Graduate student: Hager Mohamed

Ongoing research efforts follow my historical pursuit of investigations into HIV-1 infection and pathogenesis, as well as a recent and unique interest in the translational field of plasma medicine.

Even in the era of highly effective combination antiretroviral therapy used to control human immunodeficiency virus type 1 (HIV-1) infection and pathogenesis, up to 50% of infected patients are still diagnosed with mild neurological deficits referred to as HIV-associated neurocognitive disorders (HAND). The multifactorial nature of HAND likely includes contributions by the HIV-1 accessory protein viral protein R (Vpr) as an agent of neuropathogenesis. A continuing research project involves deciphering the mechanisms by which Vpr contributes to the neuropathogenesis of HIV-1 infection.

In studies described in a 2016 Journal of NeuroVirology paper (Dampier et al.), we investigated the effect of naturally occurring variations in Vpr on HAND in well-suppressed patients. Using bioinformatic analyses to correlate peripheral blood-derived Vpr sequences with patient neurocognitive performance, we demonstrated unique associations between the presence of specific amino acid changes in Vpr sequences and measures of patient neuropsychological status (Global Deficit Scores or GDS). The implication of these results is that neuropsychological impairment Vpr (niVpr) variants alter the genesis and/or progression of HAND through differences in Vpr-mediated effects in the peripheral blood and/or the brain. Ongoing studies are focused on revealing the molecular, virologic, and cellular mechanisms that underlie the role of Vpr in HIV-1-associated immunopathogenesis and neuropathogenesis. Of particular interest are changes in Vpr-induced oxidative stress linked to niVpr variants within infected and bystander cells in the peripheral circulation and the brain.

My second research interest is in the exploration of promising biomedical uses for nonthermal plasma (NTP). Specifically, our studies of NTP focus on dielectric barrier discharge plasma (DBDP), which is a form of NTP generated by applying high voltage to an electrode encased in a dielectric material. NTP has been proposed as the basis for a variety of translational applications, including wound repair, tissue sterilization, and cancer therapy. Strengths of NTP include (i) ease of generation and delivery, (ii) controlled energy delivery by known and quantifiable mediators, (iii) limited and controllable cytotoxicity during delivery, (iv) no residual cytotoxicity after delivery, and (iv) no known mechanisms of resistance to NTP.

Two lines of investigation are being followed in the pursuit of potential biomedical applications of NTP. In the first, efforts have been committed to understanding the biological effects of nanosecond-pulsed dielectric barrier discharge plasma (nsDBDP) on human epithelial tissues. In investigations outlined in a 2017 paper published in Plasma Medicine (Truong et al.), in vitro experiments were performed to demonstrate the effects of nsDBDP on viability, monolayer permeability, intracellular oxidative stress, and the release of adenosine triphosphate (ATP). Our results revealed specific biological mechanisms that drive the effects associated with NTP application to living cells. The second avenue of investigation involves the application of NTP to T lymphocytes and other cells of the immune system. These studies are being pursued as part of efforts to develop NTP-based immunotherapy strategies that facilitate HIV-1 eradication and cancer treatment.

• "Infectious Disease Scientists in Demand"
  College of Medicine Newsroom (February 16, 2015)
• "Intricate Transmission"
  Exel - Drexel University Research Magazine (2013)

Selected Publications
(See all Fred Krebs' publications in PubMed.)

“Apical Application of “Nanosecond-pulsed dielectric barrier discharge plasma causes the basolateral release of adenosine triphosphate as a damage-associated molecular pattern from polarized HaCaT cells”
Truong B, K Siegert, A Lin, V Miller, and FC Krebs
Plasma Medicine, 7: 117-131, 2017

“Specific amino acids in HIV-1 Vpr are significantly associated with differences in patient neurocognitive status”
Dampier W, GC Antell, B Aiamkitsumrit, MR Nonnemacher, JM Jacobson, V Pirrone, W Zhong, K Kercher, S Passic, JW Williams, T James, KN Devlin, T Giovannetti, DJ Libon, Z Szep, GD Ehrlich, B Wigdahl, and FC Krebs
J Neurovirol, 23:113-124, 2017

