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Michael Nonnemacher

Michael Nonnemacher, PhD

Associate Professor

Department: Microbiology & Immunology


  • PhD - Pennsylvania State University College of Medicine (2004)

Dr. Nonnemacher is an associate professor in the Department of Microbiology & Immunology at Drexel University College of Medicine.

Research Overview

Michael Nonnemacher's research interests include the impact of HIV-1 and drugs of abuse on the blood brain barrier, and HIV-1 genetic variation in disease progression.

He is the assistant director of the Center for Molecular Virology and Neuroimmunology and director of the Center for Scientific Communication and Outreach, within the Institute for Molecular Medicine and Infectious Disease.

Graduate student: Monique Maubert

Research Interests

Impact of HIV-1 and drugs of abuse on the blood-brain barrier; HIV-1 genetic variation in disease progression


Impact of HIV-1 and drugs of abuse on the blood brain barrier

The first 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. HIV-1 has demonstrated the ability to cause adverse neurological complications within a subpopulation of those infected with the virus. With the introduction of highly active antiretroviral therapy (HAART), survival rates associated with HIV-1 infection have improved. Although HAART therapy has increased survival, reduced viral loads, increased CD4 cell counts, and reduced opportunistic infections, one fact has not changed: HAND (HIV-associated neurocognitive disorder) is still a serious concern. Although the incidence of the most severe form of HAND, HIV-associated dementia (HAD), has decreased, the overall prevalence of HAND has not declined, potentially because patients with the more mild forms of HAND, including asymptomatic neurocognitive impairment and mild neurocognitive disorder are living longer with persistent impairment. Because of the more chronic nature of HIV/AIDS in the HAART era, the disease state is becoming more the result of a chronic inflammatory state induced by the production of both HIV-1 virions and viral proteins in the periphery and in the central nervous system (CNS). The development of HAND is dependent on passage of virus and virus-infected cells across the blood-brain barrier (BBB).

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 currently is 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.

Michael Nonnemacher's research - tipping point: a model of BBB dysregulation and loss of homeostasis

Figure 1 - Tipping point: A model of BBB dysregulation and loss of homeostasis.

A) During acute infection, an initial viral entry event into the CNS occurs. This is believed to be through entry of an infected cell of the monocyte-macrophage lineage. Throughout chronic infection, increased generation of or differentiation to a specific monocyte subset, CD14low/CD16+ that traffics preferentially to the BBB and constitutively secretes IL-1 and TNF-alpha is observed in patients with HIV. Once at the BBB, infected cells secrete IL-1, TNF-alpha, Tat, gp120 and other viral proteins causing altered TJ protein expression and localization and BMEC activation leading to increased passage across the BBB. Crosstalk between monocytes and BMECs in this inflammatory state leads to reciprocal activation of the two cell types, allowing for diapedesis of likely infected monocytes. Tat and gp120 are able to enter BMECs through adsorptive endocytosis, altering TJ regulation and delaying TJ closure, creating an opportunity for free virus and viral proteins to enter the CNS through non-specific passage mechanisms. In addition, gap formation has been observed under these conditions, however, the endothelium is able to repair. In the CNS, other cells including astrocytes, pericytes, and perivascular macrophages can be infected and will further secrete Tat, gp120, and proinflammatory cytokines leading to further BMEC activation. Additionally, astrocytes will express high levels of Nef, and secrete MCP-1/CCL2, IL-2, 6, and 8. This process greatly facilitates viral entry into the CNS. Additionally, Tat has been shown to be chemotactic for monocytes, bringing more monocytes to the site of infection. While homeostasis is strained, as long as the barrier is able to recover and repair balance can be restored. This state of enhanced passage may correlate with early HAND development.

B) After prolonged exposure to viral proteins, proinflammatory cytokines, and infectious virus, BBB dysregulation exceeds the threshold of what can be restored. Constant BMEC activation leads to greatly increased monocyte firm adhesion and diapedesis, further spreading infection throughout the CNS. High levels of Tat and gp120 entering BMECs, and altering TJ protein expression and stability, cause further delays in TJ closing, and there is more leakiness in passage. Gap formation is also enhanced, pushing repair mechanisms to a limit. Astrocyte death is also observed, often in cells neighboring those that are infected. Disturbance of the homeostasis between the periphery and the CNS, along with peaks in inflammatory cytokines, neurotoxic viral proteins, and infectious virions suggest a correlation with the onset of more severe neurocognitive symptoms.

HIV-1 genetic variation in clinical disease progression: The second line of investigation within the laboratory is focused on studying the impact of genetic variation and drugs of abuse 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 the DrexelMed HIV/AIDS Genetic Analysis Cohort. These patients are recruited to this cohort from the HIV/AIDS clinic in the Division of Infectious Diseases and HIV Medicine and the Internal Medicine Clinic in the Department of Medicine at the College of Medicine. 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 have classically focused on the HIV-1 promoter or LTR but have expanded to the whole viral genome.

