CROI 2020 Abstract eBook

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States. If current rates persist, 41% of black MSM and 22% of Hispanic MSM in the US will be diagnosed with HIV during their lifetimes. On February 5, 2019, at the State of the Union Address, the President announced the intention to End the HIV epidemic in the US by reducing new infections by 75%within 5 years and by 90%within 10 years. To reach these goals, the Department of Health and Human Services is proposing to target 48 counties plus Washington, DC and San Juan, Puerto Rico plus 7 Southern States that together comprise 50% of new HIV diagnoses. What will it take for this plan to be successful? We have the tools but fundamental differences in access to health care, local legislation, as well as racism, structural stigma, homelessness, and HIV laws/policies that will make implementation challenging. Steffanie A. Strathdee , University of California San Diego, San Diego, CA, USA In 1997, I presented at CROI on a new HIV outbreak that I helped identify among people who inject drugs (PWID) in Vancouver, Canada, where HIV incidence peaked at 18.6 per 100 person years. The response was to expand needle exchange programs (NEPs), medication for opioid use disorder (MOUD) and mobile HIV testing. Later, Vancouver opened North America’s first supervised injection facility (SIF) and adopted a policy of HIV treatment as prevention (TasP). HIV incidence among PWID plummeted and no social harms associated with its NEP or SIF were documented. In contrast, except for a 2-year period, US Congressional law prevented the use of federal funds to support NEPs until 2015. The US is now in the midst of its most serious opioid epidemic with several injection drug use-associated HIV outbreaks, over 40,000 new HCV infections each year and co-occurring epidemics of overdose, endocarditis and syphilis. What has been done to prevent HIV outbreaks among PWID? This presentation will identify missed opportunities and in some cases, progress made to prevent HIV outbreaks in rural settings. For example, a modeling study estimated that if Scott County, IN had launched an earlier response, 200 HIV infections could have been prevented. In W.Virginia, ongoing HIV outbreaks in Huntington and Charleston are exacerbated by restrictions and/or closure of NEPs and an effort to make them illegal, alongside a moratorium on newmethadone programs. In these and other U.S. states, structural barriers to accessing MOUD are the rule rather than the exception, although innovations like hospital-based MOUD programs show promise. Across the U.S, only one (underground) SIF exists. As we approach the 4th decade of the HIV pandemic, we know how HIV is transmitted among PWID and their networks. A plethora of scientific evidence shows that harm reduction programs can avert HIV epidemics. Yet at the federal level, most funding from the U.S. Office of National Drug Control Policy is spent on law enforcement/interdiction and little on prevention of drug use, which could have important downstream effects. Preventing HIV and co-occurring syndemics among PWID necessitates addressing the structural drivers of addiction including homelessness, unemployment, lack of health insurance and cycles of incarceration. The US needs to abandon its war on people who use drugs and treat addiction as a medical condition rather than a moral failing Eileen P. Scully , Johns Hopkins University School of Medicine, Baltimore, MD, USA Biological sex confers specific immunologic advantages and challenges to both men and women. These differences lead to distinct patterns of immune responses and differing susceptibility to infections and to autoimmune and inflammatory pathology. There are data demonstrating sex-specific features of HIV acquisition, pathogenesis and the dynamics of the HIV reservoir, but many open questions remain. Despite the high burden of HIV infection among women, estimated at more than 50% of adults in 2018, enrollment of both cis and transgender women in clinical trials and basic research cohorts has been variable. In some domains, a notable lack of representation undermines the confidence that the data can be applied to all people living with HIV infection. However, sex differences represent a rich source for discovery. A comparative biology approach can leverage differences in immune responses and viral control to highlight pathways critical for vaccine development, cure interventions, or prevention of inflammatory comorbidity for both men and women. This same lens can be used to better understand the health risks and specific clinical needs for transgender men and women. Further, insuring that interventions are efficacious in women as well as men is essential to achieve the global goals for prevention, treatment and reduction in morbidity. To address these questions, both women and men must be enrolled in studies and the