“Evidence of divergent amino acid usage in comparative analyses of R5- and X4-associated HIV-1 Vpr sequences”
Antell GC, W Dampier, B Aiamkitsumrit, MR Nonnemacher, V Pirrone, W Zhong, K Kercher, S Passic, J Williams, Y Liu, T James, JM Jacobson, Z Szep, B Wigdahl, and FC Krebs
Int J Genomics, 2017:4081585, 2017

“Variability in human semen content and its potential effects in the female reproductive tract”
Keogan S, K Siegert, B Wigdahl, and FC Krebs
Journal of Reproductive Biology and Health, 4: 1, 2016

“Defining the roles for Vpr in HIV-1-associated neuropathogenesis”
James T, MR Nonnemacher, B Wigdahl, and FC Krebs
J Neurovirol, 22:403-415, 2016

“cAMP signaling enhances HIV-1 long terminal repeat (LTR)-directed transcription and viral replication in bone marrow progenitor cells”
Banerjee A, L Li, V Pirrone, FC Krebs, B Wigdahl, and MR Nonnemacher
Clin Med Insights Pathol,10: 1179555717694535, 2016

“Utilization of HIV-1 envelope V3 to identify X4- and R5-specific Tat and LTR sequence signatures”
Antell GC, W Dampier, B Aiamkitsumrit, MR Nonnemacher, JM Jacobson, V Pirrone, W Zhong, K Kercher, S Passic, JW Williams, G Schwartz, U Hershberg, FC Krebs, and B Wigdahl
Retrovirology, 13: 32, 2016

“Critical Review: Immunomodulation by seminal factors and implications for male-to-female HIV-1 transmission
Keogan S, K Siegert, B Wigdahl, and FC Krebs
J Acquir Immune Defic Syndr, 69:131-137, 2015

"Application and removal of polyanionic microbicide compounds enhances subsequent infection by HIV-1"
Pirrone V, Passic S, Wigdahl B, and FC Krebs
Virol J, 9: 33, 2012.

"Antiviral breadth and combination potential of peptide triazole HIV-1 entry inhibitors"
McFadden K, Fletcher P, Rossi F, Kantharaju, Umashankara M, Pirrone V, Rajagopal S, Gopi H, Krebs FC, Martin-Garcia J, Shattock RJ, and I Chaiken
Antimicrob Agents Chemother, 56: 1073-1080, 2012.

"Decreased cervical epithelial sensitivity to nonoxynol-9 (N-9) after four daily applications in a murine model of topical vaginal microbicide safety"
Lozenski K, Ownbey R, Wigdahl B, Kish-Catalone T, and FC Krebs
BMC Pharmacology & Toxicology, 13: 9, 2012.

"Inhibiting early-stage events in HIV-1 replication by small-molecule targeting of the HIV-1 capsid"
Kortagere S, Madani N, Mankowski MK, Schon A, Zentner I, Swaminathan G, Princiotto A, Anthony K, Oza A, Sierra LJ, Passic SR, Wang X, Jones DM, Stavale E, Krebs FC, Martin-Garcia J, Freire E, Ptak RG, Sodroski J, Cocklin S, and AB Smith III
J Virol, 86: 8472-8481, 2012.

"Infection by CXCR4-tropic human immunodeficiency virus type 1 Is inhibited by the cationic cell-penetrating peptide derived from HIV-1 Tat"
Keogan S, Passic S, and FC Krebs
Int J Pept, 2012: 349427, 2012.

"A nipple shield delivery system for oral drug delivery to breastfeeding infants: microbicide delivery to inactivate HIV"
Gerrard SE, Baniecki ML, Sokal DC, Morris MK, Urdaneta-Hartmann S, Krebs FC, Wigdahl B, Abrams BF, Hanson CV, Slater NK, and AD Edwards
Int J Pharm, 434: 224-234, 2012.

"The rise and fall of polyanionic inhibitors of the human immunodeficiency virus type 1"
Pirrone V, Wigdahl B, and Krebs FC
Antiviral Research, 90(3): 168-182, 2011