CROI 2024 Abstract eBook

Abstract eBook

Poster Abstracts

Results: MISTRG-6-15 mice engrafted with cord blood HSPCs developed human myeloid cells (monocytes, macrophages, and neutrophils), T cells, B cells, NK cells, and other innate lymphoid cells (ILCs) in the lungs. The HIV-infected MISTRG-6-15 mice had a systematic augment of interferon gamma and alpha pathways across all cell types in the blood, spleen, and lung tissues. We found significant depletions of lung effector and tissue-resident CD4+ T cells and CD4+ regulatory T cells, as well as many subsets of antigen presenting cells (APCs). By contrast, CD8+ T cells, NK cells, and ILCs expanded and produced inflammatory cytokines in the infected lungs, which was in line with human studies. Genes associated with cell proliferation and interferon responses were significantly upregulated in the lungs of HIV-infected mice. Compared to the blood and spleen, the lungs had a larger amount of differentially expressed genes between the infected and un-infected mice. Further subset analyses identified that T-cells (both CD4+ and CD8+ T cells) and myeloid cells specifically had significantly more differential expressed genes in the lungs than in the blood and spleen. Conclusion: Our results demonstrated that MISTRG-6-15 mouse can be a useful model to evaluate lung inflammation driven by HIV infection. We identified unique features of HIV-induced immune perturbation in the lung. This humanized mouse model allows us to perform mechanical studies to better understand HIV-driven lung complications. Exogenous Estrogen Increases HIV Target Cell Frequency in the Rectal Mucosa of Male Primates Patricia A Hahn 1 , Eric S. Alexander 2 , Kimberly Weisgrau 2 , Tianling Ou 3 , Wenhui He 3 , Eva Rakasz 2 , Michael Farzan 3 , Joseph R. Kurian 2 , Mauricio A. Martins 1 1 The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, FL, USA, 2 Wisconsin National Primate Research Center, Madison, WI, USA, 3 Boston Children's Hospital, Boston, MA, USA Background: Transgender women (TGW) are 49-66 times more likely to be infected with HIV than individuals over age 15. Considering TGW's high risk of contracting HIV, they stand to benefit greatly from anti-HIV therapeutics, but little is known about the immunomodulatory effects of feminizing hormone therapy (FHT). To relieve gender dysphoria and facilitate physical feminization, many TGW utilize FHT, consisting primarily of 17β-estradiol (E2), which has immune-enhancing effects. It is well established that estrogen can influence T-cell development and impart higher resistance to infection in women versus men. Since estrogen can also amplify antibody responses, FHT could have both positive and negative immune consequences to TGW. Hence, to advance our understanding of the immunomodulatory effects of FHT in TGW, we set out to model FHT in rhesus macaques. Methods: Using slow-release subcutaneous E2 pellets, we developed a dosing regimen in male rhesus macaques that elevate levels of E2 and suppressed testosterone. We used flow cytometry to measure cellular dynamics and ELISA to evaluate the magnitude of LNP/mRNA vaccine-induced Env-binding IgG antibodies. Results: The E2 regimen significantly increased serum E2 concentrations and suppressed endogenous testosterone levels, while also inducing physical traits associated with feminization, like enlarged nipples. Importantly, immunophenotyping analysis revealed that CCR5+ CD4+ T-cells, the primary targets of HIV infection, were significantly elevated in both blood and gut from the E2-treated animals. Although the female sex is associated with enhanced immune responses to vaccines, FHT did not significantly alter vaccine-induced anti-Env antibodies in the E2 group following mRNA vaccination. Conclusion: These results demonstrate for the first time the feasibility of modeling gender affirming hormone therapy in rhesus macaques and implicate FHT as a potential driver of HIV susceptibility in TGW. Enema Use Minimally Impacts Immunity and Does Not Affect Susceptibility to Low-Dose Intrarectal SIV Alexandra Ortiz 1 , Fabiola Castello Casta 1 , Brandon Keele 2 , Jason Brenchley 1 1 National Institutes of Health, Bethesda, MD, USA, 2 AIDS and Cancer Virus Program, Frederick, MD, USA Background: Men who have sex with men (MSM) are disproportionately affected by HIV. Increased susceptibility to HIV in MSM is attributed to high frequencies of susceptible CD4+ T-cells, GI epithelial barrier disruption, and dysbiosis of the intestinal microbiome. Although colorectal epithelial barrier damage is due, in part, to inflammation resulting from receptive anal intercourse, rectal douching has also been proposed as a significant contributor. The effects of repeated enema use on the composition of the GI tract

whether circulating proteins of EC and VC at baseline were associated with loss and/or sustained viral control. Methods: The Dutch national ATHENA cohort provided baseline blood samples from 36 ECs and 145 VCs, maintaining control status for >5 years. Serial viral load (VL) measurements were documented for up to 17 years. Expression of 3072 plasma proteins was measured using proximity extension assay coupled with next- generation sequencing, with 2420 proteins used for analysis after quality control. Only one EC lost control during follow-up; analysis was therefore applied on VC only. Results: Loss of controller status occurred in 38% (55/145) of VCs after a median of 8.5 years. TC had similar demographics (age, sex, BMI, ethnicity), smoking status, and latest CD4 and VL compared to PCs. However, elevated initial VL was noted in TCs (median [Interquartile range] TCs 1347 [245, 4271] vs. PCs 443 [50, 1912.5] c/ml). Over time, TC exhibited an annual increase in VL by 1375 c/mL, while PCs exhibited stable VL. Proteomic analysis identified seven proteins (ZBP1, SH2D1A, CDH15, GIMAP7, VSIG10L, NDRG1, GZMH) associated with a higher risk of losing VC status, whereas CNGB3 was linked to a lower risk, observed over a median period of 4.2 years before loss of HIV control. Notably, certain proteins (SH2D1A, NDRG1) have been implicated in other viral infections, yet their association with HIV infections is scarce or absent in existing literature. Conclusion: Several years before loss of spontaneous viral control, TC exhibited the upregulation of plasma proteins with known immune and cellular functions, including inflammation, apoptosis, and cell adhesion. Our findings advance our understanding of ART-independent control mechanisms, underscoring the prospect of identifying early biomarkers for impending loss of HIV control.

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Poster Abstracts

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HIV-Induced Lung Inflammation in Humanized Mice Leyao Wang , Sara Nicholson, Hongbo Gao, Liang Shan Washington University in St Louis, St Louis, MO, USA

Background: HIV infection-related lung diseases continue to be one of the leading causes of morbidity and mortality for people living with HIV. The cross-sectional design of population studies has made it impossible to elucidate a causal relationship between immune biomarkers and lung disease. Therefore, we aim to establish an animal model to longitudinally monitor HIV infection and lung immune activation and perturbation. Methods: We established HIV infection in a humanized mouse model named MISTRG-6-15, in which several human cytokine-coding genes, including M-CSF, IL-3/GM-CSF, SIRPα, TPO, IL-6, and IL-15, were knocked into their respective mouse loci to promote human hematopoietic stem and progenitor cells (HSPCs) for self- renewal and differentiation. We isolated human CD45+ cells from the lungs of HIV-infected and control mice and performed single-cell RNA sequencing and ex vivo functional analyses.

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CROI 2024