• Faculty Member Photo
  • Lisa Frenkel, MD
    Professor of Pediatrics, Laboratory Medicine and Global Health; Associate Director of the Center for Childhood Infections & Prematurity Research
    Email: click here
    Phone: (206) 987-5140

Lisa Frenkel, MD, Professor of Pediatric Infectious Diseases, Laboratory Medicine and Global Health; Co-Director of Center for Global Infectious Disease Research

Over the past 20 years, our group has conducted projects in Peru, Thailand, Mozambique, Kenya and South Africa. These studies aimed to better understand the transmission, selection and persistence of drug-resistant viruses and have included collaborations with other UW, national and international investigators. We have developed economical assays with the goal of making testing accessible to resource-poor communities, to improve the management of HIV infection. Currently, our laboratory located within Seattle Children’s Research Institute (SCRI) focuses primarily on three topics and collaborates broadly with other UW, national and international investigators.




  1. Persistence of HIV infection: A major research focus of our work has been to understand the mechanisms that allow HIV to persist despite effective ART. Our group documented that among ART-treated individuals with plasma HIV RNA consistently below the limits of detection included a subset that demonstrated viral evolution, implying low-level viral replication, although the vast majority demonstrated no evolution (Frenkel, JVI, 2003). We were the first to note that transient low-level viremias, or “blips,” during ART were usually comprised of populations of identical env and pol sequences (Tobin, JVI, 2005), suggesting production of clonal virus. Our subsequent studies revealed that populations of identical viral sequences in PBMC and sputum (rich in pulmonary macrophages) increase over a decade of ART (Wagner, JVI, 2013), suggesting that clonal proliferation of cells with provirus sustains HIV infection during suppressive ART. Recently, we have documented that identical env sequences have identical integration sites, providing strong supportive evidence that HIV persistence is at least in part due to cellular proliferation, and with ongoing suppressive ART, that these proviruses are increasingly integrated into genes controlling immune functions, the cell cycle or cancers suggesting that interference with these genes expression allows the infected cells to proliferate and/or survive (Wagner, Science, 2014; http://www.sciencemag.org/cgi/content/abstract/science.1256304)


    Ongoing projects (R01 AI091550 and R01 AI114348) are focused on understanding whether specific HIV integration events lead to the persistence of HIV DNA that is infectious or defective; use in vitro mutagenesis to determine the effects of specific integration events on cellular function; and on whether during acute HIV infection the antigen specificity of HIV-infected cells that would be targeted for cure in individuals who start ART during this time.


  2. Systemic inflammation in HIV-infected individuals: Individuals whose viral replication is suppressed by ART continue to have biomarkers indicative of ongoing diffuse inflammation that accelerates atherosclerosis and cardio- and cerebral-vascular events. Given the timing of HIV acquisition by infected children, substantial morbidity could occur from inflammation despite suppressive ART. We hypothesize that ongoing production of viral RNA or proteins drives inflammation, rather than the alternative hypothesis that immune depletion of gut lymphocytes during acute infection allow bacterial translocation.


    An ongoing project (funded by SCRI) aims to determine if low-level production of HIV virions or 16sDNA correlate with immune activation and help develop a short interventional trial to diminish inflammation.


  3. HIV Resistance to antiretrovirals: Our group has conducted many studies aimed at better understanding the transmission, selection and persistence of drug-resistant viruses. We have developed economical assays with the goal of making testing accessible to resource-poor communities, to improve the management of HIV infection. Currently, we are conducting a randomized-controlled trial of our oligonucleotide ligation assay (OLA) detection of HIV-drug-resistance pre-ART in Kenya. The primary outcome is the rates of ART-associated suppression of viral replication among subjects randomized to testing or standard-of-care. In addition, we will analyze issues related to transfer of technology and will model the cost-effectiveness of the OLA in ART management. Secondly, with UW bioengineers, we are simplifying this OLA to make a simpler and faster assay.


    Ongoing projects (R01 AI100037 and R01 AI110375) aim to better understand the role of specific transmitted mutant codons and define the threshold concentration of mutants that result in virologic failure of ART; to convert our PCR-based assay to an isothermal format; optimize Illumina-based sequencing for use as a clinical assay.







  4. Current projects include collaborative studies with colleagues in India, Kenya, Mozambique, Peru, Thailand, the USA and Zimbabwe.

    1. HIV-1 reservoirs precluding clearance of infection by effective antiretroviral therapy (ART)
      HIV-1 persists in infected persons even when ART suppresses viral replication below the limit of detection in blood plasma. Viral persistence is thought to be due to reservoirs of latent virus and/or incompletely suppressed viral replication. We hypothesize that HIV-1 persists during apparently effective ART (plasma HIV-1 RNA levels <50c/mL) due to two phenomena: (1) proliferation of cells with provirus, and less frequently by (2) low-level HIV-1 replication and selection of drug-resistant viruses in specific tissues and/or cell types. Our studies examine viral evolution and the selection of mutants in specific cell types and tissues that may shelter the virus from suppressive levels of antiretrovirals, and to develop assays and test multiple tissues to prove that HIV-1 persists due to proliferation of latently infected cells.

    2. Prevention of mother-to-child-transmission of HIV-1 infection
      Considerable data indicate that HIV-1 specific humoral immunity can protect from infection with homologous virus and that cellular immunity modulates HIV-1 viral load and the associated immune depletion. We hypothesize that when HIV-1 infection is prevented in infants by administration of nevirapine during breastfeeding, sufficient exposure to virus in breast milk will induce HIV-1 specific IgA antibody responses. If protective immunity can be induced during a short period of chemoprophylaxis while breastfeeding, this would provide the basis for a novel strategy for the immunization of infants in countries where breastfeeding remains their primary source of nutrition, and of HIV-1 infection.

