CROI 2019 Abstract eBook

Abstract eBook

Oral Abstracts

significantly different in the EPIC-HIV only arm (RR=0.96, 95% CI: 0.76-1.21, p=0.72). Conclusion: Micro-incentives significantly increased the uptake of home-based HIV testing among men in rural South Africa and should thus be considered as a policy option where HIV testing rates are low. BlossomDamania , University of North Carolina at Chapel Hill, Chapel Hill, NC, USA Host cells sense viral infection through pattern recognition receptors (PRRs), which detect pathogen-associated molecular patterns (PAMPs) and stimulate an innate immune response. PRR activation initiates signal transduction events that ultimately result in interferon and inflammatory responses. Human tumor viruses, including Kaposi sarcoma-associated herpesvirus (KSHV), are detected by several different PRRs. KSHV, also known as human herpesvirus (HHV8), is associated with three different cancers in the human population and evasion of host immunity is intimately linked to viral pathogenesis and oncogenesis. We will discuss host immune pathways that are activated upon KSHV infection and we will describe how KSHV viral genes engage a variety of mechanisms to evade the host innate immune response. EBV is the principal cause of infectious mononucleosis and is associated with about 2,000 new cases of cancer worldwide each year, including epithelial cell malignancies such as gastric and nasopharyngeal carcinoma, and B cell lymphomas. EBV is associated with several malignancies in patients with HIV including Burkitt lymphoma, Hodgkin's lymphoma, diffuse large B cell lymphoma, primary CNS lymphoma, primary effusion lymphoma, plasmablastic lymphoma, and smooth muscle tumors. No vaccine has been licensed to prevent EBV infection or disease. We have developed two EBV self-assembling nanoparticle-based vaccines that present viral glycoproteins in a symmetrical array. The first contains a bacterial ferritin conjugated to a portion of EBV glycoprotein gp350, the major target for B cell neutralizing antibody in human plasma. The second nanoparticle vaccine consists of EBV gH/gL/gp42 which are viral glycoproteins important for fusion of the EBV envelope to host cell plasma membranes and entry of the virus into cells. Nanoparticles containing gp350 induced high titers of antibodies in mice and nonhuman primates that neutralized virus infection of B cells. Most of the antibody elicited in nonhuman primates targeted the host cell receptor (CD21) binding site on gp350. Nanoparticles containing gH/gL/gp42 induced potent neutralizing antibody in mice and nonhuman primates that inhibited infection of both B cells and epithelial cells. These antibodies also blocked EBV glycoprotein-mediated fusion of epithelial cells and B cells. These EBV vaccines are promising candidates to prevent EBV infection and/or disease. 57 HPV: NEW INSIGHTS INTO ONCOGENESIS AND OPPORTUNITIES FOR IMMUNE CONTROL Denise Galloway , Fred Hutchinson Cancer Research Center, Seattle, WA, USA A group of ~ 15 high risk human papillomaviruses (HPVs) cause nearly all cervical cancers and the majority of anal, vulvar, vaginal, penile, and oropharyngeal cancers. These cancers all express the two viral oncoproteins, E6 and E7. The E6 protein binds to the ubiquitin ligase E6AP, and targets the tumor suppressor p53, the proapoptotic Bak protein and a repressor of hTERT transcription for degradation. Through a C-terminal motif E6 binds various PDZ proteins that affect epithelial polarity. The E7 proteins bind and degrade pRb and p130, as well as histone remodeling and modifying enzymes, and CDK inhibitors. Together these activities promote genetic instability. We have been investigating additional mechanisms by which E6 and E7 cause genetic instability by impairing the response to DNA damage. Both oncogenes, but particularly E6, impair the Homology dependent repair pathway and the Fanconi Anemia/ BRCA pathway. Understanding the precise mechanisms provides new mechanisms for therapies to treat HPV associated cancers. 58 HBV: FROM VIRAL INTEGRATION TO LIVER CANCER, IMPACT ON CURE STRATEGIES Fabien Zoulim , INSERM, Strasbourg, France Chronic HBV infections represent a major public health problem as they are the main cause of hepatocellular carcinoma (HCC) worldwide. Viral suppression is achieved in the majority of treated patients with current antiviral approaches 55 MODULATION OF HOST INNATE IMMUNITY BY KSHV 56 EBV: IMMUNOPATHOGENESIS AND THE PATH TO AN EBV VACCINE Jeffrey Cohen , NIAID, Bethesda, MD, USA

