Felicia D Goodrum Sterling
- Associate Professor, Immunobiology
- Associate Professor, BIO5 Institute
- Director, Graduate Program in Immunobiology
- Associate Professor, Cellular and Molecular Medicine
- Associate Professor, Cancer Biology - GIDP
- Associate Professor, Genetics - GIDP
- Associate Professor, Molecular and Cellular Biology
Felicia Goodrum graduated with her Ph.D. from Wake Forest University and then trained as a postdoctoral fellow with Thomas Shenk at Princeton University where she was a Leukemia and Lymphoma Society Fellow and Special Fellow. Dr. Goodrum joined the faculty at the University of Arizona in the Department of Immunobiology and the BIO5 Institute in 2006 and is an Assoicate Professor. Dr. Goodrum is the recipient of the Pew Scholar in Biomedical Sciences Award and the Presidential Award for Early Career Scientists and Engineers. Dr. Goodrum's work throughout her career has focused on complex interaction between viruses and their host and is currently focused on the mechanisms of viral persistence of human cytomegalovirus.
- Ph.D. Molecular Genetics
- Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States
- Function of the early region 1B-55kD protein of adenovirus in promoting cell cycle-independent virus replication and mediating mRNA transport
- B.S. Biology
- Virginia Tech, Blacksburg, Virginia, United States
- Associate Professor, University of Arizona, College of Medicine, Department of Immunobiology (2013 - Ongoing)
- Assistant Professor, University of Arizona, College of Medicine, Department of Immunobiology (2006 - 2013)
- Postdoctoral Fellow, Princeton University, Department of Molecular Biology (1999 - 2006)
- Postdoctoral Fellow, Wake Forest University, Department of Microbiology and Immunology (1998 - 1999)
- Jamie McNew Endowed Lecturer
- University of Minnesota, Spring 2014
- Distinguished Speaker
- Wake Forest University, Spring 2013
- Robert Honess Lecturer
- American Society of Virology, Spring 2012
- Top 25 Reviewers
- Journal of Virology, Spring 2012
- Priscilla A. Schaffer Lecturship
- Priscilla A. Schaffer Fund, Spring 2010
- Kavli Fellow
- National Academy of Sciences, Spring 2009
- Top 20 Reviewers
- Journal of Virology, Spring 2009
- Junior Faculty International Conference Travel Award
- University of Arizona, Spring 2008
- Pew Scholar in Biomedical Sciences
- Pew Charitable Trust, Spring 2008
- Young Investigator Award
- Human Frontiers in Science Program, Spring 2008
- Howard Temin Career Development Award
- National Cancer Institute, Spring 2005
- Leukemia and Lymphoma Society, Special Fellow
- Leukemia and Lymphoma Society, Spring 2003
- Leukemia and Lymphoma Society, Fellow
- Leukemia and Lymphoma Society, Spring 2000
Our broad research interests are to understand the molecular underpinnings of viral persistence using herpesviruses as a model system.
I am interested in helping students written and oral communication skills to enhance the competitive advantage of my students.
DissertationCMM 920 (Fall 2016)
Introduction to ResearchMCB 795A (Fall 2016)
ResearchCMM 900 (Fall 2016)
Scientific GrantsmanshipIMB 521 (Fall 2016)
DissertationCMM 920 (Spring 2016)
DissertationCMM 920 (Fall 2015)
ResearchCMM 900 (Fall 2015)
Scientific GrantsmanshipIMB 521 (Fall 2015)
DissertationCMM 920 (Spring 2015)
DissertationGENE 920 (Spring 2015)
Honors Independent StudyMCB 499H (Spring 2015)
Introduction to ResearchMCB 795A (Spring 2015)
ResearchCMM 900 (Spring 2015)
DissertationCMM 920 (Fall 2014)
DissertationGENE 920 (Fall 2014)
Honors Independent StudyMCB 499H (Fall 2014)
ResearchCMM 900 (Fall 2014)
Scientific GrantsmanshipIMB 521 (Fall 2014)
Directed ResearchNSCS 492 (Spring 2014)
Introduction to ResearchMCB 795A (Spring 2014)
ResearchCMM 900 (Spring 2014)
ResearchGENE 900 (Spring 2014)
Directed ResearchNSCS 492 (Fall 2013)
Introduction to ResearchMCB 795A (Fall 2013)
ResearchCMM 900 (Fall 2013)
ResearchGENE 900 (Fall 2013)
Scientific GrantsmanshipIMB 521 (Fall 2013)
ResearchIMB 900 (Summer I 2013)
