CROI 2024 Abstract eBook

Abstract eBook

Poster Abstracts

326

Persons With Residual Viremia on ART Have Higher Frequencies of Myeloid-Derived Suppressor Cells Patrick Mehta 1 , Evgenia Aga 2 , Ronald J. Bosch 2 , Hanna Mar 2 , Deborah K. McMahon 1 , Rajesh T. Gandhi 3 , Joseph J. Eron 4 , John W. Mellors 1 , Charles R. Rinaldo 1 , Bernard Macatangay 1 , for the ACTG A 5321 Team 1 University of Pittsburgh, Pittsburgh, PA, USA, 2 Harvard TH Chan School of Public Health, Boston, MA, USA, 3 Massachusetts General Hospital, Boston, MA, USA, 4 University of North Carolina at Chapel Hill, Chapel Hill, NC, USA Background: Myeloid-derived suppressor cells (MDSC) are a heterogenous population that suppress T, B, and NK cell function through multiple mechanisms and expand with acute and chronic inflammatory conditions. We evaluated whether frequencies of MDSC are associated with measures of HIV persistence and levels of inflammation in persons with HIV (PWH) on long-term ART. Methods: In the ACTG A5321 cohort of PWH with well-documented suppression of HIV-1 viremia on ART, we measured peripheral blood frequencies of classic (c) MDSC [Lineage(-), CD33+, HLADR-] and monocytic (m) MDSC [Lineage(-), CD33+, HLADR-, CD14+, CD11b+] by flow cytometry. To evaluate anti- or pro- inflammatory profile, we calculated the ratio of %mMDSC (anti-) and %intermediate monocytes (iMono; CD14+CD16+; pro-inflammatory). We then determined associations between MDSC frequencies and mMDSC/iMono (higher ratio – more anti-inflammatory) with measures of HIV persistence, including residual viremia, HIV DNA, cell-associated HIV RNA, and intact proviral DNA, and with soluble measures of inflammation. Results: The 225 participants had a median age of 49 yrs, CD4 count of 681 cells/mm 3 , and ART duration of 7 yrs. The median cMDSC frequency was 0.13% of all live cells while mMDSC was 0.08%. Frequencies of both MDSC populations correlated with each other (r=0.31; p<0.001, Spearman). Lower mMDSC frequencies were associated with longer ART duration (r= -0.20; p<0.001). Participants with residual viremia (HIV RNA≥0.4 cps/mL) had higher %cMDSC than those with HIV RNA <0.4 cps/mL (0.14% vs 0.11%; p=0.016, Wilcoxon; Fig 1). There was also a trend for higher %mMDSC in those with residual viremia (0.09% vs 0.07%; p=0.05). Higher frequencies of mMDSC and cMDSC were associated with lower levels of pro-inflammatory cytokines IP-10 (r= -0.23, p<0.001 & r= -0.18, p=0.008, respectively) and TNF (r= -0.15, p=0.024 & = -0.15, p=0.021, respectively) even after adjusting for pre-ART RNA. The mMDSC/ iMono ratio did not correlate with any measure of HIV persistence. Higher ratios were associated with lower IP-10 (r= -0.24, p<0.001) and TNF (r= -0.15, p=0.028) levels even after further adjusting for age, pre-ART CD4 count, and years on ART. Conclusion: Our finding that higher MDSC frequencies are associated with residual viremia despite long-term ART suggests that MDSC could inhibit virally suppressive HIV-specific immune responses. Reversing MDSC- mediated suppression would possibly enhance immune control of HIV but could also increase chronic inflammation.

325

Disruption of Intestinal Germinal Centers During HIV Infection Francesca Cossarini , Azra Krek, Pablo Canales-Herrerias, Michael Tankelevich, Benjamin K. Chen, Judith A. Aberg, Francesca Petralia, Alexandros D. Polydorides, Saurabh Mehandru Icahn School of Medicine at Mt Sinai, New York, NY, USA Background: HIV infection causes a profound dysregulation of the humoral immune system. Humoral responses occur mostly in secondary lymphoid tissue and involve the formation of Germinal Center (GC) and T- dependent antibody production results from interaction between cognate T and B cells. While the impact of HIV infection on mucosal T cells is well-reported, less is known regarding the effects of HIV on the humoral immune compartment. We investigated changes induced by HIV infection on humoral immunity, focusing on GC as the sites of T-dependent antibody production in the gut-associated lymphoid tissue (GALT). Methods: We prospectively enrolled people with HIV (18 with HIV viral load (VL)>1000copes/mL and 46 with HIV VL <50copies/mL on antiretroviral treatment (ART) as well as people without HIV (n=80) and examined intestinal immune cell changes with immunohistochemistry, flow cytometry and single cell RNA sequencing (scRNA seq). Results: Immunohistochemical staining showed a significant decrease in GC size in participants with detectable VL compared to participants without HIV [median, IQR size 0.008 (0.0006–0.03) vs 0.1 (0.009– 0.15)mm 2 p=0.04], despite similar overall lymphoid follicle size. Additionally, we found a marked reduction of BCL6 expression in germinal centers in participants with detectable VL, even when accounting for the reduced GC size [556 (20–2375) vs 4120 (3363 6400) cells/mm 2 p=0.065]. Using flow cytometry, in both Ileum and colon, a significant depletion of GC B cells was observed in PWH with detectable VL as compared to both participants with undetectable VL and without HIV [0.07 (0.03–0.42) vs 0.4 (0.16-2.53) vs 0.88 (0.17–2.98)% of Live Cells in the ileum, p=0.008 and 0.39 (0.21–0.91) vs 0.75 (0.4–1.3) vs 1.04 (0.4–1.4)% of Live Cells in the colon, p=0.004]. Within the scRNAseq dataset, cells mapping to GC B cells (BCL6, AICDA, CD38) were almost absent in participants with detectable VL at both sites. Differentially expressed gene analysis revealed increased expression of genes related to B cell activation and proliferation (MIF, CD74) in GC B cells from participants with HIV and suppressed VL and in genes related to migration of B cells to the GC (GNAI2, SWAP70) and T cell dependent B cell maturation (BASP1) in GC B cells from participants without HIV. Conclusion: HIV infection is associated with a profound loss of intestinal GC B cells and may represent a major source of perturbation of humoral immunity at these sites of viral replication.

Poster Abstracts

327

Persistent HIV-1 Plasma Viremia in Patients on Therapy Caused by Macrophage-Tropic Lineage Matthew Moeser 1 , Nathan Long 1 , Abbas Mohammadi 2 , Behzad Etemad 3 , Jonathan Z. Li 3 , Ann M. Dennis 1 , Claire Farel 1 , David Wohl 1 , Mackenzie Cottrell 1 , Joseph J. Eron 1 , Julie A. Nelson 1 , Meredith Clement 4 , Tat Yau 4 , Shuntai Zhou 1 , Sarah B. Joseph 1 1 University of North Carolina at Chapel Hill, Chapel Hill, NC, USA, 2 The Valley Health System, Las Vegas, NV, USA, 3 Brigham and Women's Hospital, Boston, MA, USA, 4 Louisiana State University, New Orleans, LA, USA Background: Antiretroviral therapy (ART) usually suppresses plasma HIV-1 RNA to limits of detection within months of initiation. Rarely, persistent low-level

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CROI 2024