• Faculty Member Photo
  • Lisa Frenkel, MD
    Co-Director, Center for Global Infectious Disease Research
    Seattle Children's Research Institute

    Professor of Pediatrics and Laboratory Medicine
    Adjunct Professor, Global Health and Medicine
    University of Washington

    Affiliate Professor, Vaccine and Infectious Disease Division
    Fred Hutchinson Cancer Research Center


    Email: click here
    Phone: (206) 987-5140

Welcome to the Frenkel Lab



Investigator Biography



Dr. Lisa Frenkel is an internationally recognized expert on HIV and infectious disease. She is co-director of the Center for Global Infectious Disease Research at Seattle Children’s Research Institute. She is a Professor in the University of Washington’s Departments of Pediatrics, in the Division of Infectious Diseases and in Laboratory Medicine, and is an Affiliate Professor in Global Health and Internal Medicine in the Division of Allergy and Infectious Diseases; and co-director of Seattle Children’s pediatric infectious diseases and virology clinic.

Areas of Research



Understanding the mechanisms that allow HIV to persist despite effective ART to better enable interventions to cure HIV infection. The work from our group determined that HIV infection persists during years of suppressive ART due to proliferation of infected cells. In studies initiated to define whether low-level HIV replication allows HIV to persist despite effective ART, we found that transient low-level viremias, or “blips,” during ART were usually comprised of populations of identical env and pol sequences, which suggests that clones of infected cells produced viruses. Our subsequent studies revealed that populations of identical viral sequences from the peripheral blood mononuclear cells and sputum (rich in macrophages) increase over a decade in individuals with viral replication suppressed by antiretroviral therapy, suggesting that clonal proliferation of cells with provirus sustains HIV infection during suppressive ART. We proved that HIV-infected cells develop clones that persist during ART by documenting that identical HIV env sequences always have identical integration sites in the human genome, and conversely that diverse HIV env sequences always have different integration sites. In the latter study we observed that provirus integration in proliferating HIV-infected cells in genes controlling immune functions, the cell cycle or cancers had a statistically significant survival advantage over time; suggesting that interference with expression of these genes allows the infected cells to proliferate and/or survive. More recently, our preliminary data finds full-length, intact proviral sequences in clones of cells during suppressive antiretroviral treatment (Bull et al. Conference on Retroviruses and Opportunistic Infections, February 2015). Our most novel finding reported in the following publications:



  • Tobin NH, Learn GH, Holte SE, Wang Y, Melvin AJ, McKernan JL, Pawluk DM, Mohan KM, Lewis PF, Mullins JI and Frenkel LM. 2005. Evidence that Low-level Viremias During Effective HAART Result from Two Processes: Expression of Archival Virus and Replication of Virus. J Virol 79:9625-34. PMID16014925. PMCID: PMC1181593.


  • Bull ME, Learn GH, McElhone S, Hitti J, Lockhart D, Holte S, Dragavon J, Coombs RW, Mullins JI, Frenkel LM. 2009. Monotypic HIV-1 Genotypes across the Uterine Cervix and in Blood Suggests Proliferation of Cells with Provirus. J Virol 83:6020-6028. PMID19339344. PMCID: PMC2687376.


  • Wagner T, McKernan J, Tobin N, Tapia K, Mullins J, Frenkel L. 2013. An increasing proportion of monotypic HIV-1 DNA sequences during antiretroviral treatment suggests proliferation of HIV-infected cells. J Virol 87:1770-1778. PMID23175380. PMCID: PMC3554159.


  • Wagner TA, McLaughlin S, Garg K, Cheung CY, Larsen BB, Styrchak S, Huang HC, Edlefsen PT, Mullins JI, Frenkel LM. 2014. HIV latency. Proliferation of cells with HIV integrated into cancer genes contributes to persistent infection. Science 345(6196):570-573. PMID25011556. PMCID: PMC4230336.



Developing a practical, affordable point mutation assay for detection of drug-resistance. Given the high costs of supplies and equipment, and the technical expertise required to generate consensus Sanger sequences, combined with the fact that HIV is endemic in low-resource communities, I adapted a low-cost, relative simple assay to detect point-mutations the confer HIV-drug-resistance. My group developed and validated reagents across HIV Subtypes prevalent in Africa and Asia, as well as the Americas and Europe. We demonstrated the utility of the assay in predicting virologic failure. Currently, my group is conducting a randomized controlled trial in Kenya to evaluated the implementation of this assay prior to 1st–line–ART to improve rates of virologic suppression; and my group is collaborating with Barry Lutz and James Lai, University of Washington bioengineering faculty, to simplify the assay for point-of-care use. Our most novel results are reported in the following publications:




  • Beck IA, Mahalanabis M, Pepper G, Wright A, Hamilton S, Langston E, Frenkel LM. 2002. Rapid and sensitive oligonucleotide ligation assay for detection of mutations in human immunodeficiency virus type 1 associated with high-level resistance to protease inhibitors. J Clin Microbiol 40:1413-9. PMID11923366. PMCID: PMC140364.http://www.ncbi.nlm.nih.gov/pubmed/?term=11923366


  • Ellis GM, Mahalanabis M, Beck IA, Pepper G, Wright A, Hamilton S, Holte S, Naugler WE, Pawluk DM, Li CC, Frenkel LM. 2004. Comparison of Oligonucleotide Ligation Assay and Consensus Sequencing for Detection of Drug-Resistant Mutants of Human Immunodeficiency Virus Type 1 in Peripheral Blood Mononuclear Cells and Plasma. J Clin Microbiol 42:3670-4. PMID15297515. PMCID: PMC497615.