    3. Defining Reservoirs of Nevirapine- and Zidovudine-Resistant HIV-1 in Women and Infants Selected by Peripartum Nevirapine Chemoprophylaxis Regimens
      Nevirapine chemoprophylaxis is moderately effective in reducing mother-to-infant HIV-1 transmission at a low cost. Nevirapine, however, rapidly selects for drug resistant HIV-1 because single base mutations (i.e., K103N, Y181C and G190A) confer high-level resistance. The addition of zidovudine chemoprophylaxis during gestation further reduces mother-to-infant HIV-1 transmission and reduces the selection of nevirapine resistance. We are quantifying the selection of NVP-resistant viruses in women exposed to “single-dose” NVP and zidovudine to define the persistence of these mutants and whether the frequency of mutants at the initiation of ART is predictive of the efficacy of ART.

    4. Discordant Shedding of HIV-1 from the genital tract and rectum after starting ART
      A subset of adults who initiate ART have discordant suppression of viral replication in the blood and genital tract/rectum. We hypothesize that this discordant shedding is often be due to virus production following immune activation of latently infected cells, however, in some instances shedding will be due to continued viral replication. Discerning the relative frequency of genital/rectal shedding by these mechanisms is important for public health. Through studies of blood and genital/rectal secretions and biopsies, including viral loads and genetics over time, we aim to determine the rate of discordant shedding of virus in the blood plasma and genital tract/rectal; determine the epidemiological factors associated with discordant shedding; and provide further insight into the pathogenesis of expression of virus from activation of latent provirus versus full-cycles of replication with selection of drug-resistant virus.

    5. Immunologic and Virologic Events in Early HIV Infection
      The factors that determine which viral variants are transmitted from an HIV-1 infected person to his or her sexual partners are incompletely understood. Using specimens collected prospectively in Africa from HIV-1 sero-discordant heterosexual couples (one partner is HIV-1 infected and the other uninfected upon enrollment) we will compare virus populations between transmitting and non-transmitting partners to address hypotheses focused on heterosexual HIV-1 transmission using single-genome and pyrosequencing of virus in blood and genital specimens.

    6. Development of rapid and inexpensive tests for drug-resistant HIV-1 suitable for use in resource poor settings
      A sensitive, specific and high-throughput oligonucleotide ligation assay (OLA) for detection of genotypic HIV-1 resistance to nucleoside, non-nucleoside reverse transcriptase inhibitors and protease inhibitors has been developed. Currently, we are validating the OLA using pyrosequencing. Work is ongoing to optimize the assay for testing of non-B subtypes and is used in projects conducted in India, Kenya, Peru, South Africa, Thailand and Zimbabwe.

    7. Determining the prevalence and persistence of HIV-1 drug resistance in recently diagnosed individuals in Seattle, WA by dideoxynucleotide sequencing and an oligonucleotide ligation assay
      Specimens from persons newly diagnosed with HIV-1 infection are evaluated for evidence of drug-resistance by two assays; consensus dideoxy-sequencing and the oligoligase assay. This study will evaluate whether transmitted drug-resistance mutations tend to 'regress', as commonly observed with mutations selected by ART when the selective pressure provided by drugs are removed. Whether drug-resistant variants are transmitted and persist at levels below the usual limit of detection is relevant to optimizing the treatment of HIV-1 infected individuals.

    8. Clinical trials for HIV-1 and other viral infections in children, adolescents and pregnant women
      We participate in NIH-funded multi-centered trials to prevent and treat HIV-1 infection (Pediatric AIDS Clinical Trials Group (PACTG)/International Maternal Pediatric Adolescent AIDS Trials (IMPAACT) Network) and other viral infections (Collaborative Antiviral Study Group (CASG)).


    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

    Recent publications:



  5. Soria J, Bull M, Mitchell C, La Rosa A, Dross S, Kraft K, Coombs R, Ticona E and Frenkel L. 2012. Transmitted HIV Resistance to First-Line Antiretroviral Therapy in Lima, Peru. AIDS Res Hum Retroviruses 28(4):333-338. PMID: 21819256. PMCID: PMC3316114.


  6. Beck IA, Jang M, McKernan-Mullin J, Bull M, Wagner T, Huang S, Song LY, Nachman S, Krogstad P, Eshleman SH, Wiznia A, Frenkel LM. 2012. Monitoring of HIV Type 1 DNA Load and Drug Resistance in Peripheral Blood Mononuclear Cells During Suppressive Antiretroviral Therapy Does Not Predict Virologic Failure. AIDS Res Hum Retroviruses 28(8):780-788. PMID: 22081867. PMCID: PMC3399556.


  7. Baeten JM, Donnell D, Ndase P, Mugo NR, Campbell JD, Wangisi J, Tappero JW, Bukusi EA, Cohen CR, Katabira E, Ronald A, Tumwesigye E, Were E, Fife KH, Kiarie J, Farquhar C, John-Stewart G, Kakia A, Odoyo J, Mucunguzi A, Nakku-Joloba E, Twesigye R, Ngure K, Apaka C, Tamooh H, Gabona F, Mujugira A, Panteleeff D, Thomas KK, Kidoguchi L, Krows M, Revall J, Morrison S, Haugen H, Emmanuel-Ogier M, Ondrejcek L, Coombs RW, Frenkel L, Hendrix C, Bumpus NN, Bangsberg D, Haberer JE, Stevens WS, Lingappa JR, Celum C for the Partners PrEP Study Team. 2012. Antiretroviral Prophylaxis for HIV Prevention in Heterosexual Men and Women. N Engl J Med 367(5):399-410. PMID: 22784037.


