CROI 2024 Abstract eBook

Abstract eBook

Poster Abstracts

control acute HCV infection and if this dysfunction persists on entry to the liver, may play a role in liver fibrogenesis.

Shedding of HSV-2 and HHV-8 pre-ART versus at week-4 or week-8 post-ART was not significantly different while CMV shedding significantly increased from 53% pre-ART to 77% at week-4 visit (p-value=0.016), and 73% at week-8 visit (p-value=0.027) in participants with a pre-ART CD4 count <=200 cells/ul. At week-4 post ART, a 4-fold increase in IL-6 levels was associated with HSV-2 shedding if there was no shedding pre-ART, while a 0.76-fold decrease in IL-6 levels wµas associated with HSV-2 shedding if there was shedding pre-ART. At week 8 post-ART, a 2-fold and 8-fold increase in CRP and TNFα levels respectively were associated with the risk of CMV shedding irrespective of shedding pre-ART. A 4-fold and 1.5-fold increase in IL-6 and sCD14 levels respectively was instead associated with HSV-2 shedding if there was no shedding pre-ART while at least a 0.17-fold decrease in IL-6 and sCD14 levels was associated with HSV-2 shedding if there was shedding at baseline. Conclusion: ART initiation was associated with increased CMV, but not HSV-2, shedding at weeks 4 and 8 after starting treatment. Mucosal shedding of CMV and HSV-2 was associated with different patterns of changes in systemic inflammatory biomarkers IL-6, CD14, CRP and TNFα.

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Low SKAP1 Levels Indicate a Potential New Mechanism in HIV Immunological Non- Responders Wilhelm A Vos 1 , Jiang Xun 2 , Jessica D. Santos 1 , Albert L. Groenendijk 3 , Marc Blaauw 1 , Louise E. van Eekeren 1 , Nadira Vadaq 1 , Vasiliki Matzaraki 1 , Mike van der Kolk 4 , Willem L. Blok 5 , Janneke E. Stalenhoef 5 , Jan van Lunzen 1 , Yang Li 2 , Cheng Jian Xu 2 , Andre J. van der Ven 1 1 Radboud University Medical Center, Nijmegen, Netherlands, 2 Medizinische Hochschule Hannover, Hannover, Germany, 3 Erasmus University Medical Center, Rotterdam, Netherlands, 4 ViiV Healthcare, Brentford, United Kingdom, 5 OLVG, Amsterdam, Netherlands Background: Immunological non-responders (INRs) are people living with HIV (PLHIV) who fail to adequately restore CD4+ T-cell levels during suppressive ART. In contrast, immunological responders (IRs) do achieve CD4+ T-cell levels comparable to healthy individuals. Morbidity and mortality are increased in INRs. However, the pathogenesis of INRs is multifactorial and not fully elucidated yet. In this exploratory proteomics study, we looked for proteins which might be related to INR. SKAP1 is a lymphocyte protein which is important for T-cell migration, activation and proliferation. Previous work has shown that lymphocyte proliferation and IL- 2 production were severely impaired in SKAP1 knock-out mice. The main function of SKAP1 is activating LFA- 1, an integrin binding receptor. Knockdown of one of the LFA-1 heterodimers causes impaired CD4+ T-cell migration to the intestine and lymph nodes. SKAP1 has never been described in the context of HIV. Methods: The 2000HIV study (clinicaltrials NTC03994835) is a Dutch cross omics multi-center study enrolling 1895 virally suppressed PLHIV, divided into a discovery and an independent validation cohort. We performed linear regression differential expression analysis on targeted serum proteomics (Olink, 2368 proteins) of INRs compared to IRs. In addition, we analyzed whole blood DNA methylation (NanoDrop spectrophotometer). Results: The discovery cohort consists of 62 INRs and 1224 IRs, and the validation cohort of 26 INRs and 243 IRs. INRs were older and had more advanced HIV disease before starting cART. Proteomic analysis showed that SKAP1 was significantly downregulated in INRs in both the discovery (logFC = -0.545, FDR<0.0001) and the validation cohort (logFC = -0.628, pval<0.0001) (Figure 1A). SKAP1 was the most significant protein in both cohorts. In addition, we observed hypermethylation at cg26532208, a CpG site in the promotor area of the SKAP1 gene in the discovery cohort (logFC = -0.096, FDR = 0.042) (Figure 1B), as well as in the validation cohort (logFC = -0.093, pval = 0.00078) which suggests decreased transcription. Finally, a significant correlation between CD4+ T-cell count and SKAP1 levels was found in the overall cohort irrespective of immunological responder status. Conclusion: We found evidence for decreased SKAP1 expression levels in INRs in a large cohort study across two separate -omics layers. Previous work on SKAP1 function and these new data emphasizes its potential role in INR pathogenesis and might open new therapeutic avenues.

Poster Abstracts

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HIV-1 Coinfection Skews iNKT Cells Toward Anergy and Exhaustion in People With Hepatitis C Danielle R Nettere 1 , Grant Williams 2 , Joy Pickeral 1 , Scott White 1 , Cliburn Chan 1 , Guido Ferrari 1 , Susanna Naggie 1 1 Duke University School of Medicine, Durham, NC, USA, 2 Duke University, Durham, NC, USA Background: Hepatitis C virus (HCV) infection related liver disease remains a leading cause of morbidity and mortality in people with HIV (PWH). Liver fibrosis progression is more rapid in HIV/HCV coinfection compared to HCV monoinfection. Although direct acting antivirals (DAA) have improved treatment response substantially, access to DAA has declined since 2015, thus liver disease remains a threat to people with HIV/HCV. iNKT cells, a rare innate like subset of T cells, may play a role in the rapid progression of fibrosis because of their liver tropism and due to the early loss of "pro-healing" CD4+ iNKT cells in early HIV infection. How this impacts long term iNKT subset diversity and functionality, and the role of iNKT in fibrogenesis in people with HIV/HCV is unknown. Methods: To investigate the phenotypic and functional differences of iNKT cells in people with HIV/HCV coinfection, we consented persons with HIV (N=7), HCV (N=6), HIV/HCV (N=7), and healthy controls (N=6). All patients with HIV were virally suppressed on antiretroviral therapy and all patients with HCV had chronic active infection. We collected PBMCs and used 12-color flow cytometry to evaluate the phenotypes and functionality of iNKT following T-cell receptor (TCR) stimulation. Phenotypes were compared using Leiden clustering and dimension reduction. Results: iNKT from PWH cells showed impaired expansion to TCR stimulation (~2 fold) compared to iNKT cells from persons with HCV or neither infection (up to 50-fold). The iNKT cells from PWH also showed a higher degree of TCR downregulation and lower CD38 expression following TCR stimulation, consistent with a more anergic state. We observed a higher frequency of CD8+ iNKT cells in PWH, which represents an effector subset. In addition, they were more likely to express CD57, a marker of terminal differentiation. Conclusion: iNKT cells from PWH and people with HIV/HCV have impaired expansion, higher TCR downregulation in response to stimulation, and are biased towards "effector" and terminally differentiated subsets. These results suggest a picture of proinflammatory but relatively anergic iNKT cells. This altered distribution of iNKT subsets could explain why PLWH are less likely to

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CROI 2024