impact of both sex and gender assessed. This mandate to study both sexes is compelling from a scientific rigor and discovery perspective, and also meets our ethical responsibility to insure our innovations will work for all people living with HIV. 64 TARGETING THE KSHV TYROSINE KINASE AND VIRAL LYTIC REACTIVATION WITH INHIBITORS Guillaume Beauclair 1 , Eleonora Naimo 1 , Tatyana Dubich 2 , Dagmar Wirth 2 , Thomas F. Schulz 1 1 Medizinische Hochschule Hannover, Hannover, Germany, 2 Helmholtz Centre for Infection Research, Braunschweig, Germany Background: Kaposi’s Sarcoma-associated herpesvirus (KSHV) is the cause of three human malignancies, Kaposi’s Sarcoma, Primary Effusion Lymphoma and the plasma cell variant of Multicentric Castleman’s Disease. Previous research has shown that several cellular tyrosine kinases play crucial roles during several steps in the virus replication cycle. Two KSHV proteins also have protein kinase function: open reading frame (ORF) 36 encodes a serin-threonine kinase, while ORF21 encodes a thymidine kinase (TK), which has recently been found to be an efficient tyrosine kinase. Methods: In vitro kinase assays, virus replication assays, construction of recombinant KSHV mutants with a kinase-deficient orf21 gene, virus inhibition assays, in vivo endothelial tumor formation assays Results: In this study, we explore the role of the ORF21 tyrosine kinase function in KSHV lytic replication. By generating a recombinant KSHV mutant with an enzymatically inactive ORF21 protein we show that the tyrosine kinase function of ORF21/TK is not required for the progression of the lytic replication in tissue culture, but that it is essential for the phosphorylation and activation to toxic moieties of the antiviral drugs zidovudine and brivudine. In addition, we identify several tyrosine kinase inhibitors, approved for clinical use against human malignancies, which potently inhibit not only ORF21 TK kinase function, but also viral lytic reactivation and the development of KSHV- infected endothelial tumors in mice. The most potent inhibitors of KSHV TK autophosphorylation, KSHV reactivation and KSHV-dependent tumor formation in a xenograt model were dasatinib, ibrutinib and ponatinib. Conclusion: Since the identified kinase inhibitors target both cellular tyrosine kinases supporting productive viral replication and the KSHV tyrosine kinase, these drugs (dasatinib, ibrutinib, ponatinib), which are already approved for clinical use, may be suitable for repurposing for the treatment of KSHV-related tumors in AIDS patients or transplant recipients. 65LB A ROLE FOR IRON METABOLISM AND FERROPTOSIS IN KAPOSI SARCOMA Background: Iron is an essential element for normal cellular function, and many tumor cells satisfy their high iron requirement via altered expression of proteins that regulate iron metabolism. While iron fuels tumor growth, it presents a paradox: how to maintain redox homeostasis and resist ferroptosis, a ROS-reliant and iron-dependent form of regulated cell death. Many tumor types resist the ferroptotic cascade via increased expression/activity of antioxidant ferroptosis suppressor pathways (FSPs). To date, two complementary but non-redundant pathways have been identified: a canonical glutathione (GSH)- dependent pathway and, more recently, a novel FSP that relies on ubiquinol (the reduced form of CoQ) to prevent lethal lipid peroxidation. Our goal is to determine how the oncogenic Kaposi sarcoma herpesvirus (KSHV) manipulates host iron metabolism and antioxidant defense to promote Kaposi sarcoma (KS) tumorigenesis while resisting ferroptosis. Methods: Lymphatic endothelial cells (LEC) de novo-infected with KSHV-BAC16 were used for this study. Expression of host genes involved in iron metabolism and ferroptosis resistance was evaluated by RNA-seq, qPCR, immunoblot, FACS and IFA. Cellular iron content was measured by ICP-MS. Markers of pro/ antioxidant status (e.g., ROS, GSH) were measured via quantitative colorimetric assay. Susceptibility to ferroptosis was evaluated using selective inducers and inhibitors, and measured via cell viability and lipid peroxidation assays. Results: Our data indicate that KSHV manipulates the host iron regulon to promote iron acquisition and an iron-responsive growth phenotype. However, despite these changes, infected cells do not succumb to ferroptosis. Notably, KSHV significantly upregulates the expression of xCT, the small subunit of system xc- that functions as the upstream node of the GSH-dependent FSP. HERPESVIRUS PATHOGENESIS Ashlee V. Moses 1 , Jean Gustin 1 1 Oregon Health and Sciences University, Portland, OR, USA

62 PREVENTING HIV AMONG PEOPLE WHO INJECT DRUGS: PLUS ÇA CHANGE, PLUS ÇA MÊME CHOSE

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63 SEX DIFFERENCES IN HIV

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CROI 2020