HIV infection causes generalized global immune activation involving both the innate and adaptive arms of the immune system increasing AIDS and HIV-related non-AIDS conditions (HANA), even with successful HAART treatment. Our studies demonstrate that high levels of immune activation and senescence are seen early in HIV disease and are associated with incident AIDS, cardiovascular and liver disease especially in HCV co- infected women. The overall goal of this renewal is to continue examining mechanisms and consequences of this immune hyperactivation state and its impact on accelerated disease. We will evaluate the consequences of aberrant cytokine production that may promote fibrogenesis or tissue damage and alter T cell maturation, regulation and immune function. We find that co-infected women with liver fibrosis have significantly fewer regulatory T cells and increased percentage of senescent and terminally differentiated and effector memory T cells, indicating that immune dysregulation may accelerate """"""""inflammaging"""""""" and end organ disease. In this proposal, we will comprehensively investigate the effect of long-term activation and immune dysregulation on clinical outcome in a well characterized cohort of women in WIHS. Using multiparameter flow cytometry, real- time PCR and PCR array technologies, we developed platforms to systematically evaluate both immunologic and virologic factors impacting disease. We performed complex validation experiments allowing simultaneous evaluation of soluble and cellular biomarkers, molecular gene-signatures of immune activation, exhaustion, senescence and regulation, and virologic studies from one sample. Our central hypothesis is that HIV- associated immune dysregulation and HCV infection with liver dysfunction maintains this state of immune hyperactivation, leading to immune exhaustion and senescence and more rapid progression of HANA conditions, even with effective HAART. Furthermore, liver disease will play a major role in determining immunologic, virologic and clinical outcomes especially as women age and enter menopause.
Our specific aims are:
Specific Aim 1) Define determinants and consequences of long-term immune activation in singly and co-infected women successfully treated with HAART and Specific Aim 2) Assess gene expression patterns involved in molecular mechanisms promoting immune activation, senescence, exhaustion, and progression to clinical outcomes.
For Specific Aim 1, we will longitudinally compare levels of cytokines and soluble and cellular markers of activation and immune regulation and determine impact on immune senescence/exhaustion and disease outcome.
For Specific Aim 2, we will evaluate intrinsic host gene- signature pathways of immunity using real time PCR array technology and will evaluate interferon response related to immune activation, exhaustion and senescence. These studies will identify the impact of long-term activation and dysregulation on senescence and exhaustion and the role of HCV co-infection in hopes of developing treatment strategies that may prevent continued hyperactivation and the onset disease.

Public Health Relevance

HCV infection significantly contributes to HIV-associated immune activation resulting in accelerated HIV and HCV disease, even in the setting of long-term, successful highly active antiretroviral therapy (HAART). Mechanisms involved in maintaining this persistent inflammatory process are not well understood. Our proposed studies will help us better understand how HIV and HCV together cause increased liver disease, AIDS and HIV-associated non-AIDS (HANA) outcomes. With the advent of better HCV treatments for co-infected patients, it will be essential to understand potential barriers to successful treatment of both HIV and HCV so that new treatment strategies can be developed.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
High Priority, Short Term Project Award (R56)
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AIDS Clinical Studies and Epidemiology Study Section (ACE)
Program Officer
Sharp, Gerald B
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University of Southern California
Schools of Medicine
Los Angeles
United States
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Sarkar, Monika; Dodge, Jennifer L; Greenblatt, Ruth M et al. (2017) Reproductive Aging and Hepatic Fibrosis Progression in Human Immunodeficiency Virus/Hepatitis C Virus-Coinfected Women. Clin Infect Dis 65:1695-1702
Kerzerho, Jerome; McIlvaine, Elizabeth J; Anthony, Patricia et al. (2016) Impact of Hepatitis C Virus on the Circulating Levels of IL-7 in HIV-1 Coinfected Women. J Acquir Immune Defic Syndr 71:172-80
Spencer, LaShonda Y; Christiansen, Shawna; Wang, Chia-Hao H et al. (2016) Systemic Immune Activation and HIV Shedding in the Female Genital Tract. J Acquir Immune Defic Syndr 71:155-62
Serrao, Erik; Wang, Chia-Hao; Frederick, Toinette et al. (2014) Alteration of select gene expression patterns in individuals infected with HIV-1. J Med Virol 86:678-86
Karim, Roksana; Mack, Wendy J; Kono, Naoko et al. (2014) T-cell activation, both pre- and post-HAART levels, correlates with carotid artery stiffness over 6.5 years among HIV-infected women in the WIHS. J Acquir Immune Defic Syndr 67:349-56
Atrio, Jessica; Stanczyk, Frank Z; Neely, Michael et al. (2014) Effect of protease inhibitors on steady-state pharmacokinetics of oral norethindrone contraception in HIV-infected women. J Acquir Immune Defic Syndr 65:72-7
Karim, Roksana; Mack, Wendy J; Stiller, Tracey et al. (2013) Association of HIV clinical disease progression with profiles of early immune activation: results from a cluster analysis approach. AIDS 27:1473-81
Crystal, Howard; Kleyman, Inna; Anastos, Kathryn et al. (2012) Effects of hepatitis C and HIV on cognition in women: data from the Women's Interagency HIV Study. J Acquir Immune Defic Syndr 59:149-54
Homans, James; Christensen, Shawna; Stiller, Tracey et al. (2012) Permissive and protective factors associated with presence, level, and longitudinal pattern of cervicovaginal HIV shedding. J Acquir Immune Defic Syndr 60:99-110
Kuniholm, Mark H; Gao, Xiaojiang; Xue, Xiaonan et al. (2011) Human leukocyte antigen genotype and risk of HIV disease progression before and after initiation of antiretroviral therapy. J Virol 85:10826-33

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