Division of Pediatric Infectious Diseases, Department of Pediatrics

New and Ongoing NIH Funding

The Division has eight active NIH-funded research grants. Betsy Herold, M.D., is Principal Investigator on a Program Project titled "Multitargeted Microbicide Combinations to Block HIV." In addition, Dr. Herold is a Project Leader on two additional Program Project Grants titled "Development of Sodium Dimandelic Acid as a Topical Microbicide for HIV and HSV" (PI: Mary Klotman, Mount Sinai 9/26/01-7/31/05), and "Topical Microbicides for Prevention of STDs/HIV" (PI: L. Stanberry, University of Texas, Galveston).

Roberto Posada, M.D., is Principal Investigator of the NICHD sponsored Pediatric AIDS Clinical Trials Subunit (Parent Unit: Harlem Hospital, PI: E. Abrams), which conducts clinical research related to HIV infection in pregnant women, infants, children, and adolescents. In addition, Dr. Posada is also a co-investigator on a multicenter Program on Solid Organ Transplantation in HIV (PI: P. Stokes and M. Roland, UCSF).

Maria-Arantxa Horga, M.D., continues her research funded by a KO8 from the NIH titled "Interaction of Parainfluenza virus 3 with the host cell." In addition, Dr. Herold (co-investigator) participates in an NIH funded training grant titled "Physician Scientist Research Training Pathogenesis of Viral Diseases" (PI: Mary Klotman).

Andrew Campbell, M.D., has been awarded a Career Development Award as part of the NIAID–funded Regional Centers of Excellence for Biodefense and Emerging Infectious Diseases Research (RCE).

Development of ID Clinical Research Projects and Trials

The Division participates in the NIH funded Combined Antiviral Study Group projects (PI: R. Whitley, University of Alabama). Active trials at Sinai include two studies to evaluate suppressive therapy with oral acyclovir following neonatal herpes simplex virus infections and a study on ganciclovir/valganciclovir to prevent sequelae in neonates with congenitally-acquired CMV infections. We also have initiated several studies with the Transplantation Institute. These include a study on adenovirus infection in small bowel transplantation recipients (Transplantation, 76. 183-9; 2003) and a retrospective study on ganciclovir prophylaxis and preemptive PCR testing to prevent CMV and EBV in pediatric liver transplantation recipients.

In addition, Dr. Campbell is planning several studies on immune reconstitution in pediatric solid organ transplantation recipients including a study on the safety and efficacy of varicella vaccine in this study population. Dr. Posada is participating in several industry-based trials on anti-retroviral therapy for Pediatric HIV patients. As part of the Program Project titled "Multitargeted Microbicide Combinations to Block HIV," several clinical studies to examine the inflammatory response to candidate vaginal microbicides are ongoing. These studies are conducted at the GCRC.

Pediatric Infection Control and Antibiotic Monitoring Program

The Division has expanded its role in hospital infection control and antibiotic monitoring programs. Andrew Campbell, M.D., was recruited to join the Division of Pediatric Infectious Diseases in July 2003. Dr. Campbell has a strong interest in hospital epidemiology, infection control, and bioterrorism. He is working with members of the Infection Control Program and Umberto Conte, Pharm.D., to optimize Mount Sinai children's hospital infection control policies and guidelines for antibiotic use.

Faculty Research Descriptions

Betsy Herold, M.D.

Dr. Herold's research efforts focus on identifying the viral and cellular requirements for herpes simplex virus (HSV) entry into cells and using that knowledge to develop novel approaches to prevent infection of HSV and other related sexually transmitted diseases. Other PID faculty actively engaged in these studies are Natalia Cheshenko and Veronica MasCasullo.

The initial step in HSV invasion is binding of viral envelope glycoproteins gB and /or gC to cell surface heparan sulfate. Following this initial attachment, the viral envelope glycoprotein D (gD) then attaches to one of several co-receptor. The HSV envelope then fuses with the cell plasma membrane. Preliminary studies suggest that this fusion event requires calcium (Ca2+) signaling and triggers tyrosine phosphorylation of cellular proteins such as focal adhesion kinase (FAK). Focusing on HSV serotype 2 (HSV-2), the most common cause of genital herpes, the lab focuses on and identifying the cellular pathways required for viral envelope-cell membrane fusion.

Defining the viral and cellular requirements for viral invasion should promote rational design of safe and effective topical microbicides to prevent sexual or perinatal transmission. For example, the recognition that heparan sulfate is a common adherence receptor for HSV and HIV has led to the development of sulfonated polymers, which resemble the heparan sulfate receptor, as candidate topical contraceptive microbicides. Dr. Herold and her colleagues have characterized several of these compounds that competitively block HSV attachment, inhibit HIV fusion, and impede sperm functions including hyaluronidase and human acrosin activity. These compounds are contraceptive in the rabbit animal model and prevent genital herpes in the mouse vaginal model; their in vivo efficacy is currently being tested in Phase I/II clinical trials. In collaboration with Drs. Mary Klotman and Marla Keller, (Adult Infectious Disease), this group of Sinai investigators has successfully competed for three NIH-funded Program Project grants in the area of topical microbicide development. Their work includes in vitro studies, animal models and clinical pilot studies. Clinical studies to examine the safety of a leading microbicide, PRO 2000, are currently ongoing in the GCRC. In addition, the group is also exploring the possible role of defensins and acid buffering gels as candidate microbicides.

