Sexual transmission of human immunodeficiency virus type 1 (HIV-1) has become an increasingly significant component of the worldwide spread of HIV-1 and the acquired immune deficiency syndrome (AIDS) pandemic. Despite almost three decades of continuous research, the mechanisms by which the human immunodeficiency virus type 1 (HIV-1) is transmitted from male to female during sexual intercourse are still incompletely understood. Fundamental questions about the transmission process remain unanswered, including those concerning the specific route of infection, the progression from local infection to systemic dissemination, and factors that may raise or lower the risk of transmission.
 Ongoing investigations in my research group are focused on developing a greater understanding of the mechanisms that underlie HIV-1 heterosexual transmission. We are particularly interested in the male contribution to events that take place during HIV-1 transmission, specifically the effect of semen on HIV-1 transmission across cervicovaginal mucosal tissues.
Other areas of interest relevant to male-to-female HIV-1 transmission include cervicovaginal epithelial damage and inflammation associated with single and multiple applications of topical microbicides, and epithelial tissue repair mechanisms that may impact susceptibility to HIV-1 infection. Projects in these areas involve experiments that span molecular biology, cell biology, virology, and animal models.
Another long-term research interest has been the discovery and development of HIV-1 inhibitors to be used in safe and effective microbicides. Although safe sexual practices, including condom usage, can reduce the risk of HIV-1 transmission, cultural factors and gender inequality issues limit the consistent and effective use of condoms and other preventative measures. As a result, there is an urgent need for safe and effective approaches that can protect women from HIV-1 infection. To meet this need, increasing efforts have been directed toward the development of topical agents, collectively termed microbicides, that would be used within the female reproductive tract to prevent HIV-1 transmission.
Molecules that have been the focus of our research efforts include the biguanide-based NB325, the carbohydrate-based HPMCT, and the co-polymer PSMA (all developed in collaboration with Novaflux Technologies, Inc., Princeton, NJ). These and other agents were evaluated using a wide range of experimental approaches used to establish range of activity, mechanism of action, activity in combination with other inhibitors, and in vivo safety. These and other investigational strategies are designed to significantly advance the pre-clinical development of microbicide compounds and lay a solid foundation for clinical trials of products that can be used to reduce or eliminate the risk of HIV-1 transmission during sexual intercourse.
Selected Publications (See all Fred Krebs' publications in PubMed.)
"Combinatorial approaches to the prevention and treatment of HIV-1 infection"
Pirrone V, Thakkar-Rivera N, Jacobson JM, Wigdahl B, and Krebs FC
Antimicrobial Agents and Chemotherapy, In press, 2011
"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
"Persistent interactions between biguanide-based compound NB325 and CXCR4 result in prolonged inhibition of human immunodeficiency virus type 1 infection"
Thakkar N, Pirrone V, Passic S, Keogan S, Zhu W, Kholodovych V, Welsh W, Rando R, Labib M, Wigdahl B, and Krebs FC
Antimicrobial Agents and Chemotherapy, 54(5): 1965-1972, 2010
"A styrene-alt-maleic acid copolymer is an effective inhibitor of R5 and X4 human immunodeficiency virus type 1 infection"