- Buehler, J., Zeltzer, S., Reitsma, J., Petrucelli, A., Umashankar, M., Rak, M., Zagallo, P., Schroeder, J., Terhune, S., & Goodrum, F. (2016). Opposing Regulation of the EGF Receptor: A Molecular Switch Controlling Cytomegalovirus Latency and Replication. PLoS pathogens, 12(5), e1005655.More infoHerpesviruses persist indefinitely in their host through complex and poorly defined interactions that mediate latent, chronic or productive states of infection. Human cytomegalovirus (CMV or HCMV), a ubiquitous β-herpesvirus, coordinates the expression of two viral genes, UL135 and UL138, which have opposing roles in regulating viral replication. UL135 promotes reactivation from latency and virus replication, in part, by overcoming replication-suppressive effects of UL138. The mechanism by which UL135 and UL138 oppose one another is not known. We identified viral and host proteins interacting with UL138 protein (pUL138) to begin to define the mechanisms by which pUL135 and pUL138 function. We show that pUL135 and pUL138 regulate the viral cycle by targeting that same receptor tyrosine kinase (RTK) epidermal growth factor receptor (EGFR). EGFR is a major homeostatic regulator involved in cellular proliferation, differentiation, and survival, making it an ideal target for viral manipulation during infection. pUL135 promotes internalization and turnover of EGFR from the cell surface, whereas pUL138 preserves surface expression and activation of EGFR. We show that activated EGFR is sequestered within the infection-induced, juxtanuclear viral assembly compartment and is unresponsive to stress. Intriguingly, these findings suggest that CMV insulates active EGFR in the cell and that pUL135 and pUL138 function to fine-tune EGFR levels at the cell surface to allow the infected cell to respond to extracellular cues. Consistent with the role of pUL135 in promoting replication, inhibition of EGFR or the downstream phosphoinositide 3-kinase (PI3K) favors reactivation from latency and replication. We propose a model whereby pUL135 and pUL138 together with EGFR comprise a molecular switch that regulates states of latency and replication in HCMV infection by regulating EGFR trafficking to fine tune EGFR signaling.
- Caviness, K., Bughio, F., Crawford, L. B., Streblow, D. N., Nelson, J. A., Caposio, P., & Goodrum, F. (2016). Complex Interplay of the UL136 Isoforms Balances Cytomegalovirus Replication and Latency. mBio, 7(2), e01986.More infoHuman cytomegalovirus (HCMV), a betaherpesvirus, persists indefinitely in the human host through poorly understood mechanisms. The UL136 gene is carried within a genetic locus important to HCMV latency termed the UL133/8 locus, which also carries UL133, UL135, and UL138. Previously, we demonstrated that UL136 is expressed as five protein isoforms ranging from 33-kDa to 19-kDa, arising from alternative transcription and, likely, translation initiation mechanisms. We previously showed that the UL136 isoforms are largely dispensable for virus infection in fibroblasts, a model for productive virus replication. In our current work, UL136 has emerged as a complex regulator of HCMV infection in multiple contexts of infection relevant to HCMV persistence: in an endothelial cell (EC) model of chronic infection, in a CD34(+) hematopoietic progenitor cell (HPC) model of latency, and in an in vivo NOD-scid IL2Rγc (null) humanized (huNSG) mouse model for latency. The 33- and 26-kDa isoforms promote replication, while the 23- and 19-kDa isoforms suppress replication in ECs, in CD34(+) HPCs, and in huNSG mice. The role of the 25-kDa isoform is context dependent and influences the activity of the other isoforms. These isoforms localize throughout the secretory pathway, and loss of the 33- and 26-kDa UL136 isoforms results in virus maturation defects in ECs. This work reveals an intriguing functional interplay between protein isoforms that impacts virus replication, latency, and dissemination, contributing to the overall role of the UL133/8 locus in HCMV infection.