  8. Micek MA, Blanco AJ, Carlsson J, Beck IA, Dross S, Matunha L, Seidel K, Montoya P, Gantt S, Matediana E, Jamisse L, Gloyd S, Frenkel LM. 2012. Effects of short-course zidovudine on the selection of nevirapine-resistant HIV-1 in women taking single-dose nevirapine. J Infect Dis 205(12):1811-1815. PMID: 22492850. PMCID: PMC3415891.


  9. Gantt S, Payant R, Carlsson J, Micek MA, Blanco AJ, Beck IA, Matunha L, Montoya P, Matediana E, Gloyd S, Frenkel LM. 2012. Nevirapine-Resistant HIV-1 DNA in Breast Milk After Single-Dose Nevirapine With or Without Zidovudine for Prevention of Mother-to-Child Transmission. J Pediatric Infect Dis Soc 1(3):244-249. PMID: 23687579. PMCID: PMC3656540.


  10. 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. PMID: 23175380. PMCID: PMC3554159.


  11. Mitchell C, Balkus JE, McKernan-Mullin J, Cohn SE, Luque AE, Mwachari C, Cohen CR, Coombs R, Frenkel LM, Hitti J. 2013. Associations between genital tract infections, genital tract inflammation and cervical cytobrush HIV-1 DNA in US versus Kenyan women. J Acquir Immune Defic Syndr. 62:143-148. PMID: 23018377. PMCID: PMC3549039.
  12. Mitchell C, Balkus JE, Fredricks DN, Liu C, McKernan J, Frenkel L, Mwachari C, Luque A, Cohn SE, Cohen CR, Coombs RW, Hitti J. 2013. Interaction between lactobacilli, bacterial vaginosis-associated bacteria and HIV-1 RNA and DNA genital shedding in US and Kenyan women. AIDS Res Hum Retroviruses. 29(1):13-9. PMID: 23020644.

  13. 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. PMID: 23315326. PMCID: PMC3603533.


  14. Ellis GM, Marushchak T, Koth A, Vaz L, Dross S, Beck I, Frenkel LM. 2013. Simultaneous and Sensitive Detection of Human Immunodeficiency Virus Type 1 (HIV) Drug Resistant Genotypes by Multiplex Oligonucleotide Ligation Assay. J Virolog Meth. 192:39-43. PMID: 23660583. PMCID: PMC3708483.

  15. McLaughlin S, Swenson LC, Hu S, Hughes P, Harrigan PR, Coombs RW, Frenkel LM. 2013. Development of a Novel Codon-Specific Polymerase Chain Reaction for the Detection of CXCR4-Utilizing HIV Type 1 Subtype B. AIDS Res Hum Retroviruses 29(5):814-825. PMID: 23343425. PMCID: PMC3636599.

  16. Jacobson A, Bell F, Lejarcegui N, Mitchell C, Frenkel L, Horton H. 2013. Healthy Neonates Possess a CD56-Negative NK Cell Population with Reduced Anti-Viral Activity. PLoS One 8(6):e67700. PMID23805324. PMCID: PMC3689709.

  17. Larsen BB, Chen L, Maust BS, Kim M, Zhao H, Deng W, Westfall D, Beck I, Frenkel LM, Mullins JI. 2013. Improved detection of rare HIV-1 variants using 454 pyrosequencing. PLoS One 8(10):e76502. PMID24098517. PMCID: PMC3788733.

  18. Nachman S, Zheng N, Acosta EP, Teppler H, Homony B, Graham B, Fenton T, Xu X, Wenning L, Spector SA, Frenkel LM, Alvero C, Worrell C, Handelsman E, Wiznia A. 2014. Pharmacokinetics, Safety, and 48-Week Efficacy of Oral Raltegravir in HIV-1-Infected Children Aged 2 Through 18 Years. Clin Infect Dis 58(3):413-422. PMID24145879. PMCID: PMC3890333.

  19. Mitchell C, Dross S, Beck I, Micek M, Frenkel LM. 2014. Low concentrations of HIV-1 DNA at birth delays diagnosis, complicating identification of infants for antiretroviral therapy to potentially prevent the establishment of viral reservoirs. Clin Infect Dis 58(8):1190-1193. PMID24501389. PMCID: PMC Journal-In-Process (R01 AI058723, T32 AI07140).

  20. Micek MA, Dross S, Blanco AJ, Beck IA, Matunha L, Seidel K, Montoya P, Matediana E, Gantt S, Gloyd S, Frenkel L. 2014. Breast milk transmission of nevirapine-resistant HIV-1 to infants after single-dose nevirapine in Beira, Mozambique. J Infect Dis; Epub ahead of print 3/4/2014, in press. PMID: 24596282. PMCID: PMC Journal – In Process (R01 AI058723, P30 AI027757, T32 AI07140).

  21. Wagner TA, McLaughlin S, Garg K, Cheung CYK, Larsen BB, Styrchak S, Huang HC, Edlefsen PT,. Mullins JI, Frenkel LM. Proliferation of cells with HIV integrated into cancer genes contributes to persistent infection. Science 2014; in press (http://www.sciencemag.org/cgi/content/abstract/science.1256304).


Oligonucleotide Ligation Assay Manual:

Beck and Frenkel. Manual for Genotyping Kits for the Detection of HIV-1 pol Drug-Resistance Mutations by an Oligonucleotide Ligation Assay. Protocol Version 1.4, July 2007.

OLA and Other Rapid Economical Assays:

Frenkel LM, Wagner LE II, Atwood S, Cummings TJ, Dewhurst S. 1995. Specific, sensitive, and rapid assay for human immunodeficiency virus type 1 pol mutations associated with resistance to zidovudine and didanosine. J Clin Microbiol 33:342-47.