Pirrone V, Passic S, Wigdahl B, Rando RF, Labib M, and Krebs FC
Journal of Biomedicine and Biotechnology, 2010548749, 2010
"Structure-activity relationships of polybiguanides with activity against human immunodeficiency virus type 1"
Passic SR, Ferguson ML, Catalone BJ, Kish-Catalone T, Kholodovych V, Zhu W, Welsh W, Rando R, Howett MK, Wigdahl B, Labib M, and Krebs FC
Biomedicine and Pharmacotherapy, 64(10): 723-732, 2010
"Specific interactions between the viral coreceptor CXCR4 and the biguanide-based compound NB325 mediate inhibition of human immunodeficiency virus type 1 infection"
Thakkar N, Pirrone V, Passic S, Zhu W, Kholodovych V, Welsh W, Rando RF, Labib ME, Wigdahl B, and Krebs FC
Antimicrobial Agents and Chemotherapy, 53(2): 631-638, 2009
"Introducing metallocene into a triazole peptide conjugate reduces its off-rate and enhances its affinity and antiviral potency for HIV-1 gp120"
Gopi H, Cocklin S, Pirrone V, McFadden K, Tuzer F, Zentner I, Ajith S, Baxter S, Jawanda N, Krebs FC, and Chaiken IM
Journal of Molecular Recognition, 22(2): 169-174, 2009
"Structural determinants for affinity enhancement of a dual antagonist peptide entry inhibitor of human immunodeficiency virus type-1"
Gopi H, Umashankara M, Pirrone V, LaLonde J, Madani N, Tuzer F, Baxter S, Zentner I, Cocklin S, Jawanda N, Miller SR, Schon A, Klein JC, Freire E, Krebs FC, Smith AB, Sodroski J, and Chaiken I
Journal of Medicinal Chemistry, 51(9): 2638-2647, 2008
"Critical design features of phenyl carboxylate-containing polymer microbicides"
Rando RF, Obara S, Osterling MC, Mankowski M, Miller SR, Ferguson ML, Krebs FC, Wigdahl B, Labib M, and Kokubo H
Antimicrobial Agents and Chemotherapy, 50(9): 3081-3089, 2006
"In vitro preclinical testing of nonoxynol-9 as potential anti-human immunodeficiency virus microbicide: a retrospective analysis of results from five laboratories"
Beer BE, Doncel GF, Krebs FC, Shattock RJ, Fletcher PS, Buckheit RW, Jr., Watson K, Dezzutti CS, Cummins JE, Bromley E, Richardson-Harman N, Pallansch LA, Lackman-Smith C, Osterling C, Mankowski M, Miller SR, Catalone BJ, Welsh PA, Howett MK, Wigdahl B, Turpin JA, and Reichelderfer P
Antimicrobial Agents and Chemotherapy, 50(2): 713-723, 2006
"Polybiguanides, particularly polyethylene hexamethylene biguanide, have activity against human immunodeficiency virus type 1"
Krebs FC, Miller SR, Ferguson ML, Labib M, Rando RF, and Wigdahl B
Biomedicine and Pharmacotherapy, 59(8): 438-445, 2005
"Comparative safety evaluation of the candidate vaginal microbicide C31G"
Catalone BJ, Kish-Catalone TM, Neely EB, Budgeon LR, Ferguson ML, Stiller C, Miller SR, Malamud D, Krebs FC, Howett MK, and Wigdahl B
Antimicrobial Agents and Chemotherapy, 49(4): 1509-1520, 2005
"Mouse model of cervicovaginal toxicity and inflammation for preclinical evaluation of topical vaginal microbicides"
Catalone BJ, Kish-Catalone TM, Budgeon LR, Neely EB, Ferguson M, Krebs FC, Howett MK, Labib M, Rando R, and Wigdahl B
Antimicrobial Agents and Chemotherapy, 48(5): 1837-1847, 2004
"Comparative in vitro sensitivities of human immune cell lines, vaginal and cervical epithelial cell lines, and primary cells to candidate microbicides nonoxynol 9, C31G, and sodium dodecyl sulfate"
Krebs FC, Miller SR, Catalone BJ, Fichorova R, Anderson D, Malamud D, Howett MK, and Wigdahl B
Antimicrobial Agents and Chemotherapy, 46(7): 2292-2298, 2002
"Sodium dodecyl sulfate and C31G as microbicidal alternatives to nonoxynol 9: comparative sensitivity of primary human vaginal keratinocytes"
Krebs FC, Miller SR, Catalone BJ, Welsh PA, Malamud D, Howett MK, and Wigdahl B
Antimicrobial Agents and Chemotherapy, 44(7): 1954-1960, 2000
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