Research Summaries and Interests:

Lisa Ann Beltz, Ph.D.
W1057 Biomedical Science Tower
(412) 648-7323
Instructor, Division of Hematology/Bone Marrow Transplantation
Montefiore Hospital, University of Pittsburgh

My virology research concerns the interactions of hematopoietic cells with the human and simian immunodeficiency viruses (HIV and SIV), and is being done in collaboration with Dr. Albert Donnenberg of the School of Medicine. We have examined the ability of several strains of SIV to infect bone marrow progenitor cells in vitro and in vivo and to alter the frequency of macrophage progenitors. We have also examined pathology associated with two virus strains: (1) a molecularly cloned lymphotropic SIV strain; and (2) an in vivo-adapted macrophage-tropic variant.
Another primary area of research is the process of apoptosis which occurs in T cells of HIV-infected humans and the relationship of this phenomenon to apoptosis (programmed cell death) seen in reconstituting bone marrow transplantation patients. Future research will investigate the interactions of HIV (and Mycobacterium tuberculosis) with macrophage subsets and will focus upon the ability of the cells to function as viral hosts and their role in infection of T cells.



Peter B. Berget, Ph.D.
271 Mellon Institute
(412) 268-5648
Associate Professor, Department of Biological Sciences
Carnegie Mellon University

My research program is aimed at answering basic questions regarding how biological structures are formed and how they perform their designated functions. Using an easily manipulated prokaryotic viral system, Salmonella typhimurium bacteriophage P22, we are using genetics, molecular biology, molecular genetics and biochemistry as primary tools in our research. In one project we are attempting to determine the elements of protein structure which are involved in the attachment of the P22 tailspike protein to the completed capsid structure. We have isolated over 100 absolute defective tail protein mutant strains which are being characterized to determine (i) the effects on correct protein folding, and (ii) the effects on protein:protein interactions required for formation and assembly of tail and capsid structures. From these studies will emerge a picture of what amino acid residues are important for the "docking and stabilization" of an assembly protein during its morphogenetic reaction.
In another project, we are attempting to determine how phage P22 transports its genome from the phage capsid into the bacterium during the infection process, by characterizing three different phage-encoded structural proteins known to be involved in this "DNA-injection".




Kenneth R. Boyd, Ph.D.
Mellon Hall
(412) 396-6317
Assistant Professor, Department of Biological Sciences
Duquesne University

Our primary research interest is to identify and characterize the genetic makeup of several rhabdoviruses that are not members of the two established genera of Rhabdoviruses. At present we are studying Flanders virus, a member of the Hart Park serogroup, that has been isolated from mosquitoes and birds collected throughout many areas of North America and expect to direct our efforts toward related viruses from Africa and South America. We are identifying the genes and their respective mRNAs and proteins and are determining the gene order of the virus genome. Gene sequencing is underway to provide a basis for comparisons with other negative-sense RNA viruses.

Neal A. DeLuca, Ph.D.
E1257 Biomedical Science Tower
(412) 648-9947
Associate Professor, Department of Molecular Genetics and Biochemistry
University of Pittsburgh

Herpes Simplex Virus (HSV) exhibits much of the complexity associated with the molecular events ongoing in eukaryotic cells but is easily manipulated from genetic and biochemical standpoints. HSV is a human pathogen that is capable of both rapid productive infections which lead to destruction of the infected host cells, and latent infections in the neurons of sensory ganglia where the viral genome is relatively silent, persisting for many years. Our laboratory studies the structure and function of HSV regulatory proteins and how they interact with specific cellular pathways to produce the regulatory cascade seen in productive infection. Also of interest are modes of HSV gene regulation that are more important in vivo and possibly in latent infections, as contrasted to productive infections.