  • Beck IA, Crowell C, Kittoe R, Bredell H, Machaba M, Willamson C, Janssens W, Jallow S, van der Groen G, Shao Y, Jacob M, Samuel, NM, Lorenzana de Rivera I, Ngo-Giang-Huong N, Cassol S, Alemnji G, Frenkel LM. 2008. Optimization of the Oligonucleotide Ligation Assay, a Rapid and Inexpensive Test for Detection of HIV-1 Drug Resistance Mutations, for Non-North American Variants. J Acquir Immune Defic Syndr 48:418-427. PMID18614915. PMCID: PMC2583356.


  • Beck IA, Deng W, Payant R, Hall R, Bumgarner RE, Mullins JI, Frenkel LM. 2014. Validation of an oligonucleotide ligation assay for quantification of human immunodeficiency virus type 1 drug-resistant mutants by use of massively parallel sequencing. J Clin Microbiol 52(7):2320-2327. PMID24740080. PMCID: PMC4097683.


  • Panpradist N, Beck IA, Chung MH, Kiarie JN, Frenkel LM, Lutz BR. Simplified Paper Format for Detecting HIV Drug Resistance in Clinical Specimens by Oligonucleotide Ligation. PLoS One. 2016 Jan 11;11(1):e0145962. doi: 10.1371/journal.pone.0145962. eCollection 2016. PMID: 26751207 http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0145962



Provide insights into reservoirs of drug-resistant HIV. In the 1990’s my laboratory career as an independent HIV investigator was initiated with studies of HIV-drug-resistance and the reservoirs of resistant variants that influenced the efficacy of antiretroviral treatment. Notably, my group determined that reservoirs of nevirapine-resistant HIV were different in children compared to adults, with resistant variants persisting for longer periods of time in some infants due to selection during primary infection or transmission of resistant viruses. These findings contributed to clinicians understanding of HIV-drug-resistance and to changes in World Health Organization recommendations on use of antiretrovirals for prophylaxis. Our most novel finding reported in the following publications:




  • Frenkel LM, Wang Y, Learn GH, Melvin AJ, Ellis GM, McKernan JL, De Vange SM, Mohan KM, Holte S, Sylva GL, Naugler WE, Mahalanabis M, Beck IA, Lewis PA, Heath LM, Tobin NH, Pawluk D, Mullins JI. 2003. Multiple Viral Genetic Analyses Detect Low-level Human Immunodeficiency Virus type-1 Replication During Effective HAART. J Virol 77:5721-30. PMID12719565. PMCID: PMC154035.


  • Micek MA, Blanco AJ, Beck IA, Dross S, Matunha L, Montoya P, Seidel K, Gantt S, Matediane E, Jamisse L, Gloyd S, Frenkel LM. 2010. Nevirapine Resistance by Timing of HIV Type 1 Infection in Infants Treated with Single-Dose Nevirapine. Clin Infect Dis 50:1405-1414. PMID20384494. PMCID: PMC3038662.


  • Micek MA, Dross S, Blanco AJ, Beck IA, Matunha L, Seidel K, Montoya P, Matediana E, Gantt S, Gloyd S, Frenkel L. 2014. Transmission of nevirapine-resistant HIV Type 1 via breast milk to infants after single-dose nevirapine in Beira, Mozambique. J Infect Dis 210(4):641-645. PMID24596282
    . PMCID: PMC4133577.


  • Chung MH, Beck IA, Dross S, Tapia K, Kiarie JN, Richardson BA, Overbaugh J, Sakr SR, John-Stewart GC, Frenkel LM. 2014. Oligonucleotide Ligation Assay Detects HIV Drug Resistance Associated With Virologic Failure Among Antiretroviral-Naive Adults in Kenya. J Acquir Immune Defic Syndr 67(3):246-253. PMID25140907. PMCID: PMC4197120.



Pathogenesis of HIV disease, specifically, why despite ART do HIV-infected individuals experience morbidities and death at younger ages. My group has worked to better understand this pathology driving HIV disease during ART. We are currently engaged in studies to determine why individuals with HIV infection have higher rates of cancer. Our most novel results are reported in the following publications:




  • Bull ME, Heath LM, McKernan-Mullin JL, Kraft KM, Acevedo L, Hitti JE, Cohn SE, Tapia KA, Holte SE, Dragavon JA, Coombs RW, Mullins JI, Frenkel LM. 2013. Human immunodeficiency viruses appear compartmentalized to the female genital tract in cross-sectional analyses but genital lineages do not persist over time. J Infect Dis 207(8):1206-1215. PMID23315326. PMCID: PMC3603533.


  • Ticona E, Bull ME, Soria J, Tapia K, Legard J, Styrchak SM, Williams C, Mitchell C, La Rosa A, Coombs RW, Frenkel LM. 2015. Biomarkers of inflammation in HIV-infected Peruvian men and women before and during suppressive anti-retroviral therapy (ART). AIDS 29(13):1617-1622. PMID26372272. PMCID Journal — In Process.We are conducting collaborative studies with colleagues in Kenya, Peru, South Africa, Thailand, Uganda, the U.S. and Zimbabwe, and in the past worked with researchers in India and Mozambique.



Complete List of Published Work in MyBibliography:



http://www.ncbi.nlm.nih.gov/sites/myncbi/lisa.frenkel.1/bibliography/41149424/public/?sort=date&direction=ascending





Undergraduate
Kansas University, B.A., 1977

Medical School
Kansas University Medical School, 1981

Residency
University of California, Los Angeles, 1981-84

Fellowship
University of California, Los Angeles, 1984-87


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