In the Media

"Protecting The Barrier"
Exel - Drexel University Research Magazine (2013)


Selected Publications

"Impact of viral activators and epigenetic regulators on HIV-1 LTRs containing naturally occurring single nucleotide polymorphisms"
Shah S, Pirrone V, Alexaki A, Nonnemacher MR, and B Wigdahl
Biomed Research International, in press, 2015

"HIV Excision Utilizing CRISPR/Cas9 Technology: Attacking the Proviral Quasispecies in Reservoirs to Achieve a Cure"
Dampier W, Nonnemacher MR, Sullivan NT, Jacobson JM, and B Wigdahl.
MOJ Immunology, 1(4): 00022, 2014

"Effect of Mu-opioid agonist DAMGO on surface CXCR4 and HIV-1 replication in TF-1 human bone marrow progenitor cells"
Strazza A, Banerjee A, Alexaki A, Miller SR, Meucci O, Pirrone V, Wigdahl B and MR Nonnemacher
BMC Research Note, 7: 752, 2014
PMCID: PMC4216373

"Defining differential genetic signatures in CXCR4- and the CCR5-utilizing HIV-1 co-linear sequences"
Aiamkitsumrit B, Dampier W, Martin-Garcia J, Nonnemacher MR, Pirrone V, Ivanova T, Zhong W, Kilareski E, Aldigun H, Frantz B, Rimbey M, Wojno A, Passic S, William JS, Shah S, Blakey B, Parikh N, Jacobson J, Moldover B, and B Wigdahl.
PlosOne, 9(9): e107389, 2014
PMCID: PMC4180074

"Functional properties of the HIV-1 long terminal repeat containing single-nucleotide polymorphisms in Sp site III and CCAAT/enhancer binding protein site I"
Shah S, Alexaki A, Pirrone V, Dahiya S, Nonnemacher MR, and B Wigdahl.
Virology Journal, May 16, 11:92. doi: 10.1186/1743-422X-11-92, 2014
PMCID: PMC4047001

"Bioinformatic analysis of HIV-1 entry and pathogenesis"
Aiamkitsumrit B, Dampier W, Antell G, Rivera N, Pirrone V, Nonnemacher MR, and B Wigdahl
Current HIV Research, 12(2): 132-161, 2014

"Cocaine alters cytokine profiles within HIV-1-infected African American individuals in the DREXELMED HIV/AIDS Genetic Analysis Cohort"
Parikh N, Dampier W, Feng R, Passic SR, Zhong W, Frantz B, Blakey B, Aiamkitsumrit B, Pirrone V, Nonnemacher MR, Jacobson JM, and B Wigdahl.
JAIDS, 66(3): 256-264, 2014
PMCID: PMC4146625

"CCAAT Enhancer Binding Protein and Nuclear Factor of Activated T Cells Regulate HIV-1 LTR via a Novel Conserved Downstream Site in Cells of the Monocyte-Macrophage Lineage"
Dahiya S, Liu Y, Nonnemacher MR, Dampier W, and B Wigdahl
PlosOne, Feb 14;9(2):e88116, 2014
PMCID: PMC3925103

"Extracellular HIV-1 viral protein R (Vpr) influences astrocytic glyceraldehyde 3-phosphate dehydrogenase (GAPDH) activity and metabolism affecting neuronal glutathione synthesis and survival"
Ferrucci A, Nonnemacher MR, and B Wigdahl
Journal of Neurovirology, 19(3): 239-253, 2013
PMCID: PMC3731056

"Genetic Variation and HIV-associated neurologic disease"
Dahiya S, Irish BP, Nonnemacher MR, and B Wigdahl
Advances in Virus Research, 87:183-240, 2013
PMCID: PMC4074542

"Substance Abuse, HIV-1 and Hepatitis"
Parikh N, Nonnemacher MR, Pirrone V, Block T, Mehta A, and B Wigdahl
Current HIV Research, 10(7): 557-571, 2012

"Impact of Tat genetic variation on HIV-1 disease"
Li L, Dahiya S, Kortagere S, Cunningham D, Pirrone V, Nonnemacher MR, and B Wigdahl
Advances in Virology, Volume 2012, Article ID 123605, 2012
PMCID: PMC3414192

"Role of mu-opioids as cofactors in human immunodeficiency virus type 1 disease progression and neuropathogenesis"
Banerjee A, Strazza M, Wigdahl B, Pirrone V, Meucci O, and MR Nonnemacher
Journal of Neurovirology, 17(4): 291-302, 2011

"Breaking Down the Barrier: The effects of HIV-1 on the Blood-Brain Barrier"
Strazza M, Pirrone V, Wigdahl B, and MR Nonnemacher
Brain Research, 1399: 96-115, 2011
PMCID: PMC3139430

"Transcriptional regulation of the chemokine co-receptor CCR5 by the cAMP/PKA/CREB pathway"
Banerjee A, Pirrone V, Wigdahl B, and MR Nonnemacher
Biomedicine and Pharmacotherapy, 65(4): 293-297, 2011
PMCID: PMC3150495

Contact Information

Research Office

Department of Microbiology & Immunology
245 N. 15th Street
Philadelphia, PA 19102
Phone: 215.762.4154
Fax: 215.762.1955