- Goodrum, F. (2016). Human Cytomegalovirus Latency: Approaching the Gordian Knot. Annual Reviews in Virology, 333-357.More infoHerpesviruses have evolved exquisite virus-host interactions that co-opt or evade a number of host pathways to enable the viruses to persist. Persistence of human cytomegalovirus (CMV), the prototypical betaherpesvirus, is particularly complex in the host organism. Depending on host physiology and the cell types infected, CMV persistence comprises latent, chronic, and productive states that may occur concurrently. Viral latency is a central strategy by which herpesviruses ensure their lifelong persistence. Although much remains to be defined about the virus-host interactions important to CMV latency, it is clear that checkpoints composed of viral and cellular factors exist to either maintain a latent state or initiate productive replication in response to host cues. CMV offers a rich platform for defining the virus-host interactions and understanding the host biology important to viral latency. This review describes current understanding of the virus-host interactions that contribute to viral latency and reactivation.
- Kim, J. H., Collins-McMillen, D., Buehler, J. C., Goodrum, F. D., & Yurochko, A. D. (2016). HCMV requires EGFR signaling to enter and initiate the early steps in the establishment of latency in CD34+ human progenitor cells. Journal of virology.More infoThe establishment of human cytomegalovirus (HCMV) latency and persistence relies on the successful infection of hematopoietic cells, which serve as sites of viral persistence and contribute to viral spread. Here, using blocking antibodies and pharmacological inhibitors, we document that HCMV activation of the epidermal growth factor receptor (EGFR) and downstream phosphatidylinositol-3-kinase (PI (3)K) mediates viral entry into CD34+ human progenitor cells (HPCs), resulting in distinct cellular trafficking and nuclear translocation of the virus compared to other immune cells, such as we have documented in monocytes. We argue that the EGFR allows HCMV to regulate the cellular functions of these replication-restricted cells via its signaling activity following viral binding. In addition to regulating HCMV entry/trafficking, EGFR signaling may also shape the early steps required for the successful establishment of viral latency in CD34+ cells, as pharmacological inhibition of EGFR increases the transcription of lytic IE1/IE2 mRNA, while curbing the expression of latency-associated UL138 mRNA. EGFR signaling following infection of CD34+ HPCs may also contribute to changes in hematopoietic potential, as treatment with the EGFRK inhibitor AG1478 alters the expression of the cellular hematopoietic cytokine IL-12 in HCMV-infected, but not in mock-infected cells. These findings, along with our previous work in monocytes, suggest that EGFR likely serves as an important determinant of HCMV tropism for select subsets of hematopoietic cells. Moreover, our new data suggest that EGFR is a key receptor for efficient viral entry and that the ensuing signaling regulates important early events required for successful infection of CD34+ HPCs by HCMV.
- Lee, S. H., Caviness, K., Albright, E. R., Lee, J., Gelbmann, C. B., Rak, M., Goodrum, F., & Kalejta, R. F. (2016). Long and Short Isoforms of the Human Cytomegalovirus UL138 Protein Silence IE Transcription and Promote Latency. Journal of virology, 90(20), 9483-94.More infoThe UL133-138 locus present in clinical strains of human cytomegalovirus (HCMV) encodes proteins required for latency and reactivation in CD34(+) hematopoietic progenitor cells and virion maturation in endothelial cells. The encoded proteins form multiple homo- and hetero-interactions and localize within secretory membranes. One of these genes, UL136 gene, is expressed as at least five different protein isoforms with overlapping and unique functions. Here we show that another gene from this locus, the UL138 gene, also generates more than one protein isoform. A long form of UL138 (pUL138-L) initiates translation from codon 1, possesses an amino-terminal signal sequence, and is a type one integral membrane protein. Here we identify a short protein isoform (pUL138-S) initiating from codon 16 that displays a subcellular localization similar to that of pUL138-L. Reporter, short-term transcription, and long-term virus production assays revealed that both pUL138-L and pUL138-S are able to suppress major immediate early (IE) gene transcription and the generation of infectious virions in cells in which HCMV latency is studied. The long form appears to be more potent at silencing IE transcription shortly after infection, while the short form seems more potent at restricting progeny virion production at later times, indicating that both isoforms of UL138 likely cooperate to promote HCMV latency.