and is associated with a decreased risk of disease progression towards cirrhosis and HCC. However, the later risk is not eliminated. The development of HBV-induced HCC relies on multiple mechanism: i) random integration of HBV genome into host chromosomes leading to insertional mutagenesis, ii) expression of viral proteins interfering with cellular gene expression and signaling pathways, or to chronic oxidative stress, iii) chronic liver inflammation, iv) hepatocyte death and regeneration, that may lead to clonal expansion and selection of transformed hepatocytes. Deep sequencing of HBV associated tumors have shown telomer shortening, mutations in TERT promoter and TP53. It was shown in hepatocyte culture that viral genome integration can occur very early after infection. In patients, in the so called “immune tolerance” phase, major integration events occur and are associated with clonal expansion of hepatocytes. This suggests that molecular damage of the host genome occurs even in this phase that is generally recognized as clinically benign, and that hepatocyte death and turn over occurs leading to clonal expansion. This is a strong argument for early treatment intervention to prevent integration events. Integration has also other impact on the novel cure strategies. HBsAg loss is used as a clinical endpoint of functional cure. Recent studies showed that the expression of HBsAg is mainly driven by cccDNA in HBeAg(+) patients, but mainly by integrated viral sequences in HBeAg(-) patients. Thus, this endpoint might be more difficult to reach in patients where HBsAg is mainly expressed from integrated sequences. It was also shown, that siRNA approaches targeting the extreme 3’end of the viral transcripts may be limited by truncation of these RNAs resulting from viral genome rearrangements during the integration process. It will be also important to understand the impact of integration on circulating viral RNAs, a newly described biomarker of HBV infection, that could serve to track the pool of cccDNA and/or of integration events. In conclusion, HBV integration is a molecular event involved in liver oncogenesis which may have an impact on the development of novel cure strategies and monitoring of patients. While there are >30 antiretroviral (ARV) drugs approved for HIV therapy, there are only limited data on ARVs in pregnancy. The mean lag time from ARV approval to data availability in pregnancy is 5 years; most ARVs receive regulatory approval with only animal data to evaluate potential fetal effects. For low incidence outcomes such as birth defects, data are often only collected post-approval. To determine if a birth defect is associated with a drug or simply reflects the baseline population rate of a defect, the number of required exposures will vary based on the defect population prevalence. To rule-out >2-fold increased risk in overall defects, with 3% population prevalence, 200 early pregnancy exposures are needed, but to rule out >3-fold increased risk in a rare defect like neural tube defects (NTD), with 0.1% population prevalence, 2000 early exposures are needed. Exposure timing is critical, as teratogenic risk is highest very early in pregnancy, before most women recognize they are pregnant, but most reports do not distinguish pre-conception from first-trimester exposure. Post-pregnancy defect reports to pharmacovigilance databases have limitations including reporting bias, case duplication, and lack of denominators. Prospective reports during pregnancy, with follow-up for birth outcome, such as the Antiretroviral Pregnancy Registry, has fewer biases. In 1998, efavirenz (EFV) was approved with a warning on use in pregnancy due to animal data showing central nervous system defects with in utero exposure in primates. Retrospective reports of NTDs in humans increased concern, leading to FDA classification of “positive fetal risk” in 2005; collection of prospective cases over the subsequent 13 years has now shown no increased NTD risk. In contrast, with dolutegravir (DTG), animal data did not raise concerns, but a well-designed prospective active surveillance study in Botswana detected a potential signal of concern for NTD with preconception DTG exposure. In contrast to the delay experienced with EFV, due to active surveillance, significant numbers of already- exposed pregnancies will be collected prospectively over the next 12 months, and with coordinated global efforts to combine additional exposures with denominator data, this signal should be able to be confirmed or refuted within a year. Continuing prospective active birth outcome surveillance is required as new ARVs are introduced into populations including women of childbearing potential. Lynne M. Mofenson , Elizabeth Glaser Pediatric AIDS Foundation, Washington, DC, USA

Oral Abstracts

59 UPDATE ON ANTIRETROVIRAL DRUGS AND BIRTH DEFECTS

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CROI 2019