Our Science – Winkler Website

Cheryl Ann Winkler, Ph.D.

Laboratory of Genomic Diversity Head, Molecular Genetic Epidemiology Studies Section Senior Investigator (Contr) Building 560, Room 11-64 NCI-Frederick Frederick, MD 21702-1201 Phone:   301-846-5747 Fax:   301-846-1909 E-Mail:   winkler@ncifcrf.gov Link: Other Homepage

Biography

Dr. Winkler received her graduate degree in immunogenetics from the University of Maryland under the direction of Dr. Stephen J. O'Brien at the NIH. During graduate school, Dr. Winkler's work on the major histocompatibility complex in cats led to the notable finding that the endangered cheetah was highly inbred and more susceptible to infectious diseases as a consequence. Dr. Winkler now investigates the interaction of host genetic variation and complex diseases in humans.

Research

The primary goal of my laboratory is to identify host genetic factors that contribute to infectious and other complex diseases. Because of the tremendous impact of HIV-1 on global health, particularly in developing countries, we have focused much of our attention on HIV-1 infection and progression to AIDS, as well as HIV-1 associated conditions, such as focal segmental glomerulosclerosis (FSGS), a form of kidney disease associated with HIV-1. My group is also investigating the influence of genetic factors on other diseases, including nasopharyngeal carcinoma (NPC) and hepatocellular carcinoma (HCC), associated with the Epstein-Barr (EBV) and Hepatitis B (HBV) viruses, respectively, each of which is a significant health problem in Asia. I also present the research design for a new initiative to investigate the role of environmental and host factors in the development of antibodies (inhibitors) to Factor VIII in severe hemophiliacs resulting from a failure of immune tolerance. Approximately one third of severe hemophilia A patients develop inhibitors to factor VIII, greatly complicating clinical management.

Although the influence of host genetics on HIV-1 infection and AIDS pathogenesis is now well established, the identification of new genetic factors affecting AIDS is of ongoing importance. Genetic associations with AIDS pathogenesis are footprints of the interaction of HIV-1 and the host's cells and defenses: the associations of cellular genetic factors point to the host proteins involved in the HIV life cycle, while associations with immune response factors, but innate and acquired, indicate which aspects of the immune response are critical for controlling HIV infection. Correspondingly, understanding of the mechanisms of genetic associations with AIDS points to potential targets for therapeutic intervention. Moreover a substantial part of the heterogeneity observed in vaccine and clinical drug trials may be explainable by host genetic variation in susceptibility to infection and disease progression. These considerations apply to infectious diseases in general, and in particular to other chronic viral infections such as hepatitis B (HBV) and C (HCV) viruses.

Our investigation of genetic factors that may be important mediators of viral pathogenesis has been directed to four main classes of genes: 1) the chemokine receptor family on chromosome 3 and the chemokine ligand family on chromosome 17 that may modify HIV-1 cell entry; 2) cytokines that modify immune response to infectious agents and/or are involved in cell trafficking and inflammation; 3) internal cellular factors required by HIV-1 or other viruses for successful completion of the viral life cycle; and 4) factors that are involved in innate immunity to viral pathogens such as APOBEC3G, TRIM5, and the defensins. We have identified regulatory variants in IFN-l and RANTES that have been shown to significantly accelerate CD4 T cell depletion and progression to AIDS. We have also identified a haplotype block containing MCP1, MCP3, and eotaxin that is strongly associated with protection from HIV-1 infection; however, because of the high linkage disequilibrium observed between the three genes, the causal allele has not yet been identified. Because both immune regulation of viral pathogens and successful completion of the viral lifecycle depend on specific molecular interactions, it should not be unexpected that the course of disease may be affected by changes in protein structure or levels of expression.

In addition to host genetic factors that influence HIV-1 pathogenesis, coinfection by HCV, which has a similar transmission route, may also be an important influence. We were the first to report that HCV RNA levels are an independent predictor of AIDS progression and to provide convincing evidence that coinfection by HIV-1 increases liver enzyme levels (an indicator of liver inflammation). My collaborators and I are now investigating the role of host genetic factors on the breadth and strength of specific immune responses to HCV and HIV in a cohort of 333 HCV-infected persons of whom 207 are HIV-1 coinfected. An understanding of both genetic and immune regulation of HCV and HIV-1 viruses will provide insights into how these viruses interact in coinfected people to exacerbate liver inflammation and progression to AIDS.

HIV-1 infection is also associated with several glomerular diseases, the most common being focal segmental glomerulosclerosis (FSGS). Individuals with African ancestry have a 14-fold higher risk for FSGS compared to Europeans or Asians, and since this propensity is observed independently on three continents, it is likely a result of genetic rather than cultural or environmental factors. We therefore hypothesize that one or more genetic loci contributes to FSGS, with particular risk alleles being more common in persons of African descent. Because idiopathic FSGS is a separate syndrome from familial FSGS, and it is unusual to identify affected sib pairs, a population-based case-control study is being used to identify FSGS-associated genes in African Americans.

The human genome revolution has led to the full-length sequence of the human genome and the potential for the discovery of 3 million or more single nucleotide polymorphisms. It is now accepted that this spectrum of genetic variation present in human populations, acting in concert with environmental factors, contributes to the heterogeneity observed for susceptibility to many complex diseases and disorders. It is perhaps less well-appreciated that this variation will also affect individual responses to therapeutic interventions. An understanding of the genetic basis for complex disorders, many of which are quite common, will provide insights into pathogenic pathways and provide targets for new therapies. Similarly, the ability to predict responses to therapeutics or vaccines through genetic profiling has the potential to benefit clinical care and to advance public health.

This page was last updated on 7/18/2008.