Frenkel LM, Wagner LE II, Demeter LM, Dewhurst S, Coombs RW, Murante BL, Reichman RC. 1995. Effects of zidovudine use in pregnancy on resistance and vertical transmission of human immunodeficiency virus type 1. Clin Infect Dis 20:1321-26.

Shafer RW, Winters MA, Mayers D, Japour A, Kuritzkes D, Weislow O, White F, Erice A, Sannerud K, Iverson A, Pena F, Dimitrov D, Frenkel LM, Reichelderfer P. 1996. Inter-laboratory Comparison of Sequence-Specific PCR and Ligase Detection Reaction to Detect an HIV-1 Drug-Resistance Mutation. J Clin Microbiol 34(7):1849-53.

Edelstein RE, Nickerson DA, Tobe VO, Manns Arcuino LA, Frenkel LM. 1998. Oligonucleotide ligation assay for detecting mutations in the human immunodeficiency virus type 1 pol gene that are associated with resistance to zidovudine, didanosine, and lamivudine. J Clin Microbiol 36:569-72.

Eastman PS, Shapiro DE, Coombs RW, Frenkel LM, McSherry GD, Britto P, Herman SA, Sperling RS, for the Pediatric ACTG Protocol 076 Study Group. 1998. Maternal Viral Genotypic Zidovudine Resistance and Infrequent Failure of Zidovudine Therapy to Prevent Perinatal Transmission of Human Immunodeficiency Virus Type-1 in Pediatric AIDS Clinical Trials Group Protocol 076. J Infect Dis 177:557-64.

Zerr DM, Huang ML, Corey L Erickson M, Parker HL, Frenkel LM. A sensitive method for detection and quantification of human herpesviruses 6 and 7 in saliva collected in field studies. J Clin Microbiol 2000;38:1981-3.

Villahermosa ML, Beck I, Perez-Alvarez L, Frenkel LM, Najara R.  2001. Detection and quantification of multiple drug resistance mutations in HIV-1 reverse transcriptase by an oligonucleotide ligation assay J Human Virol, 4:238-48.

Beck IA, Drennan KD, Melvin AJ, Mohan KM, Hertz AM, Alarcón J, Piscoya J, Velázquez C, Frenkel LM. Simple, sensitive, and specific detection of HIV-1 subtype B DNA in dried blood samples for infant diagnosis in the field. J Clin Microbiol 2001;39:29-33.

Beck IA, Mahalanabis M, Pepper G, Wright A, Hamilton S, Langston E, Frenkel LM. 2002. A rapid and sensitive oligonucleotide ligation assay (OLA) for the detection of mutations in human immunodeficiency virus type 1 associated with high-level resistance to protease inhibitors. J Clin Microbiol 2002;40:1413-9.

Bardeguez AD, Shapiro DE, Mofenson LM, Coombs R, Frenkel LM, Fowler MG, Huang S, Sperling RS, Cunningham  B, Gandia J, Maupin R, Zorrilla CD, Jones T, O’Sullivan MJ for the Pediatrics AIDS Clinical Trials Group 288 Protocol Team. 2003. Effect of cessation of zidovudine prophylaxis to reduce vertical transmission on maternal HIV disease progression and survival. J Acquir Immun Defic Syndr and Human Retrovirol 32:170-181.

Ellis GM, Mahalanabis M, Beck IA, Pepper G, Wright A, Hamilton S, Holte S, Naugler WE, Pawluk DM, Li CC, Frenkel LM. Comparison of Oligonucleotide Ligation Assay (OLA) 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 2004;42:3670-4.

Dybul M, Nies-Kraske E, Dewar R, Maldarelli F, Hallahan CW, Daucher M, Piscitelli SC, Ehler L, Weigand A, Palmer S, Metcalf JA, Davey RT, Rock Kress DM, Powers A, Beck I, Frenkel L, Baseler M, Coffin J, Fauci AS. 2004. A proof-of-concept study of short-cycle intermittent antiretroviral therapy with a once-daily regimen of didanosine, lamivudine, and efavirenz for the treatment of chronic HIV infection. J Infect Dis 189:1974-82.

Melvin AJ, Alarcon J, Velasquez C, Rodriguez C, Piscoya J, Giraldo A, Dinh P, Frenkel LM. Rapid HIV-1 Testing of Women Presenting in Late Pregnancy with Unknown HIV Status in Lima, Perú. AIDS Resear Hum Retrovir 2004;20:1046-52.

Li CC, Beck IA, Seidel KD, Frenkel LM. Persistence of Human Immunodeficiency Virus Type 1 Subtype B DNA in Dried Blood Samples on FTA® Filter Paper. J Clin Microbiol 2004;42:3847-9.

Li CC, Beck IA, Seidel KD, Coombs RW, Frenkel LM. Detection and quantification of HIV-1 p24Ag in dried whole blood and plasma on filter paper stored under various conditions. J Clin Microbiol 2005;43:3901-5.

Huang DD, Bremer JW, Brambilla DJ, Palumbo PE, Aldrovandi G, Eshleman S, Brown C, Fiscus S, Frenkel L, Hamdan H, Hart S, Kovacs A, Krogstad P, LaRussa P, Sullivan J, Weinberg A, Zhao YQ, Pediatric ASWG. 2005. Model for assessment of proficiency of human immunodeficiency virus type 1 sequencing-based genotypic antiretroviral assays. J Clin Microbiol 43:3963-3970. PMCID: PMC1233968.

Zerr DM, Frenkel LM, Huang M-L, Rhoads M, Nguy L, Del Beccaro M, Corey L. PCR Diagnosis of Primary HHV-6 Infection in the Acute Care Setting. J Pediatr 2006;149:480-5.