- Bughio, F., Umashankar, M., Wilson, J., & Goodrum, F. (2015). Human Cytomegalovirus UL135 and UL136 Genes Are Required for Postentry Tropism in Endothelial Cells. Journal of virology, 89(13), 6536-50.More infoEndothelial cells (ECs) are a critical target of viruses, and infection of the endothelium represents a defining point in viral pathogenesis. Human cytomegalovirus (HCMV), the prototypical betaherpesvirus, encodes proteins specialized for entry into ECs and delivery of the genome to the nuclei of ECs. Virus strains competent to enter ECs replicate with differing efficiencies, suggesting that the virus encodes genes for postentry tropism in ECs. We previously reported a specific requirement for the UL133/8 locus of HCMV for replication in ECs. The UL133/8 locus harbors four genes: UL133, UL135, UL136, and UL138. In this study, we find that while UL133 and UL138 are dispensable for replication in ECs, both UL135 and UL136 are important. These genes are not required for virus entry or the expression of viral genes. The phenotypes associated with disruption of either gene reflect phenotypes observed for the UL133/8NULL virus, which lacks the entire UL133/8 locus, but are largely distinct from one another. Viruses lacking UL135 fail to properly envelop capsids in the cytoplasm, produce fewer dense bodies (DB) than the wild-type (WT) virus, and are unable to incorporate viral products into multivesicular bodies (MVB). Viruses lacking UL136 also fail to properly envelop virions and produce larger dense bodies than the WT virus. Our results indicate roles for the UL135 and UL136 proteins in commandeering host membrane-trafficking pathways for virus maturation. UL135 and UL136 represent the first HCMV genes crucial for early- to late-stage tropism in ECs.
- Goodrum, F., & Bughio, F. (2015). Viral infection at the endothelium. Oncotarget, 6(29), 26541-2.
- Caviness, K., Cicchini, L., Rak, M., Umashankar, M., & Goodrum, F. (2014). Complex expression of the UL136 gene of human cytomegalovirus results in multiple protein isoforms with unique roles in replication. Journal of virology, 88(24), 14412-25.More infoHuman cytomegalovirus (HCMV) is a complex DNA virus with a 230-kb genome encoding 170 and up to 750 proteins. The upper limit of this coding capacity suggests the evolution of complex mechanisms to substantially increase the coding potential from the 230-kb genome. Our work examines the complexity of one gene, UL136, encoded within the ULb' region of the genome that is lost during serial passage of HCMV in cultured fibroblasts. UL136 is expressed as five protein isoforms. We mapped these isoforms and demonstrate that they originate from both a complex transcriptional profile and, possibly, the usage of multiple translation initiation sites. Intriguingly, the pUL136 isoforms exhibited distinct subcellular distributions with varying association with the Golgi apparatus. The subcellular localization of membrane-bound isoforms of UL136 differed between when they were expressed exogenously and when they were expressed in the context of viral infection, suggesting that the trafficking of these isoforms is mediated by infection-specific factors. While UL136, like most ULb' genes, was dispensable for replication in fibroblasts, the soluble 23- and 19-kDa isoforms suppressed virus replication. In CD34(+) hematopoietic progenitor cells (HPCs) infected in vitro, disruption of the 23- and 19-kDa isoforms resulted in increased replication and a loss of the latency phenotype, similar to the effects of the UL138 latency determinant encoded within the same genetic locus. Our work suggests a complex interplay between the UL136 isoforms which balances viral replication in multiple cell types and likely contributes to the cell type-dependent phenotypes of the UL133/8 locus and the outcome of HCMV infection.
- Li, G., Rak, M., Nguyen, C. C., Umashankar, M., Goodrum, F. D., & Kamil, J. P. (2014). An epistatic relationship between the viral protein kinase UL97 and the UL133-UL138 latency locus during the human cytomegalovirus lytic cycle. Journal of virology, 88(11), 6047-60.More infoWe report that UL133-UL138 (UL133/8), a transcriptional unit within the ULb' region (ULb') of the human cytomegalovirus (HCMV) genome, and UL97, a viral protein kinase encoded by HCMV, play epistatic roles in facilitating progression of the viral lytic cycle. In studies with HCMV strain TB40/E, pharmacological blockade or genetic ablation of UL97 significantly reduced the levels of mRNA and protein for IE2 and viral early and early-late genes during a second wave of viral gene expression that commenced at between 24 and 48 h postinfection. These effects were accompanied by significant defects in viral DNA synthesis and viral replication. Interestingly, deletion of UL133/8 likewise caused significant defects in viral DNA synthesis, viral gene expression, and viral replication, which were not exacerbated upon UL97 inhibition. When UL133/8 was restored to HCMV laboratory strain AD169, which otherwise lacks the locus, the resulting recombinant virus replicated similarly to the parental virus. However, during UL97 inhibitor treatment, the virus in which UL133/8 was restored showed significantly exacerbated defects in viral DNA synthesis, viral gene expression, and production of infectious progeny virus, thus recapitulating the differences between wild-type TB40/E and its UL133/8-null derivative. Phenotypic evaluation of mutants null for specific open reading frames within UL133/8 revealed a role for UL135 in promoting viral gene expression, viral DNA synthesis, and viral replication, which depended on UL97. Taken together, our findings suggest that UL97 and UL135 play interdependent roles in promoting the progression of a second phase of the viral lytic cycle and that these roles are crucial for efficient viral replication.
