CROI 2018 Abstract eBook

Abstract eBook

Poster Abstracts

219 CONTROLLED STUDY TO EVALUATE IMMUNOLOGIC EFFECT OF ISOTRETINOIN ON HIV-1 INFECTION

220 HIV-1 UNMASKS THE PLASTICITY OF INNATE LYMPHOID CELLS Yetao Wang, Kyle Gellatly, Alan Derr, Smita Jaiswal, Alper Kucukural, Patrick McDonel, Thomas Greenough, Jean Marie Houghton, Manuel Garber, Jeremy Luban University of Massachusetts, Worcester, MA, USA Background: Pharmacologic suppression of HIV-1 viremia preserves CD4+ T cells and prevents AIDS but does not eliminate systemic inflammation. As possible explanation for ongoing inflammation we examined the effect of HIV-1 infection on innate lymphoid cells (ILCs). ILCs are innate counterparts of T cells that lack clonotypic antigen receptors or other lineage-defining cell surface markers, and carry out a large range of biological functions, including roles in host defense against pathogens and maintenance of homeostasis in inflamed tissues. Methods: We characterized the ILC subpopulations present in the blood and colon lamina propria of HIV-1-negative people and HIV-1+ people. Results: Homeostatic cytokine-producing CD127+ innate lymphoid cells (ILCs) were depleted from the blood and colon of HIV-1+ people, irrespective of antiretroviral therapy. Common γ-chain cytokines that are elevated during HIV-1 infection converted CD127+ILCs into inflammatory CD127-ILCs, and shifted CD127-ILC1s into cytotoxic NK cells. Pseudotemporal clustering of transcriptomes from thousands of cells identified a developmental trajectory from CD127-ILC1s to memory NK cells that was defined by WNT-transcription factor TCF7. WNT inhibition prevented the cytokine-induced transition of CD127-ILC1 cells into NK cells. Consistent with reported HIV-1-specific killing activity, TCF7+memory NK cells were increased in the blood of HIV-1+ people, concomitant with the reduction in CD127-ILC1s. Conclusion: These studies demonstrate that ILC plasticity contributes to ongoing inflammation and expanded NK cell memory in HIV-1 infection, and indicate that targeted WNT inhibition may augment antiviral therapy. 221 SYSTEMIC ACTIVATION OF NOVEL IGA+ NATURAL KILLER-LIKE B CELLS IN HIV/SIV INFECTIONS Background: Recently, a novel innate immune cell subset termed natural killer-like B (NKB) cells was identified in mice that rapidly responded to microbial infection and primed the innate antiviral response. Despite a critical role for innate immunity in blocking or limiting viral transmission and disease, the presence and role of NKB in primate HIV/SIV infections is completely unknown. Methods: To identify NKB in primates, up to 18-color polychromatic flow cytometry was used for phenotypic and functional assays. NKB were identified in both rhesus macaques and human samples by flow cytometry excluding lineage markers (CD3–CD14–CD127–) and then positive boolean gating of CD20, NKG2A/C and/or NKp46. Results: NKB were found at similar frequencies in the circulation of humans (n = 20) and rhesus macaques (n = 12) (range, 0.01 to 0.2% of total lymphocytes) and were systemically distributed at similar frequencies in tonsil, mesenteric and peripheral lymph nodes, colon, and jejunum. NKB were notably enriched in spleen (median, 0.4% of lymphocytes) but frequencies were not altered in any tissue following HIV/SIV infections, and not influenced by ART status. Interestingly, NKB uniquely and uniformly expressed high levels of IgA regardless of tissue, but demonstrated increased IgM and IgG in HIV-infected patients and SIV-infected macaques, which could suggest class-switching or mobilization of de novo cells. NKB also upregulated CD40, HLA-DR, CD16 and NKp46 during infection - highly suggestive of virus-induced activation. Work from our lab and others have shown NKB production of IFN-γ, IL-12, and IL-18, but we found only low-to-moderate expression of granzyme B, and NKB were negative for perforin and had low evidence of cytolytic potential. Conclusion: These results demonstrate the first conclusive evidence of for systemic NKB in rhesus macaques and humans, and demonstrate their significant perturbation during HIV/SIV infections. Although the full functional niche of this subset is unknown, our preliminary evidence suggests they may be most closely related to other innate B cell lineages (B1). Regardless, their systemic distribution, particularly accumulation in mucosal tissues and secondary lymphoid organs, as well as strikingly high expression of IgA could make these novel cells unique targets for future HIV immunotherapeutics or vaccine strategies. Chiadika Nwanze, Cordelia Manickam , R. Keith Reeves Beth Israel Deaconess Medical Center, Boston, MA, USA