Halvas EK, Aldrovandi GM, Balfe P, Beck IA, Boltz VF, Coffin JM, Frenkel LM, Hazelwood JD, Johnson VA, Kearney M, Kovacs A, Kuritzkes DR, Metzner KJ, Nissley DV, Nowicki M, Palmer S, Ziermann R, Zhao RY, Jennings CL, Bremer J, Brambilla D, Mellors JW. 2006. Blinded, Multicenter Comparison of Methods To Detect a Drug-Resistant Mutant of Human Immunodeficiency Virus Type 1 at Low Frequency. J Clin Micro 44:2612–2614.

Frenkel LM, McKernan J, Dinh PV, Goldman D, Hitti J, Watts DH, Cooper ER, Dragavon J, Coombs RW. 2006. HIV-1 zidovudine (ZDV) resistance in blood and uterine cervical secretions of pregnant women. AIDS Research Hum Retro 22;870-73.

Buskin, SE, Ellis GM, Pepper GG, Frenkel LM, Pergam SA, Gottlieb GS, MD, Horwitch C, Olliffe J, Johnson K, Shalit P, Heinen C, Schwartz M, Wood RW. 2008. Transmission cluster of multiclass highly drug-resistant HIV-1 among 9 men who have sex with men in Seattle/King County, WA, 2005-2007. J Acquir Immune Defic Syndr 49:205-212. PMCID: PMC2586929.

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. 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 2008;48:418-427. PMCID: PMC2583356

Mitchell, C, Jennings C, Brambilla D, Aldrovandi C, Amedee AM, Beck IA, Bremer JW, Coombs RW, Decker D, Fiscus S, Fitzgibbon J, Luzuriaga K, Moye J, Palumbo P, Reichelderfer P, Somasundaran M, Stevens W and Frenkel LM for the Dried Blood Spot Working Group of the Infant Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Network. Diminished human immunodeficiency virus type 1 DNA yield from dried blood spots is diminished after storage in a humid incubator at 37oC compared to -20oC. J Clin Micro 2008;46:2945-2949. PMCID: PMC2546762.

Buskin, SE, Ellis GM, Pepper GG, Frenkel LM, Pergam SA, Gottlieb GS, MD, Horwitch C, Olliffe J, Johnson K, Shalit P, Heinen C, Schwartz M, Wood RW. 2008. Transmission cluster of multiclass highly drug-resistant HIV-1 among 9 men who have sex with men in Seattle/King County, WA, 2005-2007. J Acquir Immune Defic Syndr 49:205-212. PMCID: PMC2586929.

Ellis GM, Page LC, Burman BE, Buskin S, Frenkel LM. 2009. Increased detection of HIV-1 drug resistance at time of diagnosis by testing viral DNA with a sensitive assay. J Acquir Immune Defic Syndr 51(3):283-289.

Chi BH, Ellis GM, Chintu N, Cantrell RA, Sinkala M, Aldrovandi GM, Warrier R, Mbewe F, Nakamura K, Stringer EM, Frenkel LM, Stringer JS. 2009. Intrapartum tenofovir and emtricitabine reduces low-concentration drug resistance selected by single-dose nevirapine for perinatal HIV prevention. AIDS Res Hum Retroviruses 25:1099-1106.

Lallemant M, Ngo-Giang-Huong N, Jourdain G, Traisaithit P, Cressey TR, Collins IJ, Jarupanich T, Sukhumanant T, Achalapong J, Sabsanong P, Chotivanich N, Winiyakul N, Ariyadej S, Kanjanasing A, Ratanakosol J, Hemvuttiphan J, Kengsakul K, Wannapira W, Sittipiyasakul V, Pornkitprasarn W, Liampongsabuddhi P, McIntosh K, Van Dyke RB, Frenkel LM, Koetsawang S, Le Coeur S, Kanchana S; for the PHPT-4 Study Team. 2010. Efficacy and safety of 1-month postpartum zidovudine and didanosine to prevent HIV-resistance mutations after intrapartum single-dose nevirapine. Clin Infect Dis Mar 15;50:898-908.

Jourdain G, Wagner TA, Ngo-Giang-Huong N, Sirirungsi W, Klinbuayaem V, Fregonese F, Nantasen I, Techapornroong M, Halue G, Nilmanat A, Wittayapraparat P, Chalermpolprapa V, Pathipvanich P, Yuthavisuthi P, Frenkel LM, Lallemant M,  for the Program for HIV Prevention and Treatment (PHPT) Study Group. 2010. Association between detection of HIV-1 DNA resistance mutations by a sensitive assay at initiation of antiretroviral therapy and virologic failure. Clin Infect Dis 50(10):1397-1404. PMCID: PMC2856716.

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. PMCID: PMC3038662.

Wagner TA, Kress CM, Beck I, Techapornroong M5, Wittayapraparat P, Tansuphasawasdikul S, Jourdain G, Ngo-Giang-Huong N, Lallemant M, Frenkel LM. 2010. Detection of HIV-1-Drug-Resistance in Women Following Single-Dose-Nevirapine: Comparison of Plasma RNA versus Cellular DNA by Consensus Sequencing and by Oligonucleotide Ligation Assay. J Clin Micro 48:1555-1561. PMCID: PMC2863880.

Baeten JM, Lingappa J, Beck I, Frenkel LM, Pepper G, Celum C, Wald A, Fife KH, Were E, Mugo N, Sanchez J, Essex M, Makhema J, Kiarie J, Farquhar C, Corey L. 2011. Herpes simplex virus type 2 suppressive therapy with acyclovir or valacyclovir does not select for specific HIV-1 resistance in HIV-1/HSV-2 dually-infected persons. J Infect Dis 203(1):117-121. PMCID: PMC3024584.