- Sansoni, P., Vescovini, R., Fagnoni, F. F., Akbar, A., Arens, R., Chiu, Y., Cičin-Šain, L., Dechanet-Merville, J., Derhovanessian, E., Ferrando-Martinez, S., Franceschi, C., Frasca, D., Fulöp, T., Furman, D., Gkrania-Klotsas, E., Goodrum, F., Grubeck-Loebenstein, B., Hurme, M., Kern, F., , Lilleri, D., et al. (2014). New advances in CMV and immunosenescence. Experimental gerontology, 55, 54-62.More infoImmunosenescence, defined as the age-associated dysregulation and dysfunction of the immune system, is characterized by impaired protective immunity and decreased efficacy of vaccines. An increasing number of immunological, clinical and epidemiological studies suggest that persistent Cytomegalovirus (CMV) infection is associated with accelerated aging of the immune system and with several age-related diseases. However, current evidence on whether and how human CMV (HCMV) infection is implicated in immunosenescence and in age-related diseases remains incomplete and many aspects of CMV involvement in immune aging remain controversial. The attendees of the 4th International Workshop on "CMV & Immunosenescence", held in Parma, Italy, 25-27th March, 2013, presented and discussed data related to these open questions, which are reported in this commentary.
- Umashankar, M., & Goodrum, F. (2014). Hematopoietic long-term culture (hLTC) for human cytomegalovirus latency and reactivation. Methods in molecular biology (Clifton, N.J.), 1119, 99-112.More infoOf the many research challenges posed by human cytomegalovirus latency, perhaps the most notable is the requirement for primary hematopoietic cell culture. Culturing hematopoietic subpopulations while maintaining physiological relevance must be given utmost consideration. We describe a long-standing primary CD34(+) hematopoietic progenitor cell (HPCs) system as an experimental model to study human cytomegalovirus (HCMV) latency and reactivation. Key aspects of our model include infection of primary human CD34(+) HPCs prior to ex vivo expansion, maintenance of undifferentiated cells in a long-term culture with a stromal cell support, and an assay to quantitate infectious centers produced prior to and following a reactivation stimulus. Our method offers a unique way to quantitatively assess HCMV latency and reactivation to study the contribution of viral and host genes in latency and reactivation.
- Umashankar, M., Rak, M., Bughio, F., Zagallo, P., Caviness, K., & Goodrum, F. D. (2014). Antagonistic determinants controlling replicative and latent states of human cytomegalovirus infection. Journal of virology, 88(11), 5987-6002.More infoThe mechanisms by which viruses persist and particularly those by which viruses actively contribute to their own latency have been elusive. Here we report the existence of opposing functions encoded by genes within a polycistronic locus of the human cytomegalovirus (HCMV) genome that regulate cell type-dependent viral fates: replication and latency. The locus, referred to as the UL133-UL138 (UL133/8) locus, encodes four proteins, pUL133, pUL135, pUL136, and pUL138. As part of the ULb' region of the genome, the UL133/8 locus is lost upon serial passage of clinical strains of HCMV in cultured fibroblasts and is therefore considered dispensable for replication in this context. Strikingly, we could not reconstitute infection in permissive fibroblasts from bacterial artificial chromosome clones of the HCMV genome where UL135 alone was disrupted. The loss of UL135 resulted in complex phenotypes and could ultimately be overcome by infection at high multiplicities. The requirement for UL135 but not the entire locus led us to hypothesize that another gene in this locus suppressed virus replication in the absence of UL135. The defect associated with the loss of UL135 was largely rescued by the additional disruption of the UL138 latency determinant, indicating a requirement for UL135 for virus replication when UL138 is expressed. In the CD34(+) hematopoietic progenitor model of latency, viruses lacking only UL135 were defective for viral genome amplification and reactivation. Taken together, these data indicate that UL135 and UL138 comprise a molecular switch whereby UL135 is required to overcome UL138-mediated suppression of virus replication to balance states of latency and reactivation.
