The past four years of NIH/NIDA support has enabled a highly successful translational research study of acute hepatitis C virus HCV infection in young injection drug users (IDU), and this application proposes to build on and expand our scientific aims. HCV remains a problematic human pathogen;it is the most common blood borne infection in the U.S. It chronically infects up to 170 million people worldwide and causes an estimated 460,000 deaths per year, primarily due to cirrhosis, liver failure and hepatocellular cancer. Young IDU comprise the population most at risk and with the highest incidence rates (10-40%). Current treatments cure only ~50% and are too toxic for many patients;new ones are likely to have the same limitations. A protective vaccine is plainly needed to prevent productive HCV transmission in at-risk groups. Better understanding of the natural history, detailed correlates of protective immunity, and host genetic factors which impact acute HCV infection (within the first 12-24 weeks after inoculation) is likely to provide the necessary guide for vaccine and therapeutic development. For the majority of persons that are infected, the acute phase lasts six months;and those that remain viremic beyond six months will remain chronically infected. Accurate analyses of the rate, time-course, and immunological predictors of viral clearance in natural HCV infection, have been limited by the relative lack of acute cases available for prospective scientific study as well as lack of generalizability to the population most at risk (IDU). In the past four years, we have characterized acute HCV infection outcomes, clearance rates, transmission dynamics in injecting partners, immunological correlates (HCV-specific CD4+ and CD8+ cellular responses) of clearance, and acute HCV treatment candidacy. This application seeks a five-year renewal to continue and expand our multidisciplinary investigation of acute HCV infection. Our prospective study of 95 acute HCV infections has confirmed and shown robust associations between gender and HCV infection, with females clearing HCV at three times the rate of their male counterparts. Gender has been vastly understudied with respect to HCV infection (and other infections). We have also shown a cycle of recurring infection followed by clearance, demonstrating immune responses may potentially protect from persistent chronic infection. We will examine the effect of gender in more depth, and assess whether gender differences in clearance and reinfection and reclearance are explained by differences in lipid profiles, genetics, immunological responses, and/or injecting behaviors. We will continue the study of transmission dynamics in HCV discordant injecting partnerships to examine transmission events and quantify infectivity, examine the effect of viral load on infectivity and to examine whether susceptibility to infection may differ by gender. We will expand our immunological studies to examine both innate and adaptive cellular immune responses to include NK/T and Tregs. Finally, we add a significant new aim, to study host genetics; assessing the impact of gender-specific polymorphisms in the HCV co-receptor SR-BI on host lipoprotein response to HCV infection. All of these studies will expand the depth and breadth of knowledge regarding acute HCV infection and clearance, including host control of HCV, overall and by gender, to inform improved vaccine designs and potentially therapeutic approaches.

Public Health Relevance

This project seeks a five-year renewal to continue and expand our multidisciplinary investigation of acute HCV infection in young injection drug users. A protective vaccine is urgently needed to prevent productive infection of this most common blood borne virus. Better understanding of the natural history, detailed correlates of protective immunity, and host genetic factors which impact acute HCV infection will guide development of such. We have shown that women clear HCV infection at three times the rate of men, yet gender has been highly understudied with respect to HCV infection. In our prospective study of young IDU (the UFO Study) recurring infection and clearance events demonstrate that successful immune responses can be elicited. This study offers a unique opportunity to study gender differences in epidemiological, immunological and host genetic studies of acute infections prospectively. Results from this work will expand the depth and breadth of knowledge regarding acute HCV infection and clearance, and address fundamental questions of host control of HCV to inform improved vaccine designs and potentially therapeutic approaches.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA016017-11
Application #
8469841
Study Section
Infectious Diseases, Reproductive Health, Asthma and Pulmonary Conditions Study Section (IRAP)
Program Officer
Khalsa, Jagjitsingh H
Project Start
2002-09-25
Project End
2014-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
11
Fiscal Year
2013
Total Cost
$757,294
Indirect Cost
$119,274
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Morris, Meghan D; Evans, Jennifer; Montgomery, Martha et al. (2014) Intimate injection partnerships are at elevated risk of high-risk injecting: a multi-level longitudinal study of HCV-serodiscordant injection partnerships in San Francisco, CA. PLoS One 9:e109282
Dokubo, E Kainne; Evans, Jennifer; Winkelman, Valerie et al. (2014) Comparison of Hepatitis C Virus RNA and antibody detection in dried blood spots and plasma specimens. J Clin Virol 59:223-7
Tracy, Daniel; Hahn, Judith A; Fuller Lewis, Crystal et al. (2014) Higher risk of incident hepatitis C virus among young women who inject drugs compared with young men in association with sexual relationships: a prospective analysis from the UFO Study cohort. BMJ Open 4:e004988
Thompson, Fiona; Ghanem, Mohamed; Conway, Katie et al. (2014) Intravenous iron and vertical HIV transmission: any connection? AIDS 28:1245-6
Hayes, Benjamin; Briceno, Alya; Asher, Alice et al. (2014) Preference, acceptability and implications of the rapid hepatitis C screening test among high-risk young people who inject drugs. BMC Public Health 14:645
White, Bethany; Madden, Annie; Prins, Maria et al. (2014) Assessing the feasibility of hepatitis C virus vaccine trials: results from the Hepatitis C Incidence and Transmission Study-community (HITS-c) vaccine preparedness study. Vaccine 32:5460-7
Asher, Alice K; Santos, Glenn-Milo; Evans, Jennifer et al. (2014) A closer look at hepatitis C clearance in HIV controllers: a response. AIDS 28:1241-2
Evans, Jennifer L; Morris, Meghan D; Yu, Michelle et al. (2014) Concordance of risk behavior reporting within HCV serodiscordant injecting partnerships of young injection drug users in San Francisco, CA. Drug Alcohol Depend 142:239-44
Etcheverry, M Florencia; Evans, Jennifer L; Sanchez, Emilia et al. (2013) Enhanced retention strategies and willingness to participate among hard-to-reach female sex workers in Barcelona for HIV prevention and vaccine trials. Hum Vaccin Immunother 9:
Montgomery, Martha E; Fatch, Robin S; Evans, Jennifer L et al. (2013) Injecting risk behavior among traveling young injection drug users: travel partner and city characteristics. J Urban Health 90:500-15

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