Albert D. Donnenberg, Ph.D.
W1057 Biomedical Science Tower
(412) 624-9596
Associate Professor of Medicine
Director of Laboratory Research, Hematology/Bone Marrow Transplantation
University of Pittsburgh

Our laboratory is involved in human immunology/experimental hematology research on the development of new approaches to bone marrow transplantation (BMT). Related basic science research centers on the mechanisms of immunodeficiency induced concomitant to BMT or acquired through infection with human immunodeficiency virus (HIV). A major area of interest is in the interactions of HIV with hematopoietic progenitor cells. The mechanisms of HIV induced dysregulation of bone marrow growth are not understood. Current efforts in the rhesus macaque/simian immune deficiency virus (SIV) model are directed toward: (1) understanding how infection affects the production and regulation of bone marrow growth factors, and (2) defining the range of permissive hematopoietic cells by lineage and maturational stage. Another exciting area of research is the role of apoptosis in the pathogenesis of HIV infection.




Patricia Whitaker-Dowling, Ph.D.
E1255 Biomedical Science Tower
(412) 648-9492
Research Associate Professor, Department of Molecular Genetics and Biochemistry
University of Pittsburgh

Our main research effort concerns the phenomenon of viral interference; that is, the ability of mutant viruses to dominate in mixed infections with wild-type viruses. In the case of live virus vaccines, this is a particularly desirable trait. We have demonstrated that the cold-adapted vaccine strain for influenza A is a dominant mutant and are investigating the mechanism of this dominance. We are also pursuing the use of this dominant virus as an antiviral therapeutic agent for influenza infections of man. Our interests also include persistent viral infections. We are examining the genetic changes that are associated with the adaptation of acute cytolytic viruses into viruses that are capable of long term persistence in cell culture.




Garth D. Ehrlich, Ph.D.
730A Scaife Hall
(412) 648-9064
Associate Professor, Department of Medicine
University of Pittsburgh

Our laboratory is engaged in studying several aspects of human retroviral pathogenesis. Several current projects are aimed at elucidating the interaction of the various structural and functional domains of the HIV-1 envelope proteins by exchanging genetic information between isolated and laboratory proviral clones. As part of these studies, novel methods for recognizing sites suitable for silent mutagenesis have been developed into computer software programs, and this has been expanded practically to create several HIV-1 infectious clones carrying restriction sites which serve as vectors for a cassette mutagenesis strategy.

In collaboration with Dr. Peter Nara of the National Cancer Institute, we are determining the domains of the envelope proteins which interact with the immunodominant V3 loop of gp120. Our results suggest that there is "action at a distance", i.e. that there are mutations at a remote locus which interact with the V3 loop and contribute to the phenotype of viral neutralization. In collaboration with Dr. Charles Rinaldo of the Pittsburgh Multi-center AIDS Cohort Study, a program has been designed to look at the degree of viral variation within an individual host at a given time point and to assess the degree of evolution over time of the quasispecies in HIV-1 infected persons.

A separate project, in collaboration with Dr. Jerry Zack of UCLA, is to study T-cell receptor depletion in HIV-1 infected persons to investigate their loss of T-cells. The lab's efforts in this field are currently being expanded to look at the effect of HIV-1 infection on the T-cell repertoire in human liver/thymus reconstituted SCID mice.




Joseph C. Glorioso III, Ph.D.
E1246 Biomedical Science Tower
(412) 648-8105
Professor and Chairman, Department of Molecular Genetics and Biochemistry
University of Pittsburgh

The natural history of herpes simplex virus involves repeated cycles of recurrent infection initiated by endogenous latent virus residing in the peripheral nervous system. The overall aims of our research are: 1) to investigate the genetics and immunology of the HSV glycoproteins, 2) to understand the genetic basis of latency and neurovirulence, and 3) to develop HSV as a gene transfer vector for the central nervous system whereby nonviral genes can be expressed from the latent viral genome in a manner suitable for gene complementation therapy of human neurologic disease.