- Bughio, F., Elliott, D. A., & Goodrum, F. (2013). An endothelial cell-specific requirement for the UL133-UL138 locus of human cytomegalovirus for efficient virus maturation. Journal of virology, 87(6), 3062-75.More infoHuman cytomegalovirus (HCMV) infects a variety of cell types in humans, resulting in a varied pathogenesis in the immunocompromised host. Endothelial cells (ECs) are considered an important target of HCMV infection that may contribute to viral pathogenesis. Although the viral determinants important for entry into ECs are well defined, the molecular determinants regulating postentry tropism in ECs are not known. We previously identified the UL133-UL138 locus encoded within the clinical strain-specific ULb' region of the HCMV genome as important for the latent infection in CD34(+) hematopoietic progenitor cells (HPCs). Interestingly, this locus, while dispensable for replication in fibroblasts, was required for efficient replication in ECs infected with the TB40E or fusion-inducing factor X (FIX) HCMV strains. ECs infected with a virus lacking the entire locus (UL133-UL138(NULL) virus) complete the immediate-early and early phases of infection but are defective for infectious progeny virus production. ECs infected with UL133-UL138(NULL) virus exhibited striking differences in the organization of intracellular membranes and in the assembly of mature virions relative to ECs infected with wild-type (WT) virus. In UL133-UL138(NULL) virus-infected ECs, Golgi stacks were disrupted, and the viral assembly compartment characteristic of HCMV infection failed to form. Further, progeny virions in UL133-UL138(NULL) virus-infected ECs inefficiently acquired the virion tegument and secondary envelope. These defects were specific to infection in ECs and not observed in fibroblasts infected with UL133-UL138(NULL) virus, suggesting an EC-specific requirement for the UL133-UL138 locus for late stages of replication. To our knowledge, the UL133-UL138 locus represents the first cell-type-dependent, postentry tropism determinant required for viral maturation.
- Zalckvar, E., Paulus, C., Tillo, D., Asbach-Nitzsche, A., Lubling, Y., Winterling, C., Strieder, N., Mücke, K., Goodrum, F., Segal, E., & Nevels, M. (2013). Nucleosome maps of the human cytomegalovirus genome reveal a temporal switch in chromatin organization linked to a major IE protein. Proceedings of the National Academy of Sciences of the United States of America, 110(32), 13126-31.More infoHuman CMV (hCMV) establishes lifelong infections in most of us, causing developmental defects in human embryos and life-threatening disease in immunocompromised individuals. During productive infection, the viral >230,000-bp dsDNA genome is expressed widely and in a temporal cascade. The hCMV genome does not carry histones when encapsidated but has been proposed to form nucleosomes after release into the host cell nucleus. Here, we present hCMV genome-wide nucleosome occupancy and nascent transcript maps during infection of permissive human primary cells. We show that nucleosomes occupy nuclear viral DNA in a nonrandom and highly predictable fashion. At early times of infection, nucleosomes associate with the hCMV genome largely according to their intrinsic DNA sequence preferences, indicating that initial nucleosome formation is genetically encoded in the virus. However, as infection proceeds to the late phase, nucleosomes redistribute extensively to establish patterns mostly determined by nongenetic factors. We propose that these factors include key regulators of viral gene expression encoded at the hCMV major immediate-early (IE) locus. Indeed, mutant virus genomes deficient for IE1 expression exhibit globally increased nucleosome loads and reduced nucleosome dynamics compared with WT genomes. The temporal nucleosome occupancy differences between IE1-deficient and WT viruses correlate inversely with changes in the pattern of viral nascent and total transcript accumulation. These results provide a framework of spatial and temporal nucleosome organization across the genome of a major human pathogen and suggest that an hCMV major IE protein governs overall viral chromatin structure and function.