Dorton BJ, Mulindwa J, Li MS, Chintu NT, Chibwesha CJ, Mbewe F, Frenkel LM, Stringer JS, Chi BH. 2011. CD4+ cell count and risk for antiretroviral drug resistance among women using peripartum nevirapine for perinatal HIV prevention. BJOG 118(4):495-499. PMCID: PMC3076308.

Ellis GM, Huang S, Hitti J, Frenkel LM, for the P1022 Study Team. 2011. Selection of HIV resistance associated with antiretroviral therapy initiated due to pregnancy and suspended postpartum. J Acquir Immune Defic Syndr 58:241-247. PMCID: PMC3196829.

Van Dyke RB, Ngo-Giang-Huong N, Shapiro DE, Frenkel L, Britto P, Roongpisuthipong A, Beck IA, Yuthavisuthi P, Prommas S, Puthanakit T, Achalapong J, Chotivanich N, Rasri W, Cressey TR, Maupin R, Mirochnick M, Jourdain G, for the IMPAACT P1032 Protocol Team. 2011. A comparison of three regimens to prevent nevirapine-resistance mutations in HIV-infected pregnant women receiving a single intrapartum dose of nevirapine. Clin Infect Dis. In press.

Soria J, Bull M, Mitchell C, La Rosa A, Dross S, Kraft K, Coombs R, Ticona E, Frenkel L. 2011. Transmitted HIV resistance to first-line antiretroviral therapy in Lima, Peru. 2011. AIDS Res Hum Retroviruses. In press; published on-line 8/9/2011.

Beck IA, Jang M, McKernan-Mullin J, Bull M, Wagner T, Huang S, Song LY, Nachman S, Krogstad P, Eshleman SH, Wiznia A, Frenkel LM. 2011. Monitoring of HIV-1 DNA Load and Drug Resistance in Peripheral Blood Mononuclear Cells during Suppressive Antiretroviral Therapy does not Predict Virologic Failure. AIDS Res Hum Retroviruses. Published on-line 11/16/2011; in press.

Stekler JD, Ellis GM, Carlsson J, Eilers B, Holte S, Maenza J, Stevens CE, Collier AC, Frenkel LM. 2011. Prevalence and impact of minority variant drug resistance mutations in primary HIV-1 infection. PLoS One. In press.

Ellis GM, Marushchak T, Koth A, Vaz L, Dross S, Beck I, Frenkel LM. Simultaneous and Sensitive Detection of Human Immunodeficiency Virus Type 1 (HIV) Drug Resistant Genotypes by Multiplex Oligonucleotide Ligation Assay. J Virolog Meth. In press.

Mother-to-Child- and Sexual HIV-1 Transmission:

Frenkel LM, Mullins JL, Learn GH, Manns Arcuino LA, Herring BL, Kalish ML, Steketee RW, Thea DM, Nichols JE, Liu S-L, Harmache A, He X, Muthui D, Madan A, Hood L, Haase AT, Zupancic M, Staskus K, Wolinsky S, Krogstad P, Zhao JQ, Chen I, Koup R, Ho D, Korber B, Apple RJ, Coombs RW, Pahwa S, Roberts NB Jr. Genetic evaluation of suspected cases of transient HIV-1 infection of infants. Science 1998;280:1073-7.

Gantt S, Shetty AK, Seidel KD, Matasa K, Musingwini G, Woelk G, Zijenah LS, Katzenstein DA, Frenkel LM. Laboratory Indicators of Mastitis were Not Associated with Changes in HIV-1 DNA or Predictive of HIV-1 RNA Concentrations in Breast Milk. J Infect Dis 2007;196:570-6.

Gantt S, Carlsson J, Shetty AK, Seidel KD, Qin X, Mutsvangwa J, Musingwini G, Woelk G, Zijenah LS, Katzenstein DA, Frenkel LM. Cytomegalovirus and Epstein-Barr Virus in Breast Milk are Associated with HIV-1 Shedding but Not With Mastitis. AIDS 2008;22:1453-1460. PMCID: PMC2504751.

Nett RJ, Bartschi JL, Ellis GM, Hachey DM, Frenkel LM, Roscoe JC, et al. Two clusters of HIV-1 infection, rural Idaho, USA, 2008 [letter]. Emerg Infect Dis 2010;16:1807-1809.

Heath L, Frenkel LM, Foley BT, Mullins JI. Comment on “The Origins of Sexually Transmitted HIV Among Men Who Have Sex with Men”. Science Transl Med 2010;2;501e.

Wagner TA and Frenkel LM. 2010. Antiretroviral treatment for HIV-infected infants exposed to nevirapine. JAMA 304(23):2589; author reply 2589-2590. PMID: 21156944.

Sha BE, Tierney C, Cohn SE, Sun X, Coombs RW, Frenkel LM, Kalams SA, Aweeka FT, Bastow B, Bardeguez A, Kmack A, Stek A. 2011. Postpartum viral load rebound in HIV-1-infected women treated with highly active antiretroviral therapy: AIDS Clinical Trials Group Protocol A5150. HIV Clin Trials 12(1):9-23. PMID: 21388937.

HIV-1 Evolution, Dynamics and Persistence during ART:


Wagner TA, McLaughlin S, Garg K, Cheung CYK, Larsen BB, Styrchak S, Huang HC, Edlefsen PT, Mullins JI, Frenkel LM. 2014. Proliferation of cells with HIV integrated into cancer genes contributes to persistent infection. Science; in press. PMCID: PMC Journal – In Process. http://www.sciencemag.org/cgi/content/abstract/science.1256304


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. Multiple Viral Genetic Analyses Detect Low-level Human Immunodeficiency Virus type-1 Replication During Effective HAART. J Virol 2003;77:5721-30.