William F. Goins, Ph.D.
E1251 Biomedical Science Tower
(412) 648-9461
Research Associate Professor, Department of Molecular Genetics and Biochemistry
University Of Pittsburgh

Herpes simplex virus (HSV) displays a natural propensity for establishment of a latent or quiescent infection of peripheral neurons following primary infection of the host. Latently infected neurons shown an extremely restricted and characteristic pattern of viral gene expression. A sole viral transcription unit has been shown to function during latency and encodes a series of latency-associated transcripts (LATs). A major goal of my work has been to characterize the viral promoter-regulatory regions for this transcription unit and identify cellular transcription factors present within neurons that interact with cis-acting sites within the LAT promoter-regulatory region. We have demonstrated that two latency active promoters are present within the LAT region, one containing a TATA box and transacting factor binding sites typical of most eukaryotic RNA polymerase II genes, while the second promoter lacks both TATA and CAAT box homologies and resembles the promoters of RNA polymerase II class cellular housekeeping genes. This promoter, or modifications of this promoter-regulator, may be ideal for expressing foreign genes from HSV vectors in neurons of the peripheral nervous system or in brain.




Phalguni Gupta, Ph.D.
426 Parran Hall, GSPH
(412) 624-7998
Associate Professor, Department Infectious Diseases and Microbiology
Graduate School of Public Health, University of Pittsburgh

Our laboratory, the Pittsburgh Retrovirus Laboratory, plays a central role in many virological studies related to human immunodeficiency virus (HIV) at the University of Pittsburgh. Studies are being conducted to elucidate the mechanism of HIV induced pathogenesis at the cellular and molecular level. This study has demonstrated the presence of HIV with distinct biologic and genetic properties that are associated with different stages of HIV disease. We have recently shown that enhanced expression of HIV RNA is associated with the development of AIDS. Consequently, HIV-infected subjects who remain asymptomatic for a long period of time harbor low levels of HIV-1 RNA. Recent studies have indicated that lower expression of viral RNA could be due to a defect in translocation of proviral DNA into nucleus which results in loss of integration of proviral DNA into host chromosome. Studies are also being done to investigate the mechanism of cell-to-cell transmission of HIV and to examine the interaction of HIV and herpes viruses which may act as cofactors in the development of AIDS. The retrovirus laboratory is also involved in multicenter epidemiological studies on the natural history of AIDS which examine genetic variation of HIV and the latency period of HIV infection in infected subjects.




Graham F. Hatfull, Ph.D.
378 Crawford Hall
(412) 624-6975
Assistant Professor, Department of Biological Sciences
University of Pittsburgh

Mycobacteriophage L5 is a temperate phage of the mycobacteria, an important group of organisms that includes the causative agents of tuberculosis and leprosy. A detailed molecular analysis of L5 is aimed at understanding the mechanisms of gene expression in mycobacteria and in developing tools for mycobacterial genetic manipulation. Phage-derived tools such as integration-proficient vectors, suitable genetic selectable genes, and expression signals contribute to the goal of constructing multi-disease single shot recombinant BCG vaccines. In addition, recombinant mycobacteriophages carrying luciferase reporter genes offer a novel approach for the rapid diagnosis and drug susceptibility testing of mycobacterial infections including tuberculosis.



Roger W. Hendrix, Ph.D.
340 Langley Hall
(412) 624-4674
Professor, Department of Biological Sciences
University of Pittsburgh

We use the double stranded DNA bacteriophages as models to study mechanisms of virus assembly and virus structure. A major interest is the head assembly of the E. coli phage HK97. This phage shows multiple transitions in the state of the major head protein as it passes along the assembly pathway, including: polypeptide folding under the influence of the host GroE chaperonins; assembly into hexamers and pentamers; assembly from hexamers and pentamers into a T=7 shell with a concomitant conformational change; cleavage (by a phage-encoded protease that co-assembles with the head protein) to remove about 1/4 of each subunit and induce another conformational change; a third, major conformational change triggered by DNA packaging; and autocatalytic covalent crosslinking (amide bond) triggered by the major conformational change. Other current interests include structure and assembly of phage lambda tails, developing unconventional cloning vectors based on lambda , and translational regulation of phage head and tail genes.



