COVID-19 Information

Edit Entry | Edit CV

Alexandra L. Howell, PhD

Title(s)
Professor of Medicine
Professor of Microbiology and Immunology

Additional Titles/Positions/Affiliations
Research Biologist, Veterans Affairs Medical Center (White River Junction, VT)

Department(s)
Medicine
Microbiology and Immunology

Education
University of Texas Graduate School of Biomedical Sciences, Ph.D., 1982
Colby College, BA, 1977

Programs
Program in Experimental and Molecular Medicine

Websites
http://geiselmed.dartmouth.edu/microbio/
http://geiselmed.dartmouth.edu/immuno/
http://graduate.dartmouth.edu/pemm/

Contact Information

VA Medical Center
Research Service, Box 151
215 North Main St.
White River Jct. VT 05009

Office: Building 44-VA Hospital
Phone: 603-727-8514
Email: alexandra.howell@dartmouth.edu


Professional Interests

Research Area:
Use of CRISPR/Cas to cleave the integrate HIV proviral sequence in primary macrophages and lymphocytes
Analysis of off-target cleavage events in human cells
Development of novel Cas enzymes (CasX, CasY)
Use of humanized mouse models to study anti-HIV therapeutics
Research projects in Dr. Howell's laboratory are focused on developing viral and non-viral vectors to deliver the CRISPR/Cas guide RNA and Cas genes to HIV infected cells as well as to uninfected cells to provide protection from infection. Analysis of both on-target as well as off-target cleavage events are determined by Circle-Seq and Guide-Seq methodologies. We are developing novel Cas enzymes (Cas12d and Cas12e) from newly identified bacterial species that show advantages over the use of Cas9.
Our previous work focused on mechanisms to block HIV-1 infection in mucosal tissue sites, specifically the female reproductive tract. These experimental model systems included the study of RNA interference to block expression of host cell receptors used by HIV-1 for infection (CD4 and CCR5), as well as a novel humanized mouse that possesses a human immune system. This humanized mouse model system can be infected with HIV-1 intravenously and also at mucosal sites including the reproductive and gastrointestinal tracts, and has been successfully used to model human infection.

Rotations and Thesis Projects

1. Determine optimal conditions for the transduction of human cells with AAV vectors expressing CRISPR/Cas genes.
2. Develop novel Cas enzymes and guide RNA to target the hepatitis B virus (HBV), both the integrated and covalently closed circular DNA versions of the HBV genome.
3. Assess efficacy of viral and non-viral delivery mechanisms for CRISPR/Cas genes to liver and bone marrow in humanized mice models.


Grant Information

Merit Review from the VA (2021-2024)
SBIR Phase I grant- NIH (2020)

Biography

Dr. Howell received her B.A. from Colby College in 1977, and her Ph.D. from the University of Texas Graduate School of Biomedical Sciences, Houston, TX, in 1982. After postdoctoral work as a research fellow and research associate in the department of Microbiology/Immunology at Dartmouth Medical School, Dr. Howell joined the faculty of the Departments of Microbiology/Immunology and Medicine at Dartmouth Medical School in 1984. She moved to the VA Medical Center in 1989 to develop an HIV core facility and has been funded by the VA since 1993 to support studies in HIV.

Mentoring Information

Dr. Howell has mentored several PEMM graduate students in her laboratory, both through rotations and for their thesis. In addition, she has mentored Dartmouth undergraduate senior thesis scholars.


Selected Publications

 

Attitudes of Virginia Dentists Toward Dental Therapists: A pilot study.
Howell AL, Lynn Tolle S, Ludwig EA, Claiborne DM
J Dent Hyg. 2021 Dec;95(6):6-12.
PMID: 34949678

The intrinsic neonatal hippocampal network: rsfMRI findings.
Howell AL, Osher DE, Li J, Saygin ZM
J Neurophysiol. 2020 Nov 1;124(5):1458-1468. doi: 10.1152/jn.00362.2020. Epub 2020 Sep 23.
PMID: 32965151

Analysis of CRISPR/Cas9 Guide RNA Efficiency and Specificity Against Genetically Diverse HIV-1 Isolates.
Sessions KJ, Chen YY, Hodge CA, Hudson TR, Eszterhas SK, Hayden MS, Howell AL
AIDS Res Hum Retroviruses. 2020 Oct;36(10):862-874. doi: 10.1089/AID.2020.0055. Epub 2020 Aug 26.
PMID: 32640832

A mathematical model of HIV dynamics treated with a population of gene-edited haematopoietic progenitor cells exhibiting threshold phenomenon.
Ratti V, Nanda S, Eszterhas SK, Howell AL, Wallace DI
Math Med Biol. 2020 May 29;37(2):212-242. doi: 10.1093/imammb/dqz011.
PMID: 31265056

Toll-like receptor agonists are potent inhibitors of human immunodeficiency virus-type 1 replication in peripheral blood mononuclear cells.
Buitendijk M, Eszterhas SK, Howell AL
AIDS Res Hum Retroviruses. 2014 May;30(5):457-67. doi: 10.1089/AID.2013.0199. Epub 2014 Jan 20.
PMID: 24328502

Gardiquimod: a Toll-like receptor-7 agonist that inhibits HIV type 1 infection of human macrophages and activated T cells.
Buitendijk M, Eszterhas SK, Howell AL
AIDS Res Hum Retroviruses. 2013 Jun;29(6):907-18. doi: 10.1089/AID.2012.0313. Epub 2013 Feb 5.
PMID: 23316755

Breast milk from Tanzanian women has divergent effects on cell-free and cell-associated HIV-1 infection in vitro.
Lyimo MA, Mosi MN, Housman ML, Zain-Ul-Abideen M, Lee FV, Howell AL, Connor RI
PLoS One. 2012;7(8):e43815. doi: 10.1371/journal.pone.0043815. Epub 2012 Aug 28.
PMID: 22952771

Nanoparticles containing siRNA to silence CD4 and CCR5 reduce expression of these receptors and inhibit HIV-1 infection in human female reproductive tract tissue explants.
Eszterhas SK, Ilonzo NO, Crozier JE, Celaj S, Howell AL
Infect Dis Rep. 2011 Sep 7;3(2):e11. doi: 10.4081/idr.2011.e11. Epub 2011 Sep 7.
PMID: 24470908

Human uterine natural killer cells but not blood natural killer cells inhibit human immunodeficiency virus type 1 infection by secretion of CXCL12.
Mselle TF, Howell AL, Ghosh M, Wira CR, Sentman CL
J Virol. 2009 Nov;83(21):11188-95. doi: 10.1128/JVI.00562-09. Epub 2009 Aug 19.
PMID: 19692460

HIV type 1 infection in women: increased transcription of HIV type 1 in ectocervical tissue explants.
Asin SN, Eszterhas SK, Rollenhagen C, Heimberg AM, Howell AL
J Infect Dis. 2009 Sep 15;200(6):965-72. doi: 10.1086/605412.
PMID: 19671015

View more publications on PubMed