Nickle DC, Jensen MA, Shriner D, Frenkel LM, Mittler J, Mullins JI. 2003. Evolutionary indicators of HIV-1 reservoirs and compartments. J Virol 77: 5540-6.

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

Holte SE, Melvin AJ, Mullins JI, Tobin NH, Frenkel LM. Density-Dependent Decay in HIV-1 Dynamics. J Acquir Immune Defic Syndr. 2006;41:266-76.

Bull ME, Learn GH, Mullins JI, Frenkel LM. Methods used to examine compartmentalization of viral populations between the genital tract and peripheral blood (letter). J Infect Dis. 2007;196:493-4.

Wagner TA, Tobin NH, McKernan JK, Xu,M, Melvin AJ, Mohan KM, Learn GH, Mullins JI, Frenkel LM. Increased Mutations in HIV-1 Env and Pol Suggest Greater HIV-1 Replication in Sputum- Compared to Blood-Derived Viruses. AIDS 2009;23:923-928. PMCID: PMC2677633.

Bull ME, Learn GH, McElhone S, Hitti J, Lockhart D, Holte S, Dragavon J, Coombs RW, Mullins JI, Frenkel LM. Monotypic HIV-1 Genotypes across the Uterine Cervix and in Blood Suggests Proliferation of Cells with Provirus. J Virol. 2009;83:6020-6028. PMCID: PMC19339344.

Bull ME, Learn GH, Genowati I, McKernan J, Hitti J, Lockhart D, Tapia K, Holte S, Dragavon J, Coombs R, Mullins J, Frenkel L. Compartmentalization of HIV-1 within the female genital tract is due to monotypic and low-diversity variants not distinct viral populations. PLoS One 2009;4:e7122. PMCID: PMC2741601.

Gantt S, Carlsson J, Heath L, Bull ME, Shetty AK, Mutsvangwa J, Musingwini G, Woelk G, Zijenah LS, Katzenstein DA, Mullins JI, Frenkel LM. Genetic analyses of HIV-1 env sequences demonstrate limited 1 compartmentalization in breast milk and suggest viral replication within the breast that increases with mastitis. J Virol 2010;84:10812-10819.

HIV-1 Drug Resistance:

Frenkel LM, Mullins JI. Should patients with drug-resistant HIV-1 continue to receive antiretroviral therapy? (editorial) N Engl J Med 2001;344:520-2.

Frenkel LM and Tobin NH. Understanding HIV-1 Drug Resistance. (editorial) Therapeutic Drug Monitoring 2004;26:116-21.

Buskin, SE, Ellis GM, Pepper GG, Frenkel LM, Pergam SA, Gottlieb GS, MD, Horwitch C, Olliffe J, Johnson K, Shalit P, Heinen C, Schwartz M, Wood RW. Transmission cluster of multiclass highly drug-resistant HIV-1 among 9 men who have sex with men in Seattle/King County, WA, 2005-2007. J Acquir Immune Defic Syndr 2008;49:205-212. PMCID: PMC2586929.

Wagner T, Frenkel LM. Potential Limitation of CCR5 Antagonists: Drug Resistance more often linked to CXCR4- than to CCR5- utilizing HIV-1. AIDS 2008;22:2393-2395. PMCID: PMC2585823

Hare CB, Mellors J, Krambrink A, Su Z, Skiest D, Margolis DM, Patel SS, Barnas D, Frenkel LM, Coombs RW, Aweeka F, Morse GD, Haas DW, Boltz V, Palmer S, Coffin J, Havlir DV. Detection of NNRTI-Resistant HIV-1 after Discontinuation of Virologically Suppressive Antiretroviral Therapy. Clin Infect Dis 2008;47:421-424. NIHMSID: NIHMS75375.

Ellis GM, Page LC, Burman BE, Buskin S, Frenkel LM. Increased detection of HIV-1 drug resistance at time of diagnosis by testing viral DNA with a sensitive assay. J Acquir Immune Defic Syndr 2009;51:283-289.

Chi BH, Ellis GM, Chintu N, Cantrell RA, Sinkala M, Aldrovandi GM, Warrier R, Mbewe F, Nakamura K, Stringer EM, Frenkel LM, Stringer JS. Intrapartum tenofovir and emtricitabine reduces low-concentration drug resistance selected by single-dose nevirapine for perinatal HIV prevention. AIDS Res Hum Retroviruses 2009;25:1099-1106.

Lallemant M, Ngo-Giang-Huong N, Jourdain G, Traisaithit P, Cressey TR, Collins IJ, Jarupanich T, Sukhumanant T, Achalapong J, Sabsanong P, Chotivanich N, Winiyakul N, Ariyadej S, Kanjanasing A, Ratanakosol J, Hemvuttiphan J, Kengsakul K, Wannapira W, Sittipiyasakul V, Pornkitprasarn W, Liampongsabuddhi P, McIntosh K, Van Dyke RB, Frenkel LM, Koetsawang S, Le Coeur S, Kanchana S; for the PHPT-4 Study Team. Efficacy and safety of 1-month postpartum zidovudine and didanosine to prevent HIV-resistance mutations after intrapartum single-dose nevirapine. Clin Infect Dis 2010;50:898-908.

