection. This was shown using our primary macrophage SARS-CoV-2 infection models (SARS-CoV-2 virus-like particles and replication-competent ORF8+/− viruses) and proteomics analysis on ORF8-stimulated macrophages. Results: Exposure to extracellular ORF8 enhances ACE2 expression on primary macrophages thereby promoting virion entry and macrophage pyroptosis. ORF8-exposed proinflammatory M1 macrophages exhibit a significant shift in protein expression toward an M2-like phenotype associated with immunosuppression. Importantly, efficient infection of macrophages depends on ORF8 expression, and co-culture of macrophages with primary human alveolar type 2 (AT2) cells reverses the negative effect of ORF8 on AT2 infection, enabling full viral replication. In animal experiments using mouse-adapted viruses, the addition of extracellular ORF8 enhances viral replication and increases IL-1β production. Conclusions: This study highlights the role of extracellular ORF8 in modulating immunity and its contribution to the spread of infection. Our results demonstrate a paracrine function of ORF8 in targeting macrophages and promoting a proviral circuit between macrophages and lung epithelial cells in COVID-19 pathogenesis. The figure, table, or graphic for this abstract has been removed.

364

Poster Abstracts

366

IL-10/PD-1 Blockade Leads to Enhanced BA Synthesis and Type I IFN Production Khader Ghneim, Felipe Ten-Caten, Susan P. Ribeiro, Mirko Paiardini, Rafick P. Sekaly Emory University, Atlanta, GA, USA Background: Elevated levels of IL-10 and PD1 contribute to HIV reservoir persistence, an impediment for HIV eradication. IL-10 contributes to the lack of effector function, antigen-presentation and promotes HIV reservoir survival. PD-1 expression is associated with T cell exhaustion and HIV latency. We hypothesized that the dual blockade of IL-10 and PD-1 could synergize and lead to viral rebound control post-ATI (Analytical Treatment Interruption) and to reduced SIV reservoir size.

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CROI 2025