Nina Lin 1 , Bernard J. Macatangay 2 , Ellen S. Chan 3 , Heather Ribaudo 3 , Karin L. Klingman 4 , Linda Boone 5 , Jonathan Z. Li 6 , Maureen A. Kane 7 , Francesca Aweeka 8 , Charles Rinaldo 2 , Ian McGowan 9 , Daniel R. Kuritzkes 6 , Douglas Kwon 10 1 Boston University, Boston, MA, USA, 2 University of Pittsburgh, Pittsburgh, PA, USA, 3 Harvard University, Cambridge, MA, USA, 4 DAIDS, NIAID, Bethesda, MD, USA, 5 Social &Scientific Systems, Silver Spring, MD, USA, 6 Brigham and Women’s Hospital, Boston, MA, USA, 7 University of Maryland, Baltimore, MD, USA, 8 University of California San Francisco, San Francisco, CA, USA, 9 Magee–Womens Research Institute, Pittsburgh, PA, USA, 10 Massachusetts General Hospital, Boston, MA, USA Background: HIV-associated immunologic defects in the gut are thought to contribute to chronic inflammation, which is central to HIV disease progression. Since retinoic acid (RA) is known to play an important role in gut homeostasis, we conducted a multicenter clinical trial to investigate the effects of RA on systemic and gut T cell activation, inflammation, and CD4+ T cell reconstitution. Methods: HIV-infected adults on suppressive ART were randomized 2:1 to receive 16-wks of isotretinoin or no treatment (control). A subset underwent baseline and wk 16 colonoscopies for terminal ileum and transverse colon mucosal biopsies. All participants were followed to wk 28 to assess durability of effects. Per-protocol analyses included only participants who completed treatment (for isotretinoin arm) without virologic failure. Treatment group differences were assessed via Wilcoxon rank-sum tests. Results: 76 participants were enrolled, with 39 isotretinoin vs 26 control included in the per-protocol analyses. 12 isotretinoin vs 6 control participants underwent the colonoscopy substudy. Participants were 7% female, with median age 49 yrs, and median CD4+ T cell count 552 cells/mm 3 . No deaths or grade 4 adverse events were reported. Greater increases in T cell activation (%HLA-DR+/CD38+) among CD4+ (median +1.01% vs +0.17%) and CD8+ (+3.24% vs +0.52%) cells were observed in the isotretinoin than control arm at wk 16, but reverted post-treatment. Similarly, soluble markers of inflammation (IL-6, sCD163, CRP, sCD14) had greater increases with isotretinoin that reverted post-treatment. In contrast to blood, the median decrease in gut CD8+ T cell activation was greater with isotretinoin vs control (-6.3% vs 1.6%). Notably, blood CD4+ T cell numbers increased over the study in the isotretinoin arm (+27 cells/mm 3 to wk 28). CD4+T cell cycling (%Ki67+) did not change in the blood but increased in the terminal ileumwith isotretinoin (+2.6%). Conclusion: Isotretinoin treatment resulted in increases in cellular and soluble markers of immune activation and inflammation that were not sustained after removal of therapy. There was an overall increase in systemic CD4+ T cell count with isotretinoin treatment over 28 wks. This was accompanied by an increase in gut CD4+ T cell proliferation and decreased intestinal CD8+ T cell activation during treatment. Together, these data suggest that RA has differential effects on systemic and gut compartments, with immunological benefits in HIV- infected adults on suppressive ART.

Poster Abstracts

78

CROI 2018