Alexandra L. Howell, PhD
Professor of Medicine
Professor of Microbiology and Immunology
Research Biologist, Veterans Affairs Medical Center (White River Junction, VT)
Microbiology and Immunology
University of Texas Graduate School of Biomedical Sciences, Ph.D., 1982
Colby College, BA, 1977
Program in Experimental and Molecular Medicine
VA Medical Center
Research Service, Box 151
215 North Main St.
White River Jct. VT 05009
Office: Building 44-VA Hospital
Phone: 802-295-9363 ext 5612
Use of CRISPR/Cas to cleave the integrate HIV proviral sequence in primary macrophages and lymphocytes
Mechanisms of HIV infection at mucosal tissue sites
Use of humanized mouse models to study mucosal HIV transmission and to design therapeutics
Research projects in Dr. Howell's laboratory are focused on developing lentiviral vectors to deliver the CRISPR/Cas guide RNA and hCas9 genes to HIV infected cells as well as to uninfected cells to provide protection from infection. These genes permanently integrate into the transduce cell's genome providing continuous transcription of the HIV-specific guide RNA and the associated Cas enzyme. We currently are developing approaches to cleave both the integrated provirus as well as the CCR5 gene. Our goals are to both eliminate HIV from an infected cell as well as to "arm" uninfected cells to resist HIV infection.
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 primary cells with lentiviral vectors expressing CRISPR/Cas genes.
2. Determine the innate immune mechanisms, including toll like receptor (TLR) activation, that occurs in phagocytic cells after transduction with lentiviral vectors. We feel that there are secondary benefits to using lentiviral vectors to deliver CRISPR/Cas genes, and these include non-specific activation of anti-viral mechanisms.
3. Assess efficacy of lentiviral vector delivery in vivo in a humanized mouse model of HIV infection.
Merit Review from the VA (2015-2019)
SBIR Phase I grant- NIH (2014-2016)
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.
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.
Mselle TF, Howell AL, Ghosh M, Wira CR, Sentman CL Human uterine natural killer cells but not blood natural killer cells inhibit human immunodeficiency virus type 1 infection by secretion of CXCL12. J Virol 2009; 83:11188-95 (view details on MedLine)
Peteron AE, Eszterhas SK, Howell AL The role of estradiol and progesterone in mucosal HIV-1 infection, transmission and pathogenesis. Current Women’s Health, 2010, 6: 372-7
Eszterhas SK, Celaj S, Crozier JE, Howell AL Nanoparticles containing siRNA to silence HIV-1 receptor expression inhibit HIV-1 infection in human female reproductive tract tissue explants. Infect Dis Rep. 2011;3:e11. (view details on MedLine)
Lyimo MA, Mosi MN, Housman ML, Zain-Ul-Abideen, Lee FV, Howell AL, Connor RI. Breast milk from Tanzanian women has divergent effect on cell-free and cell-associated HIV-1 infection in vitro. PLoS One. 2012;7:e43815. (view details on MedLine)
Buitendijk M, Eszterhas SK, Howell AL. Gardiquimod: a Toll-like receptor-7 agonist that inhibits HIV type 1 infection of human macrophages and activated T cells. AIDS Res Hum Retroviruses. 2013;29:907-18. (view details on MedLine)
Howell AL. Toll-like receptor agonists induce anti-viral responses that inhibit HIV-1 replication. J Immunol & Clin Res. 2013, 1(1007-8).
Buitendijk M, Eszterhas SK, Howell AL. Toll-like receptor agonists are potent inhibitors of human immunodeficiency virus-type 1 replication in peripheral blood mononuclear cells. AIDS Res Hum Retroviruses. 2014;30:457-67. (view details on MedLine)
Eszterhas SK, Flint KL, Fields JL, Fiering SN, Howell AL. Female genital tract delivery of short-interferring RNA (siRNA) inhibits mucosal transmission of HIV-1 in humanized mice. PLoS One, 2014
Macura SL, Howell AL Harnessing innate immune responses to enhance anti-HIV-1 therapies. Medical Research Archives, 2015.
Ratti V, Nanda S, Eszterhas SK, Howell AL, Wallace DI. A mathematical model of HIV dynamics treated with a population of gene-edited haematopoietic progenitor cells exhibiting threshold phenomenon. Math Med Biol. 2019 Jul 2. (view details on MedLine)