Monto Ho, M.D.
A427 Parran Hall/GSPH
(412) 624-2692
Professor. Department of Infectious Diseases and Microbiology
Graduate School of Public Health, University of Pittsburgh

Our recent research interests are in the area of pathogenesis, treatment and evaluation of viral diseases, particularly those caused by human cytomegalovirus, Epstein Barr virus and human immunodeficiency virus. We discovered the transmission of CMV in transplant recipients by organs from seropositive donors, and we also outlined the major role of primary EBV infections in the development of lymphoproliferative disorders and lymphomas. In the area of HIV, our group also used infusion in a phase 1 study of autologous in vitro grown CD8+ cytotoxic T lymphocytes in HIV infected subjects as a potential antiviral treatment modality. Several other projects are ongoing in which molecular methodology is used to solve clinical and epidemiological problems in virology.



Frank Jenkins Ph. D.
Iroquois building
(412) 624 4630
Associate Professor, Department of Pathology
University of Pittsburgh

My laboratory is involved in the investigation of three focused areas of herpesvirus biology growth and latency.
In the first, we are studying functions of proteins made by HSV-1, particularly the those encoded by the HSV-1 UL37 gene. We have shown that this gene, whose exact function remains unknown, encodes proteins that form an association with a well characterized protein involved in DNA replication and possibly late gene expression. We are currently studying the function(s) of this complex and possible roles of the UL37 protein in the viral replication cycle.

In the second area, our laboratory is involved in studies designed to unravel the interactions between the endocrine, nervous and immune systems in the maintenance and reactivation of latent HSV-1 infections within the trigeminal ganglia. We are currently using a mouse model of HSV-1 latency and reactivation to analyze the role of different immune cells and cytokines in this process. My third area of Research involves epidemiological studies of the recently discovered Human herpes virus 6 (HHV-6) in normal and immunocompromised adults. We are interested in learning what percentage of the adult population has latent HHV-6 infections, how often the latent infections reactivate, and what consequences reactivation and viral replication have on the immune function of both T cells and macrophages.



Jeanne Jordan, M.D.
Rm 446 MWHRI, 204 Craft Avenue
(412) 641 4104
Department of Pathology, Magee Womens Hospital Research Institute

My virology research has dealt with the association of Human Parvovirus B19 and fetal demise; most notably that of non-immune hydrops fetalis. We have examined hydropic fetal tissues and corresponding placentas using the polymerase chain reaction assay and in situ hybridization to detect B19 DNA, and have found that 18% of all non-immune hydrops fetalis cases of unknown etiology contain Human Parvovirus B19 DNA. Future research efforts will encompass estimating the incidence of Human Parvovirus B19 infection in fetal demise that is not associated with hydrops fetalis.

Another of our interests is to identify the range of cell types infected by this virus and to relate this to its pathogenesis. In addition, we plan to determine whether a newly proposed viral receptor, the P blood group antigen, is consistently present on the non-euthyroid cell types found harboring the virus. We are also developing molecular-based diagnostic tools for the rapid identification of infectious diseases important to maternal-fetal medicine, including Human Parvovirus B19, Human Papilloma Virus and four Candida species.




Saleem A. Khan, Ph.D.
W1243 Biomedical Science Tower
(412) 648-9019
Professor, Department of Molecular Genetics and Biochemistry
University of Pittsburgh

We are involved in the characterization of proteins and DNA sequences required for the replication of the genomes of human papilloma viruses (HPVs). We have shown that plasmids containing the long control region of HPVs replicate in human cells when cotransfected with plasmids expressing the E1 and E2 proteins of HPVs. Our studies have localized and defined the HPV-18 origin of replication to within a 118 basepair region. Although the E2 protein is necessary for HPV replication, higher levels of this protein appear to inhibit replication. The E1 and E2 proteins of different HPVs are quite homologous. However, our results show that these proteins have specificity in DNA replication. We have overexpressed the E1 and E2 proteins of HPVs using the baculovirus system and are investigating their sequence-specific DNA binding and replication activities. We are also developing an in vitro system for the replication of HPVs using nuclear extracts from human cells and the E1 and E2 proteins of HPVs. A final goal is to develop an HPV-based vector for the delivery of genes into human cells.



Paul. R. Kinchington, Ph.D.
1020 Eye & Ear Institute
(412) 647-6319
Associate Professor of Ophthalmology and of Molecular Genetics and Biochemistry
Director, Molecular Biology Module of Ophthalmology Core Facility

Our research efforts are directed towards understanding the molecular basis for pathogenesis of two viral agents which cause ocular problems, namely Varicella zoster virus (VZV) and human Adenovirus.

