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Helen Horton, Ph.D.
Associate Professor, Seattle Biomedical Research Institute
Affiliate Associate Professor, Depts of Global Health and Medicine, University of Washington
Area of Expertise: HIV/AIDS, immunology, vaccinology
Helen Horton’s research focuses on understanding the mechanisms that enable some individuals to control chronic viral infections such as HIV-1. Uncovering this new knowledge could lead to novel therapeutic interventions and more rational design of prophylactic or therapeutic vaccines components.
Several key questions drive the research in the Horton Lab:
- Why are some viral infections cleared while others persist? Can the knowledge gained from rare individuals who can control chronic viral infections be used to design more efficacious vaccines?
- Can ineffective immune responses induced in the majority of individuals with chronic viral infection be manipulated to possess more effective phenotypes?
- Are there age-specific differences in anti-viral immunity that could explain why HIV-infected infants have poorer clinical outcomes than HIV-infected adults?
Hypothetically, persistent viral infections may perturb innate mechanisms (DC/NK interactions) early in infection, which eventually lead to T cell tolerance. This tolerance induction in virus-specific CD8+ T cells may ultimately lead to progression to disease. Initial studies in the Horton laboratory have focused on HIV-1 infection but this work should be applicable to many other chronic viral infections (e.g. Hepatitis C).
Innate and adaptive cellular immunity are compromised during chronic HIV-1 infection. NK cell dysfunction is characterized by weak cytolytic activity. HIV-specific CD8+ T cells become tolerant in that they do not proliferate or kill infected targets as efficiently as virus-specific T cells from other non-persistent viral infections (e.g. influenza). However, rare HIV-1-infected individuals maintain extraordinary control of HIV-1 indefinitely (Long-Term Non-progressors; LTNP). Horton’s research has shown that T cells restricted by HLA alleles associated with non-progression (HLA-B27 and -B57) are resistant to this type of peripheral tolerance and that this may explain why LTNP are protected from progression to AIDS (Horton, Frank et al. 2006). The mechanism(s) leading to HIV-specific CD8+ T cell tolerance and NK cell dysfunction are not known but are important to understand to enable therapeutic intervention and enhance rational vaccine design.
Dendritic cells (DCs) bridge innate and adaptive immunity and interactions between DCs and NK and/or T cells determine the functional profiles of the engaged effectors. Thus DCs decide whether NK and T cells become activated or tolerized. In general, immature DCs are tolerogenic and secrete suppressive cytokines/enzymes (e.g. IL-10 and indoleamine 2, 3-dioxygenase (IDO)) whereas mature DCs are stimulatory and secrete IFN-α (plasmacytoid DCs) and IL-12 (myeloid DCs) as well as upregulating receptors which are critical for full T cell activation (e.g. CD70). Conversely, NK cells lead to maturation of DCs and are responsible for lysing immature DCs. Thus it is feasible that viruses that cause persistent infection have developed means to interfere with the normal NK:DC cross-talk. This would result in dysfunctional NK and more immature DCs which, in turn, would ultimately result in induction of T cell tolerance.
Horton’s work is currently supported by the Division of AIDS (DAIDS), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH).