Nominated by Dean’s office to participate in “Department Head and Leadership Workshop Series: Managing Up, Managing Out and Managing Within” a series is led by Dr. Harris Sokoloff from the Penn Center for Education Leadership, 2018.

Michael Nonnemacher's research interests include HIV-1 genetic variation in disease progression, role of viral accessory proteins in pathogenesis, use of gene-editing strategies for HIV cure research, and the impact of HIV-1 and drugs of abuse on the CNS.

Graduate students: Cassandra Spector, Jill Lawrence, Alexis Brantly, MacKenzie Collins, Diehl DeSouza

HIV-1 genetic variation in clinical disease progression

One line of investigation within the laboratory is focused on studying the impact of genetic variation on HIV-1 and SIV replication and pathogenesis. Studies in this line of investigation are focused on understanding if genetic variation that occurs throughout a patient’s course of disease can be utilized as a diagnostic or predictive marker of peripheral or neurologic disease progression. This study is being performed utilizing patients enrolled in a longitudinal study in Drexel's CNS AIDS Research and Eradication Study (CARES) Cohort. These patients are recruited to this cohort from the Partnership Comprehensive Care Practice at Drexel. As these markers are identified, the laboratory then focuses on understanding the functional implications these variations may have on HIV-1 replication and pathogenesis. These studies are currently focused on two areas of the HIV genome: Tat and the long terminal repeat (LTR).

The studies on Tat are currently focused on genetic variants that may alter the many pathogenic functions of the protein. These are currently focused on secretion from various cell types, neuronal and astrocyte dysfunction, and LTR transactivation.

The HIV-1 promoter or LTR studies are being conducted in a long-term collaboration with Dr. Wigdahl’s laboratory. These studies span examining the effect of LTR variation on transcriptional control of the virus, as well as designing novel “cure” therapeutics. These currently focus on using the CRISPR/cas9 system for excision of the HIV provirus from cells.

HIV/HBV coinfection in cancer

The hypothesis of this work is that in an HIV/HBV co-infection, the effects of Tat, as an extracellular protein or in combination with other cellular macromolecules from HIV-infected Kupffer cells (KCs), enhance HBx-driven cellular signals that regulate HBV replication and/or apoptosis, leading to an elevated risk for liver disease, including HCC, as compared to mono-infection. The goal of this work is to determine whether cooperative HBx and Tat activities affect HBV replication and apoptosis in HBV-infected hepatocytes and define mechanisms underlying cooperative effects.

Impact of HIV-1 and drugs of abuse on the CNS

Another line of investigation the laboratory focuses on is the impact of drugs of abuse, especially opioids, in combination with HIV-1, on blood-brain barrier (BBB) structure and function. The integrity of the BBB is compromised by the actions of the HIV-1 virions, viral proteins, and host cytokines and chemokines from both sides of this barrier alone and in combination with drugs of abuse. This compromise results in disruption and dysregulation of the normal function of the BBB. Changes in BBB permeability following HIV-1 infection are likely the result of multiple intracellular and intercellular events involving several cell types in addition to both viral and host proteins. Cells actively infected with HIV-1 exhibit changes in cytokine expression, produce virions, and secrete viral proteins. Damage to the BBB allows increased cell migration from peripheral circulation, increasing the access of virus-infected cells, viral proteins, and free virus to the CNS. The laboratory is currently using in vitro BBB models to assess these alterations in structure and function to understand the full impact of HIV-1 and drugs of abuse on the BBB.

Funding

The College of Medicine’s Brian Wigdahl, PhD, professor and chair of microbiology and immunology, and Michael Nonnemacher, PhD, professor of microbiology and immunology, received funding from National Institutes of Health (NIH)’s Martin Delaney Collaboratories for HIV Cure Research Program. Their combined total awards were $2.4 million.

HIV: What's Next - Six Drexel Scientists Share Their Work
Alumni Magazine Spring/Summer 2019

Protecting The Barrier
Exel - Drexel University Research Magazine 2013

(See most of Michael Nonnemacher’s publications in PubMed.)

Selected Publications

"Morphine exposure exacerbates HIV-1 Tat driven changes to neuroinflammatory factors in cultured astrocytes"
Chen K, Phan T, Lin A, Sardo L, Mele AR, Nonnemacher MR, Klase Z
PLoS One. 2020 Mar 25;15(3):e0230563. doi: 10.1371/journal.pone.0230563. eCollection 2020. PMID:32210470. Free PMC Article (2020)

"HIV-1 Tat Length: Comparative and Functional Considerations"
Mele AR, Marino J, Dampier W, Wigdahl B, Nonnemacher MR
Front Microbiol. 2020 Mar 24;11:444. doi: 10.3389/fmicb.2020.00444. eCollection 2020. No abstract available. PMID: 32265877 (2020)

"Computational Analysis Concerning the Impact of DNA Accessibility on CRISPR-Cas9 Cleavage Efficiency"
Chung CH, Allen AG, Sullivan NT, Atkins A, Nonnemacher MR, Wigdahl B, Dampier W
Mol Ther. 2020 Jan 8;28(1):19-28. doi: 10.1016/j.ymthe.2019.10.008. Epub 2019 Oct 15. PMID: 31672284 (2020)