VZV is the agent of chicken pox and shingles. While often considered benign, these diseases are serious and can lead to blindness, pain, and even mortality in the adult and the patient immune compromised through disease, age or iatrogenic causes. Our efforts are to ultimately identify new targets for antivirals and new proteins for subunit vaccine development. A group of proteins which surprisingly are candidates for both are the proteins involved in the control of viral transcription. Our research has centered around the large, essential viral encoded protein called IE62, which is the major viral transcriptional activator. We are studying how this protein functions to mediate transcriptional activation and with which cellular and viral proteins it interacts with to carry out these processes. Using biochemical and genetic manipulation techniques of both eukaryotic expression systems and of the VZV genome, we aim to delineate the importance of such interactions on the VZV infectious process and whether they can be inhibited. A recent discovery that IE62 is itself controlled by a protein kinase in a fashion similar to that found in many cellular control pathways has highlighted VZV is a new model to study the role of phosphorylation on protein function. Finally, we know that IE62 is also a major component to which immunity is directed, and collaborative studies with Dr Ann Arvin of Stanford University have focused upon the role of this protein in development of human immunity to VZV.

The second virus of ocular importance is Adenovirus, which causes infectious epidemic conjunctivitis. Our studies focus on an ocular model of adenovirus pathogenesis that has been developed in collaboration with Dr Y. J. Gordon of the Ophthalmology Research Center. This model has been used to identify novel antiviral strategies aimed at preventing adenovirus replication, such as cidofovir, which is now the first effective antiviral to adenovirus ocular disease. The model is now being used to determine the effects of the development of antiviral resistance upon pathogenicity and disease.

John W. Mellors, M.D.
A-West Montefiore Hospital
(412) 648-6397
Assistant Professor, Department of Infectious Diseases and Microbiology
Graduate School of Public Health, University of Pittsburgh

I am interested in antiviral therapy of HIV infection. This includes the evaluation of new antiretroviral compounds, both in vitro and in clinical trials, as well as studies on the mechanisms of antiviral drug resistance. The Latter is an important obstacle to effective long term treatment of patients with HIV infection and effective strategies are needed to prevent the emergence of and treat drug resistant HIV.

The primary focus of research is to detect and characterize viral variants that have altered sensitivity to antiviral compounds. Resistant viral variants are either selected in tissue culture or identified in clinical samples and characterized in terms of biological properties, cross-resistance patterns, and the genetic and biochemical changes that are responsible for drug resistance. This line of research can elucidate the mechanisms of drug action and drug resistance, identify alternative drug therapies for resistant virus, and help devise strategies to prevent the development of drug resistance.

Other research interests include HIV-1 infection of monocyte-macrophages (important target cells for HIV), antiviral drug interactions, and the development of rapid systems to screen compounds for antiretroviral activity and to test clinical HIV isolates for drug sensitivity.



Ronald C. Montelaro, Ph.D.
W1144 Biomedical Science Tower
(412) 648-8869
Professor, Department of Molecular Genetics and Biochemistry
University of Pittsburgh

Our research program is a comprehensive interdisciplinary effort to elucidate at the molecular level the various mechanisms of lentivirus persistence and pathogenesis and to apply this information in designing and evaluating various strategies for the prevention or control of lentiviral infection and disease. A major focus of our current efforts is the characterization of protective and pathogenic immune responses during persistent infections by animal and human lentiviruses and the evaluation of various strategies for the development of effective lentiviral vaccines. Lentiviral systems under investigation include equine infectious anemia virus (EIAV), simian immunodeficiency virus (SIV), feline immunodeficiency virus (FIV), and the human immunodeficiency virus (HIV-1). The projects applied to these viral systems include the computer modeling of viral proteins to define functional a antigenic domains, the experimental analyses of immunogenic determinants and immune responses by recombinant and synthetic peptide methodologies, and the production and evaluation of vaccine candidates in animal systems.




