CROI 2015 Program and Abstracts

Abstract Listing

Poster Abstracts

Conclusions: Soluble CD163 and TNFRII levels were significantly higher in liver disease progressors than non-progressors and the differences in these activation markers were apparent prior to the liver fibrosis outcome. 677 HIV/HCV Co-Infection Accelerated Liver Disease is AssociatedWith Induction of M2-Like Macrophages Moses T. Bility 1 ; Feng Li 1 ; Junichi Nunoya 1 ; Guangming Li 1 ; Eoin Feeney 2 ; Raymond Chung 2 ; Lishan Su 1 1 University of North Carolina, Chapel Hill, NC, US; 2 Massachusetts General Hospital, Harvard Medical School, Boston, MA, US Background: Chronic hepatitis B/C virus-induced liver diseases including fibrosis and cancer are exacerbated by human immunodeficiency virus (HIV) co-infection. Furthermore, HCV and HIV co-infection is a major cause of mortality in HIV-infected patients in western countries. The underlying pathogenic mechanisms by which chronic hepatitis viruses and HIV-1 co-infection induce and exacerbate liver diseases respectively remain unclear due to a lack of appropriate small animal models. Several studies showmacrophages and other innate immune cells play a critical role in modulating host response and pathology; with M1 macrophages promoting pathogen clearance and immunity via secretion of Th1 associated cytokines, while M2-like macrophages impair Th1 immune response and promote tissue fibrosis and neoplasia via secretion of immunosuppressive cytokines. Methods: We recently developed humanized mouse models, which carry both human immune system and human liver cells. The humanized mouse model is permissive for chronic hepatitis B/C virus and HIV infections. Briefly, to generate humanized mice, immunodeficient mice are transplanted with human fetal liver - derived hematopoietic stem cells and progenitor liver cells, followed by mouse hepatocyte depletion. Importantly, the humanized mouse model is the only in vivo model that support anti-viral human immune responses, and develops human immune cells mediated chronic liver inflammation, fibrosis and neoplasia in chronic hepatitis virus infections. HIV infection of humanized mice results in AIDS associated pathogenesis including CD4+ T cells depletion and hyper-immune activation. Additionally, preliminary results show HIV/HCV co-infection of humanized mice results in exacerbated liver pathogenesis. Lastly, we uterlized patient liver samples frommono-infected or co-infected HIV/HCV patients. Results: Analysis of HCV-induced liver inflammation in both humanized mice and patient liver samples showed high levels of macrophages of predominately M2-like phenotypes localized to cirrhotic and neoplastic regions. Interestingly, chronic HIV infection is also associated with M2-like macrophage polarization in both humanized mice and patients. Importantly, HIV/HCV co-infection-induced accelerated liver disease was associated with increased M2-like macrophage activation. Conclusions: Results from this study suggests a critical role for macrophage polarization in HIV/HCV-induced accelerated liver pathogenesis. 678 HIV Infection Is AssociatedWith an Impaired Anti-HCV Activity of NK-Like T Cells Pavlos Kokordelis 1 ; Benjamin Krämer 1 ; Christoph Boesecke 1 ; EstherVoigt 2 ; Patrick Ingiliz 3 ; Andreas Glässner 1 ; FranziskaWolter 1 ; Ulrich Spengler 1 ; Jürgen K. Rockstroh 1 ; Jacob Nattermann 1 1 University of Bonn, Bonn, Germany; 2 Praxis am Ebertplatz, Cologne, Germany; 3 Medical Center for Infectious Diseases, Berlin, Germany Background: Co-infection with the hepatitis C virus (HCV) is a major cause of morbidity and mortality in HIV(+) patients. In HIV(-) patients CD3+CD56+ NK-like T cells, a subset of innate lymphocytes, have been suggested to modulate outcome of acute hepatitis C. However, it remained unclear Methods: Eight HIV mono-infected patients, 12 HIV(+) patients with chronic hepatitis C, 8 HIV(-) patients with chronic HCV infection as well as 12 healthy individuals were enrolled into this study. Peripheral NKT cells (CD3+CD56+) were phenotypically analyzed by flow-cytometry. IFN- γ secretion and anti-HCV activity of NKT cells were analyzed using the HuH7 HCV replicon system. Results: Un-stimulated CD3+CD56+ NK-like T cells from healthy donors only displayed a moderate anti-HCV function. However, stimulation with IL-12/IL-15 significantly increased the ability of CD3+CD56+ NK-like T cells to block HCV replication. Supernatants of IL-12/IL-15 stimulated CD3+CD56+ NK-like T cells also significantly inhibited HCV replication in vitro, suggesting that non-cytolytic mechanisms may play a major role. Accordingly, we only observed minimal killing of HuH7 HCV-replicon cells by CD3+CD56+ NK-like T cells. Moreover, we found stimulation with IL-12/IL-15 to significantly increase IFN- γ production and blocking of IFN- γ with a specific antibody significantly reduced the anti-viral activity of CD3+CD56+ NK-like T cells. However, when CD3+CD56+ NK-like T cells from HIV(+) patients were studied we found HIV infection to be associated with a significantly impaired IFN- γ production, irrespective of HCV co-infection. Accordingly, CD3+CD56+ NK-like T cells from HIV(+) patients were significantly less effective in blocking HCV replication in vitro than cells from healthy individuals. Phenotypic analysis revealed that HIV(+) patients displayed a significantly lower frequency of CD161+CD3+CD56+ NK-like T cells compared to controls. Of note, frequency of CD161-expressing cells was positively correlated with IFN- γ production. Conclusions: Taken together, our data indicate that HIV infection is associated with an impaired anti-HCV activity of CD3+CD56+ NK-like T cells which might represent a novel mechanism of dysregulated immune response in HIV/HCV co-infected patients. whether these cells display direct anti-HCV activity and how HIV co-infection may modulate functions of CD3+CD56+ NK-like T cells. Here, we show that CD3+CD56+ NK-like T cells can effectively block HCV replication but are functionally impaired in HIV(+) patients.

Poster Abstracts

422

CROI 2015