Graduate students: Anthony Mele (4^th-year PhD), Jamie Marino (3^rd-year PhD), Cassandra Spector (3^rd-year PhD), Jill Lawrence (2^nd-year PhD)

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 HIV/AIDS genetic analysis cohort. These patients are recruited to this cohort from the Partnership Comprehensive Care Practice in the Division of Infectious Diseases & HIV Medicine and Drexel Internal Medicine practices. 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.

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

• 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

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

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

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

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

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

Evidence of Divergent Amino Acid Usage in Comparative Analyses of R5- and X4-Associated HIV-1 Vpr Sequences
Antell GC, Dampier W, Aiamkitsumrit B, Nonnemacher MR, Pirrone V, Zhong W, Kercher K, Passic S, Williams J, Liu Y, James T, Jacobson JM, Szep Z, Wigdahl B, Krebs FC
Int J Genomics. 2017;2017:4081585. doi: 10.1155/2017/4081585. Epub 2017 May 17.
PMID: 28620613

Mitochondrial Haplogroup Influences Motor Function in Long-Term HIV-1-Infected Individuals
Azar A, Devlin K, Mell JC, Giovannetti T, Pirrone V, Nonnemacher MR, Passic S, Kercher K, Williams JW, Jacobson JM, Wigdahl B, Dampier W, Libon DJ, Sell C
PLoS One. 2016 Oct 6;11(10):e0163772. doi: 10.1371/journal.pone.0163772. eCollection 2016.
PMID: 27711166

Co-culture model consisting of human brain microvascular endothelial and peripheral blood mononuclear cells
Strazza M, Maubert ME, Pirrone V, Wigdahl B, Nonnemacher MR
J Neurosci Methods. 2016 Aug 30;269:39-45. doi: 10.1016/j.jneumeth.2016.05.016. Epub 2016 May 20.
PMID: 27216631

Prolonged Morphine Exposure Induces Increased Firm Adhesion in an in Vitro Model of the Blood-Brain Barrier
Strazza M, Pirrone V, Wigdahl B, Dampier W, Lin W, Feng R, Maubert ME, Weksler B, Romero IA, Couraud PO, Nonnemacher MR
Int J Mol Sci. 2016 Jun 9;17(6). pii: E916. doi: 10.3390/ijms17060916.
PMID: 27294916

HIV-1 Genetic Variation Resulting in the Development of New Quasispecies Continues to Be Encountered in the Peripheral Blood of Well-Suppressed Patients
Dampier W, Nonnemacher MR, Mell J, Earl J, Ehrlich GD, Pirrone V, Aiamkitsumrit B, Zhong W, Kercher K, Passic S, Williams JW, Jacobson JM, Wigdahl B
PLoS One. 2016 May 19;11(5):e0155382. doi: 10.1371/journal.pone.0155382. eCollection 2016.
PMID: 27195985

Utilization of HIV-1 envelope V3 to identify X4- and R5-specific Tat and LTR sequence signatures
Antell GC, Dampier W, Aiamkitsumrit B, Nonnemacher MR, Jacobson JM, Pirrone V, Zhong W, Kercher K, Passic S, Williams JW, Schwartz G, Hershberg U, Krebs FC, Wigdahl B
Retrovirology. 2016 May 3;13(1):32. doi: 10.1186/s12977-016-0266-9.
PMID: 27143130

HIV-1 Promoter Single Nucleotide Polymorphisms Are Associated with Clinical Disease Severity
Nonnemacher MR, Pirrone V, Feng R, Moldover B, Passic S, Aiamkitsumrit B, Dampier W, Wojno A, Kilareski E, Blakey B, Ku TS, Shah S, Sullivan NT, Jacobson JM, Wigdahl B
PLoS One. 2016 Apr 21;11(4):e0150835. doi: 10.1371/journal.pone.0150835. eCollection 2016.
PMID: 27100290

Interaction between Tat and Drugs of Abuse during HIV-1 Infection and Central Nervous System Disease
Maubert ME, Pirrone V, Rivera NT, Wigdahl B, Nonnemacher MR
Front Microbiol. 2016 Jan 11;6:1512. doi: 10.3389/fmicb.2015.01512. eCollection 2015. Review.
PMID: 26793168

HIV-1 Latency and Eradication: Past, Present and Future
Datta PK, Kaminski R, Hu W, Pirrone V, Sullivan NT, Nonnemacher MR, Dampier W, Wigdahl B, Khalili K
Curr HIV Res. 2016;14(5):431-441. Review.
PMID: 27009094

Effect of μ-opioid agonist DAMGO on surface CXCR4 and HIV-1 replication in TF-1 human bone marrow progenitor cells
Strazza M, Banerjee A, Alexaki A, Passic SR, Meucci O, Pirrone V, Wigdahl B, Nonnemacher MR
BMC Res Notes. 2014 Oct 23;7:752. doi: 10.1186/1756-0500-7-752.
PMID: 25338959