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. Investigations focused on reproductive biology indicate that factors in semen, including cytokines, chemokines, and growth factors, modulate the immune response of the female reproductive tract (FRT), priming it for conception. These same factors are also highly likely to have roles in human immunodeficiency virus type 1 (HIV-1) male-to-female transmission. In addition, the effects of these factors on transmission will be dependent on their concentrations, which vary with HIV-1 infection and will likely change in association with other clinical variables (see figure below). Projects in this area 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. Our overall goal is 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.)
"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
"Cervicovaginal safety of the formulated, biguanide-based human immunodeficiency virus type 1 (HIV-1) inhibitor NB325 in a murine model"
Lozenski K, Kish-Catalone T, Pirrone V, Rando RF, Labib M, Wigdahl B, and FC Krebs
J Biomed Biotechnol, 2011: 941061, 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
"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