- Goodrum, F., Caviness, K., & Zagallo, P. (2012). Human cytomegalovirus persistence. Cellular microbiology, 14(5), 644-55.More infoViral persistence is the rule following infection with all herpesviruses. The β-herpesvirus, human cytomegalovirus (HCMV), persists through chronic and latent states of infection. Both of these states of infection contribute to HCMV persistence and to the high HCMV seroprevalence worldwide. The chronic infection is poorly defined molecularly, but clinically manifests as low-level virus shedding over extended periods of time and often in the absence of symptoms. Latency requires long-term maintenance of viral genomes in a reversibly quiescent state in the immunocompetent host. In this review, we focus on recent advances in the biology of HCMV persistence, particularly with respect to the latent mode of persistence. Latently infected individuals harbour HCMV genomes in haematopoietic cells and maintain large subsets of HCMV-specific T-cells. In the last few years, impressive advances have been made in understanding virus-host interactions important to HCMV infection, many of which will profoundly impact HCMV persistence. We discuss these advances and their known or potential impact on viral latency. As herpesviruses are met with similar challenges in achieving latency and often employ conserved strategies to persist, we discuss current and future directions of HCMV persistence in the context of the greater body of knowledge regarding α- and γ-herpesviruses persistence.
- Petrucelli, A., Umashankar, M., Zagallo, P., Rak, M., & Goodrum, F. (2012). Interactions between proteins encoded within the human cytomegalovirus UL133-UL138 locus. Journal of virology, 86(16), 8653-62.More infoWe previously described a novel genetic locus within the ULb' region of the human cytomegalovirus (HCMV) genome that, while dispensable for replication in fibroblasts, suppresses replication in hematopoietic progenitors and augments replication in endothelial cells. This locus, referred to as the UL133-UL138 locus, encodes four proteins, pUL133, pUL135, pUL136, and pUL138. In this work, we have mapped the interactions among these proteins. An analysis of all pairwise interactions during transient expression revealed a robust interaction between pUL133 and pUL138. Potential interactions between pUL136 and both pUL133 and pUL138 were also revealed. In addition, each of the UL133-UL138 locus proteins self-associated, suggesting a potential to form higher-order homomeric complexes. As both pUL133 and pUL138 function in promoting viral latency in CD34(+) hematopoietic progenitor cells (HPCs) infected in vitro, we further focused on this interaction. pUL133 and pUL138 are the predominant complex detected when all proteins are expressed together and require no other proteins in the locus for their association. During infection, the interaction between pUL133 and pUL138 or pUL136 can be detected. A recombinant virus that fails to express both pUL133 and pUL138 exhibited a latency phenotype similar to that of viruses that fail to express either pUL133 or pUL138, indicating that these proteins function cooperatively in latency and do not have independent functions that additively contribute to HCMV latency. These studies identify protein interactions among proteins encoded by the UL133-UL138 locus and demonstrate an important interaction impacting the outcome of HCMV infection.
- Umashankar, M., Petrucelli, A., Cicchini, L., Caposio, P., Kreklywich, C. N., Rak, M., Bughio, F., Goldman, D. C., Hamlin, K. L., Nelson, J. A., Fleming, W. H., Streblow, D. N., & Goodrum, F. (2011). A novel human cytomegalovirus locus modulates cell type-specific outcomes of infection. PLoS pathogens, 7(12), e1002444.More infoClinical strains of HCMV encode 20 putative ORFs within a region of the genome termed ULb' that are postulated to encode functions related to persistence or immune evasion. We have previously identified ULb'-encoded pUL138 as necessary, but not sufficient, for HCMV latency in CD34+ hematopoietic progenitor cells (HPCs) infected in vitro. pUL138 is encoded on polycistronic transcripts that also encode 3 additional proteins, pUL133, pUL135, and pUL136, collectively comprising the UL133-UL138 locus. This work represents the first characterization of these proteins and identifies a role for this locus in infection. Similar to pUL138, pUL133, pUL135, and pUL136 are integral membrane proteins that partially co-localized with pUL138 in the Golgi during productive infection in fibroblasts. As expected of ULb' sequences, the UL133-UL138 locus was dispensable for replication in cultured fibroblasts. In CD34+ HPCs, this locus suppressed viral replication in HPCs, an activity attributable to both pUL133 and pUL138. Strikingly, the UL133-UL138 locus was required for efficient replication in endothelial cells. The association of this locus with three context-dependent phenotypes suggests an exciting role for the UL133-UL138 locus in modulating the outcome of viral infection in different contexts of infection. Differential profiles of protein expression from the UL133-UL138 locus correlated with the cell-type dependent phenotypes associated with this locus. We extended our in vitro findings to analyze viral replication and dissemination in a NOD-scid IL2Rγ(c) (null)-humanized mouse model. The UL133-UL138(NULL) virus exhibited an increased capacity for replication and/or dissemination following stem cell mobilization relative to the wild-type virus, suggesting an important role in viral persistence and spread in the host. As pUL133, pUL135, pUL136, and pUL138 are conserved in virus strains infecting higher order primates, but not lower order mammals, the functions encoded likely represent host-specific viral adaptations.
