LABORATORY OF RETROVIRUS RESEARCH: LAB STRUCTURE

1. LABORATORY OF RETROVIRUS RESEARCH:LAB STRUCTURE • SECTION OF RETROVIRAL PATHOGENESIS • Hana Golding, Ph.D. (PI, Lab Chief) • Keith Peden, Ph.D. (PI) • Marina Zaitseva, Ph.D. (Senior Staff Fellow) SECTION OF RETROVIRAL IMMUNOLOGY Dennis Klinman, MD, Ph.D. (PI) SECTION OF MOLECULAR RETROVIROLOGY Arifa Khan, Ph.D. (PI)

2. LABORATORY OF RETROVIRUS RESEARCH:REGULATORY MISSION (I) • Review of HIV vaccines (pre-IND, original IND submissions, IND amendments, pre-BLA, BLA) • Provide expert opinions to other CBER Laboratories and Divisions on: • Novel Cell Substrates • Adventitious agents detection • Retrovirus contamination • Lentivirus vectors • Plasmid DNA vaccines • CpG oligonucleotides and other adjuvants

3. LABORATORY OF RETROVIRUS RESEARCH:REGULATORY MISSION (II) • Presentations to CBER Advisory Committees • Presentations to the World Health Organization and to other international regulatory authorities • Participation in Interagency Working Groups • Organization and/or participation in special workshops on HIV vaccines, plasmid DNA vaccines, and novel cell substrates

4. LABORATORY OF RETROVIRUS RESEARCH:REGULATORY MISSION (III) Preparation of Guidance Documents for sponsors of new vaccines: • Considerations for plasmid DNA vaccines for infectious disease indications (Klinman) • Characterization and qualification of cell substrates and other biological starting materials for the production of viral vaccines (Peden, Khan) • Preclinical toxicity assessments of preventive vaccines to support phase 1 clinical trials (Golding)

5. SECTION OF RETROVIRAL IMMUNOLOGY Dennis Klinman (PI) Monitor the Safety and Immunomodulatory Activity of DNA-based Products DNA-based products regulated by the FDA: • DNA vaccines • Synthetic oligodeoxynucleotides (ODN) for therapy, immune modulation, adjuvants • Regulated products in which DNA exists as a “contaminant”: • Proteins produced in bacteria containing bacterial DNA. • Vaccines produced in mammalian cell lines containing mammalian DNA.

6. Dennis Klinman : Accomplishments • Discovered and patented a new class of stimulatory CpG ODN. • vaccine adjuvants • immunoprotective agents • anti-allergens. • Discovered and patented a new class of suppressive ODN. • for prevention or treatment of autoimmune and inflammatory diseases. • mechanism of action of these ODN.

7. SECTION OF RETROVIRAL PATHOGENESIS Hana Golding (PI) • STUDIES ON HIV CELL ENTRY • HIV coreceptor expression and function in primary human cells • new entry inhibitors targeting the HIV coreceptor CCR5 • HIV VACCINE TRIALS • new HIV EIA for differential diagnosis of HIV infections in the presence of vaccine-generated antibodies • COUNTER TERRORISM PREPAREDNESS • new in vitro assays and animal models for evaluation of smallpox vaccines potency and safety.

8. Hana Golding: Accomplishments • HIV-SELECTEST • Uninfected vaccine trial participants score negative, while all HIV infections are diagnosed early • Simple and economical test. Can be implemented in sites of future HIV vaccine trials and in blood collection centers around the globe. • SMALLPOX VACCINE EVALUATION • Reporter-gene based vaccinia neutralization assay (high throughput) • Collaborative work on monkeypox primate challenge for “2-animal rule” • Mouse models for tracking vaccinia dissemination: vaccine safety and post-exposure prophylaxis

9. SECTION OF RETROVIRAL PATHOGENESISMarina Zaitseva (Senior Staff Fellow): Accomplishments CELLULAR GENES INVOLVED IN THYMIC RECONSTITUTION AND IMMUNE MODULATION • Murine models of transient thymic atrophy: low-dose irradiation; dexamethasone; estrogen. • Use models to identify salvage mechanisms important for thymic regeneration.

10. Marina Zaitseva (Senior Satff Fellow) CELLULAR GENES INVOLVED IN IMMUNE RECONSTITUTION • ongoing experiments in irradiated mice: reconstitution of T cells in the Gut-associated lymphoid tissues

11. SECTION OF RETROVIRAL PATHOGENESIS Keith Peden (PI) • Safety of tumorigenic cell substrates for vaccine manufacture • SV40 contamination in human vaccines • HIV coreceptor evolution and pathogenesis

12. Keith Peden: Accomplishments Animal models to assess the oncogenic activity of cellular DNA - combination of oncogene-expressing plasmids induced tumors in newborn mice. • ready to test DNA from new cell-substrate Quantitative assays to measure infectivity of integrated retroviral DNA - estimates for safe levels of residual cell-substrate DNA in viral vaccines - tools to evaluate removal of cellular DNA

13. Keith Peden: Accomplishments (2) •quantitative assays to detect the presence of primate polyomavirus DNA in biological specimens • single-cycle, reporter-gene based neutralization assays for BKV, JCV, and SV40

14. MOLECULAR RETROVIROLOGY SECTION Arifa Khan (PI): Accomplishments Simian Foamy Virus Transmission Studies - assess risk of human infection by SFV-infected blood donors. Studies of Simian Foamy Virus Replication - potential risk of SFV propagation in simian and human cells used for vaccine manufacturing.

15. Arifa Khan: Accomplishments Strategies for Detection of Infectious Agents in Vaccine Cell Substrates • quantitative assays for detection of retroviruses • induction of endogenous retroviruses in cells from different animal species • induction of HHV-8 as a model of latent DNA virus