Roberto Posada, M.D.

Dr. Posada is the Director of the Pediatric HIV program and Principal Investigator of the NICHD sponsored Pediatric AIDS Clinical Trials Subunit, which conducts clinical research related to HIV infection in pregnant women, infants, children, and adolescents. The scope of the studies include primary therapy, complications, natural history, prevention, vaccines, psychosocial issues, and so on. The studies are for the most part developed by the Pediatric AIDS Clinical Trial Group, the Adult AIDS Clinical Trials Group and The Adolescent Trials Network.. Other faculty are co-investigators in some of these trials. In addition, Dr. Posada is a co-investigator on a new program titled "Solid Organ Transplantation in HIV: Multi-Site Study." This project (PI: P. Stokes and M. Roland, UCSF) will study the impact of liver and renal transplantation in HIV infected adults and children. Dr. Posada has also initiated clinical pharmaceutical trials in the HIV clinic and has played an instrumental role in initiating some of the clinical studies with the Transplant Institute described above.

Maria-Aranxta Horga, M.D.

Dr. Horga was granted a Mentored Physician Scientist Development Award (K08) from the National Institutes of Allergy and Infectious Diseases (NIAID) in 2000. In 2001, her scientific work was recognized with the Child Health Research Center Award, from the National Institute of Child Health Research (NIHRC). Dr. Horga's areas of expertise are respiratory viruses, West Nile Virus, and HIV. Dr. Horga devotes approximately 85 percent of her time to basic science research that focuses on molecular mechanisms of interference with human parainfluenza 3 virus (HPF3) infection. Dr. Horga is currently working on HPF3 immunomodulatory effects on antigen presenting cells.

Andrew Campbell, M.D.

Dr. Campbell is the Director of Pediatric Infection Control at The Mount Sinai Hospital. In addition to his infection control responsibilities, he has taken special interest in the prevention and management of infectious diseases complications in pediatric solid organ transplant recipients. He is vigorously pursuing the establishment of a research program directed at this high-risk population as well as an antibiotic monitoring/stewardship program. He has recently received a Career Development Award from the Bioterrorism Regional Centers of Excellence to investigate the immune response of pediatric liver transplant recipients to the influenza vaccine as a predictor of how high-risk patient populations may respond to new vaccines in development. In addition to his research, Dr. Campbell is also co-director of the emerging pathogens committee and very involved in medical student and resident education.

Recent Research Publications from the Division

Cheshenko N and Herold BC. Glycoprotein B plays key role in mediating HSV-2 binding and is essential for entry and cell-cell spread. J Gen Vir 83: 2247-52, 2002.

Herold BC, Scordi-Bello I, Chesenhko N, Marcellino D, Dzuzelewski M, Francois F, Morin R, Mas Casullo V, Anderson RA, Chaney C, Waller DP, Zaneveld LJD, and Klotman ME. Mandelic Acid Condensation Polymer: Novel Candidate Microbicide for Prevention of Human Immunodeficiency Virus and Herpes Simplex Virus Entry. J. Virology 76: 11236-44, 2002.

Sinha S, Cheshenko N, Lehrer RI, Herold BC. NP-1, a rabbit a-defensin, prevents the entry and intercellular spread of HSV-2. Antimicrobial Agents and Chemo 47: 494-500, 2003.

Keller MJ, Klotman ME, Herold BC. Rigorous pre-clinical evaluation of topical microbicidesto prevent human immunodeficiency virus. J Antimicrobial Chemotherapeutics, 51: 1099-102; 2003.

Cheshenko N, Del Rosario, B, Woda C, Marcellino D, Satlin L, and Herold BC. Calcium signaling pathways are required for herpes simplex virus entry. J Cell Biology 163; 283-93; 2003.

Cheshenko N, Keller, MJ, MasCasullo V, Jarvis, G, Cheng, H., John, M, Li, J-H., Hogarty, K., Anderson RA, Waller, DP, Zaneveld L, Profy, AT., Klotman ME, and Herold BC. Sulfonated polymers bind HSV glycoprotein B and prevent viral entry and cell-cell spread. Antimicrobial Agents and Chemo: June 2004, in press.

Campbell, AL and Herold, BC. Preemptive and Prophylactic Strategies to Prevent CMV in Pediatric Liver Transplantation Recipients. Pediatric Transplantation, in press.

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