George J. Pazin, M.D., M.S.
W931 Montefiore Hospital
(412) 648-6616
Associate Professor, Infectious Diseases, Department of Medicine
University of Pittsburgh

My interest is in clinical trials in treatment of human immunodeficiency virus (HIV) infections through the Pittsburgh Treatment Evaluation Unit (PTEU). I am involved in treatment and counseling regarding oral and genital herpes virus infections, varicella-zoster infections and sexually transmitted diseases. The clinical trials involve phase 1 and 2 safety, toxicity, pharmacokinetics and efficacy trials of nucleotide analogue and non-nucleotide inhibitors of reverse transcriptase and other retroviral enzyme inhibitors. Other treatment modalities such as the effects of stress reduction or hypnosis on recurrent genital herpes and immunologic parameters may be studied in the future.



Bruce A. Phillips, Ph.D.
W1251 Biomedical Science Tower
(412) 648-9023
Professor, Department of Molecular Genetics and Biochemistry
University of Pittsburgh

In collaboration with others, I am attempting to devise a novel, RNA viral-based, vector for application in animal and human gene therapy. Conceptually, the MART (MART=mRNA Auto Replication and Translation) vector will contain: (1) the cDNA for any gene whose expression is desired in eukaryotic cells; 2) those DNA sequences encoding the RNA replicase and protease genes of a non-cytocidal human picornavirus. The vector will be transcribed into an RNA molecule in vitro, and the RNA transfected into target cells. We expect the RNA molecule to direct the protein synthesis of the cellular and viral genes such that the RNA will replicate itself in the cytoplasm of the cell while producing therapeutic amounts of the cellular gene product. This approach is expected to bypass any damage to cellular DNA, a possible consequence of gene therapy approaches employing DNA-based molecules. Based on feasibility studies using a MART constructed with LacZ (_-galactosidase) as a reporter gene, we hope to utilize MART vectors to target specific cells with therapeutic or antiviral proteins. With that aim in mind, we will attempt to encapsidate MART RNA molecules into viral particles thus utilizing viral capsids to specifically target cells for MART "infection".




Charles R. Rinaldo, Jr., Ph.D.
A417 Parran Hall/GSPH
(412) 624-3928
Professor, Departments of Pathology and Infectious Diseases and Microbiology
Graduate School of Public Health, University of Pittsburgh

Our laboratory is investigating cellular immune parameters of the natural history of human immunodeficiency virus (HIV) infection in a cohort study of over 1,000 homosexual men. Specific interests are in delineating various aspects of interaction of HIV with dendritic cells, particularly cytokine production and viral replication as assessed by biologic and molecular techniques. There is evidence that these as yet ill-defined cells have a central role in the immunopathogenesis of HIV and other viral infections.

The second major emphasis in the laboratory is the characterization of cytotoxic T lymphocyte (CTL) reactivity to HIV infection. Such CTL responses are considered to be of primary importance in host immunity to this retroviral infection. Anti-HIV CTL reactivity is being analyzed by standard lytic assays, as well as CTL precursor frequency by limiting dilution assays and the fine specificity of cloned CTL by HIV peptide mapping.

We are also investigating various aspects of diagnosis, drug sensitivity and immunopathogenesis of human herpesvirus infections in the Clinical Virology Laboratory of UPMC. These studies include development and application of polymerase chain reaction (PCR)-based methods for diagnosis of clinically relevant cytomegalovirus (CMV) and human herpesvirus types 6 and 7 (HHV6/HHV7) infections in organ transplant recipients and AIDS patients, PCR-based methods for characterization of the sensitivity of CMV to antiviral chemotherapeutic agents, and cellular immune reactivity to CMV and HSV infections.




Paul D. Robbins, Ph.D.
W1246 Biomedical Science Tower
(412) 648-9268
Assistant Professor, Director, Virus Vector Core Facility
Department of Molecular Genetics and Biochemistry, University of Pittsburgh

My research interests fall in two distinct areas. One area of interest is concerned with understanding how tumor suppressor genes function to maintain normal cell growth. In this regard, my laboratory has been examining the ability of two tumor suppressor gene products, Rb and p53, to regulate transcription and the cell cycle. Since certain cyclins, proteins regulating cell division, can either bind to and/or phosphorylate Rb and p53, we recently have extended our studies to examine transcriptional regulation by the G1 cyclins. The second area of interest is concerned with treating human disease with gene therapy. As director of the Virus Vector Core facility, I have been involved in the construction and utilization of both retroviral and Adeno-associated Virus vectors carrying therapeutic genes for gene therapy treatment for Gaucher disease, arthritis, and cancer.