"Novel gRNA design pipeline to develop broad-spectrum CRISPR/Cas9 gRNAs for safe targeting of the HIV-1 quasispecies in patients"
Sullivan NT, Dampier W, Chung CH, Allen AG, Atkins A, Pirrone V, Homan G, Passic S, Williams J, Zhong W, Kercher K, Desimone M, Li L, C Antell G, Mell JC, Ehrlich GD, Szep Z, Jacobson JM, Nonnemacher MR, Wigdahl B
Sci Rep. 2019 Nov 19;9(1):17088. doi: 10.1038/s41598-019-52353-9. PMID: 31745112 Free PMC Article (2019)

"Investigating the distribution of HIV-1 Tat lengths present in the Drexel Medicine CARES cohort"
Link RW, Mele AR, Antell GC, Pirrone V, Zhong W, Kercher K, Passic S, Szep Z, Malone K, Jacobson JM, Dampier W, Wigdahl B, Nonnemacher MR
Virus Res. 2019 Oct 15;272:197727. doi: 10.1016/j.virusres.2019.197727. Epub 2019 Aug 19. PMID: 31437485 (2019)

"Genetic variation and function of the HIV-1 Tat protein"
Spector C, Mele AR, Wigdahl B, Nonnemacher MR
Med Microbiol Immunol. 2019 Apr;208(2):131-169. doi: 10.1007/s00430-019-00583-z. Epub 2019 Mar 5. Review. PMID: 30834965 Free PMC Article (2019)

Gene Editing of HIV-1 Co-receptors to Prevent and/or Cure Virus Infection
Allen AG, Chung CH, Atkins A, Dampier W, Khalili K, Nonnemacher MR, Wigdahl B
Front Microbiol. 2018 Dec 17;9:2940. doi: 10.3389/fmicb.2018.02940. eCollection 2018. Review. PMID: 30619107 Free PMC Article (2018)

"Broad-Spectrum and Personalized Guide RNAs for CRISPR/Cas9 HIV-1 Therapeutics"
Dampier W, Sullivan NT, Mell JC, Pirrone V, Ehrlich GD, Chung CH, Allen AG, DeSimone M, Zhong W, Kercher K, Passic S, Williams JW, Szep Z, Khalili K, Jacobson JM, Nonnemacher MR, Wigdahl B
AIDS Res Hum Retroviruses. 2018 Nov;34(11):950-960. doi: 10.1089/AID.2017.0274. Epub 2018 Aug 27. PMID: 29968495 Free PMC Article (2018)

"Prediction of Human Immunodeficiency Virus Type 1 Subtype-Specific Off-Target Effects Arising from CRISPR-Cas9 Gene Editing Therapy"
Link RW, Nonnemacher MR, Wigdahl B, Dampier W
CRISPR J. 2018 Aug;1:294-302. doi: 10.1089/crispr.2018.0020. PMID: 31021222 Free PMC Article (2018)

"Defining the molecular mechanisms of HIV-1 Tat secretion: PtdIns(4,5)P₂ at the epicenter"
Mele AR, Marino J, Chen K, Pirrone V, Janetopoulos C, Wigdahl B, Klase Z, Nonnemacher MR
Traffic. 2018 Apr 30. doi: 10.1111/tra.12578. [Epub ahead of print] Review. PMID: 29708629 Free PMC Article (2018)

"Functional Studies of CCAAT/Enhancer Binding Protein Site Located Downstream of the Transcriptional Start Site"
Liu Y, Nonnemacher MR, Alexaki A, Pirrone V, Banerjee A, Li L, Kilareski E, Wigdahl B
Clin Med Insights Pathol. 2017 Nov 15;10:1179555717694556. doi: 10.1177/1179555717694556. eCollection 2017. PMID: 29162980 Free PMC Article (2017)

Designing broad-spectrum anti-HIV-1 gRNAs to target patient-derived variants
Dampier W, Sullivan NT, Chung CH, Mell JC, Nonnemacher MR, Wigdahl B.
Sci Rep. 2017 Oct 31;7(1):14413. doi: 10.1038/s41598-017-12612-z. PMID: 29089503 (2017)

Opinion: Inhibition of Blood-Brain Barrier Repair as a Mechanism in HIV-1 Disease
Maubert ME, Wigdahl B, Nonnemacher MR
Front Neurosci. 2017 Apr 26;11:228. doi: 10.3389/fnins.2017.00228. eCollection 2017. No abstract available. PMID: 28491017 (2017)

cAMP Signaling Enhances HIV-1 Long Terminal Repeat (LTR)-directed Transcription and Viral Replication in Bone Marrow Progenitor Cells
Banerjee A, Li L, Pirrone V, Krebs FC, Wigdahl B, Nonnemacher MR
Clin Med Insights Pathol. 2017 Mar 10;10:1179555717694535. doi: 10.1177/1179555717694535. eCollection 2017. PMID: 28469516 (2017)

Specific amino acids in HIV-1 Vpr are significantly associated with differences in patient neurocognitive status
Dampier W, Antell GC, Aiamkitsumrit B, Nonnemacher MR, Jacobson JM, Pirrone V, Zhong W, Kercher K, Passic S, Williams JW, James T, Devlin KN, Giovannetti T, Libon DJ, Szep Z, Ehrlich GD, Wigdahl B, Krebs FC
J Neurovirol. 2017 Feb;23(1):113-124. doi: 10.1007/s13365-016-0462-3. Epub 2016 Jul 11. PMID: 27400931 (2017)