Jourdain G, Wagner TA, Ngo-Giang-Huong N, Sirirungsi W, Klinbuayaem V, Fregonese F, Nantasen I, Techapornroong M, Halue G, Nilmanat A, Wittayapraparat P, Chalermpolprapa V, Pathipvanich P, Yuthavisuthi P, Frenkel LM, Lallemant M, for the Program for HIV Prevention and Treatment (PHPT) Study Group. Association between detection of HIV-1 DNA resistance mutations by a sensitive assay at initiation of antiretroviral therapy and virologic failure. Clin Infect Dis 2010;50:1397-1404. PMCID: PMC2856716.

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

Wagner TA, Kress CM, Beck I, Techapornroong M5, Wittayapraparat P, Tansuphasawasdikul S, Jourdain G, Ngo-Giang-Huong N, Lallemant M, Frenkel LM. Detection of HIV-1-Drug-Resistance in Women Following Single-Dose-Nevirapine: Comparison of Plasma RNA versus Cellular DNA by Consensus Sequencing and by Oligonucleotide Ligation Assay. J Clin Micro 2010;48:1555-1561. PMCID: PMC2863880.

Nett RJ, Bartschi JL, Ellis GM, Hachey DM, Frenkel LM, Roscoe JC, et al. 2010. Two clusters of HIV-1 infection, rural Idaho, USA, 2008 [letter]. Emerg Infect Dis 16:1807-1809. PMID: 21029556.

Dorton BJ, Mulindwa J, Li MS, Chintu NT, Chibwesha CJ, Mbewe F, Frenkel LM, Stringer JS, Chi BH. 2011. CD4+ cell count and risk for antiretroviral drug resistance among women using peripartum nevirapine for perinatal HIV prevention. BJOG 118(4):495-499. PMCID: PMC3076308.

Ellis GM, Huang S, Hitti J, Frenkel LM, for the P1022 Study Team. 2011. Selection of HIV resistance associated with antiretroviral therapy initiated due to pregnancy and suspended postpartum. J Acquir Immune Defic Syndr 58:241-247. PMCID: PMC3196829.

Van Dyke RB, Ngo-Giang-Huong N, Shapiro DE, Frenkel L, Britto P, Roongpisuthipong A, Beck IA, Yuthavisuthi P, Prommas S, Puthanakit T, Achalapong J, Chotivanich N, Rasri W, Cressey TR, Maupin R, Mirochnick M, Jourdain G, for the IMPAACT P1032 Protocol Team. 2011. A comparison of three regimens to prevent nevirapine-resistance mutations in HIV-infected pregnant women receiving a single intrapartum dose of nevirapine. Clin Infect Dis. In press.

Soria J, Bull M, Mitchell C, La Rosa A, Dross S, Kraft K, Coombs R, Ticona E, Frenkel L. 2011. Transmitted HIV resistance to first-line antiretroviral therapy in Lima, Peru. 2011. AIDS Res Hum Retroviruses. In press; published on-line 8/9/2011. PMID: 21819256.

Herpes Viruses:

Diamond C, Mohan K, Hobson A, Frenkel L, Corey L. Viremia in neonatal herpes simplex virus infections. Pediatr Infect Dis J 1999;18:487-9.

Kimberlin DW, Lin CY, Jacobs RF, Powell DA, Frenkel LM, Gruber WC, Rathore M, Bradley JS, Diaz PS, Kumar M, Arvin AM, Gutierrez K, Shelton M, Weiner LB, Sleasman JW, de Sierra TM, Soong SJ, Kiell J, Lakeman FD, Whitley RJ and the National Institute of Allergy and Infectious Disease Collaborative Antiviral Study Group. Natural history of neonatal Herpes Simples Virus infection in the acyclovir era. Pediatrics 2001;108:223-9.

Kimberlin DW, Lin CY, Jacobs RF, Powell DA, Corey L, Gruber WC, Rathore M, Bradley JS, Diaz PS, Kumar M, Arvin AM, Gutierrez K, Shelton M, Weiner LB, Sleasman JW, de Sierra TM, Weller S, Soong SJ, Kiell J, Lakeman FD, Whitley RJ and the National Institute of Allergy and Infectious Disease Collaborative Antiviral Study Group (Frenkel LM). Safety and efficacy of high-dose intervenous acyclovir in the management of neonatal Herpes Simplex Virus infections. Pediatrics 2001;108:230-8.

Frenkel LM. Challenges in the Diagnosis and Management of Neonatal Herpes Simplex Virus Encephalitis. (Solicited editorial), Pediatrics 2005;115:795-797.

Zerr DM, Meier AS, Selke SS, Frenkel LM, Huang ML, Wald A, Rhoads M, Nguy L, Bornemann R, Morrow RA, Corey L. Virologic and Clinical Characteristics of Primary Human Herpesvirus 6: A Population-Based Study. N Engl J Med 2005;352:768-76.

Baeten JM, Lingappa J, Beck I, Frenkel LM, Pepper G, Celum C, Wald A, Fife KH, Were E, Mugo N, Sanchez J, Essex M, Makhema J, Kiarie J, Farquhar C, Corey L. 2011. Herpes simplex virus type 2 suppressive therapy with acyclovir or valacyclovir does not select for specific HIV-1 resistance in HIV-1/HSV-2 dually-infected persons. J Infect Dis 203(1):117-121. PMCID: PMC3024584.

Kimberlin D, Whitley R, Wan W, Powell D, Storch G, Ahmed A, Palmer A, Sanchez, P, Jacobs R, Bradley J, Robinson J, Shelton M, Dennehy P, Leach C, Rathore M, Abughali N, Wright P, Frenkel L, Brady R, Van Dyke R, Weiner L, Guzman-Cottrill J, McCarthy C, Griffin J, Jester P, Parker M, Lakeman F, Kuo H, Lee C, Cloud G. 2011. Oral acyclovir suppression and neurodevelopment following neonatal herpes. N Engl J Med. 365:1284-92. PMID: 21991950.


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