David T. Rowe, Ph.D.
435 Parran Hall/GSPH
(412) 624-1529
Assistant Professor, Department of Infectious Diseases and Microbiology
Graduate School of Public Health, University of Pittsburgh

My laboratory has several ongoing projects that investigate latent infection by Epstein-Barr virus. In the human population greater than 90% of all individuals harbor EBV latently in the B subset of peripheral blood lymphocytes. A vigilant host immune surveillance normally holds the virus in check, but problems (lymphoproliferative disorders) do arise when this surveillance fails. We are using RNA and DNA polymerase chain reaction to explore control of viral gene expression in latency using blood cells from human volunteers. In addition we are studying the functions of two of the gene products of the virus, EBNA4 and TP. EBNA4 (Epstein-Barr virus nuclear antigen 4) is the first gene product made by the virus when it initially infects B cells and has a central role in establishing the immortal proliferative phenotype. EBNA4 is a phosphoprotein whose phosphorylation state is cell cycle stage dependent and whose function appears to be involved in early G1 progression decisions. TP (terminal protein) is the product of the only gene whose RNA is consistently detected in B cells purified from blood samples of normal individuals. This makes TP the best candidate for a latency-inducing or latency-maintaining viral gene. TP is a membrane protein that interacts with components of the signal transduction machinery normally responsible for activating the B cells in response to antigenic stimulation. We anticipate that our studies will lead to a better understanding of how latency is achieved and that should suggest ways to intervene against latent virus when immune surveillance is compromised.




Frederick L Ruben, M.D.
6 West Montefiore Hospital
(412) 648-6411
Professor of Medicine and Head, Infectious Diseases, Unit\Montefiore University Hospital
Department of Medicine, University of Pittsburgh

I am interested in viral vaccines, particularly in activated influenza vaccines. I am exploring and promoting a wider use of vaccines to prevent influenza and pneumococcal pneumonia in the hospital setting.




Clayton A. Wiley M.D., Ph.D.
A 506, Scaife Hall
University of Pittsburgh Medical Center
(412) 648-9459
Professor, Director of Neuropathology, Department of Pathology
University of Pittsburgh

My research concentrates on the pathogenesis of viral induced nervous system diseases. Viruses damage the nervous system either by direct infection of neural cells or by secondary effects of the host immune response. In recent years, our studies have focused on central nervous system (CNS) retroviral infections. We have pioneered the use of molecular techniques to quantitatively assess viral burden, and have applied it assessment of neurologic damage, the productions of cytokines and the effects of potential neurotoxins. In addition, we have several ongoing clinical studies investigating the role of specific MHC haplotypes in modulating the development of CNS disease after retroviral infection. . We have expanded these in vivo studies to include in vitro nervous system infections. Using embryonic human and murine nervous system cultures, we are evaluating the effects of various retroviral proteins and immune cytokines on CNS cell function and viability. Implantation of these in SCID mice have allowed us to study experimental HIV-mediated human neurologic damage. In particular, interuterine and perinatal infection by neurotropic murine retroviruses leads to nervous system disease that in many ways mimics diseases seen in immune compromised patients and in normal aging.



Julius S. Youngner, Sc.D.
E1254 Biomedical Science Tower
(412) 648-9459
Distinguished Service Professor Emeritus, Department of Molecular Genetics and Biochemistry
University of Pittsburgh

Our laboratory is using biochemical and molecular techniques to define the phenotypes that evolve during persistent viral infections. In particular, we are investigating the dominance of mutants recovered from persistence over the replication of wild-type parental virus during mixed infection and the mechanism of this trans dominance. The use of trans-dominant mutants as a new antiviral strategy is also being explored.


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