- Grainger, L., Cicchini, L., Rak, M., Petrucelli, A., Fitzgerald, K. D., Semler, B. L., & Goodrum, F. (2010). Stress-inducible alternative translation initiation of human cytomegalovirus latency protein pUL138. Journal of virology, 84(18), 9472-86.More infoWe have previously characterized a 21-kDa protein encoded by UL138 (pUL138) as a viral factor inherent to low-passage strains of human cytomegalovirus (HCMV) that is required for latent infection in vitro. pUL138 is encoded on 3.6-, 2.7-, and 1.4-kb 3' coterminal transcripts that are produced during productive and latent infections. pUL138 is encoded at the 3' end of each transcript and is preceded by an extensive 5' sequence (approximately 0.5 to 2.5 kb) containing several putative open reading frames (ORFs). We determined that three putative ORFs upstream of UL138 (UL133, UL135, and UL136) encode proteins. The UL138 transcripts are polycistronic, such that each transcript expresses pUL138 in addition to the most-5' ORF. The upstream coding sequences (CDS) present a significant challenge for the translation of pUL138 in mammalian cells. We hypothesized that sequences 5' of UL138 mediate translation initiation of pUL138 by alternative strategies. Accordingly, a 663-nucloetide (nt) sequence overlapping the UL136 CDS supported expression of a downstream cistron in a bicistronic reporter system. We did not detect cryptic promoter activity or RNA splicing events that could account for downstream cistron expression. These data are consistent with the sequence element functioning as an internal ribosome entry site (IRES). Interestingly, pUL138 expression from the 3.6- and 2.7-kb transcripts was induced by serum stress, which concomitantly inhibited normal cap-dependent translation. Our work suggests that an alternative and stress-inducible strategy of translation initiation ensures expression of pUL138 under a variety of cellular contexts. The UL138 polycistronic transcripts serve to coordinate the expression of multiple proteins, including a viral determinant of HCMV latency.
- Tey, S., Goodrum, F., & Khanna, R. (2010). CD8+ T-cell recognition of human cytomegalovirus latency-associated determinant pUL138. The Journal of general virology, 91(Pt 8), 2040-8.More infoRecent studies have shown that long-term persistence of human cytomegalovirus (HCMV) in mononuclear cells of myeloid lineage is dependent on the UL138 open reading frame, which promotes latent infection. Although T-cell recognition of protein antigens from all stages of lytic HCMV infection is well established, it is not clear whether proteins expressed during latent HCMV infection can also be recognized. This study conducted an analysis of T-cell response towards proteins associated with HCMV latency. Ex vivo analysis of T cells from healthy virus carriers revealed a dominant CD8(+) T-cell response to the latency-associated pUL138 protein, which recognized a non-canonical 13 aa epitope in association with HLA-B*3501. These pUL138-specific T cells displayed a range of memory phenotypes that were in general less differentiated than that previously described in T cells specific for HCMV lytic antigens. Antigen-presentation assays revealed that endogenous pUL138 could be presented efficiently by HCMV-infected cells. However, T-cell recognition of pUL138 was dependent on newly synthesized protein, with little presentation from stable, long-lived protein. These data demonstrate that T cells targeting latency-associated protein products exist, although HCMV may limit the presentation of latent proteins, thereby restricting T-cell recognition of latently infected cells.
- Petrucelli, A., Rak, M., Grainger, L., & Goodrum, F. (2009). Characterization of a novel Golgi apparatus-localized latency determinant encoded by human cytomegalovirus. Journal of virology, 83(11), 5615-29.More infoHuman cytomegalovirus (HCMV) exists indefinitely in infected individuals by a yet poorly characterized latent infection in hematopoietic cells. We previously demonstrated a requirement for the putative UL138 open reading frame (ORF) in promoting a latent infection in CD34(+) hematopoietic progenitor cells (HPCs) infected in vitro. In our present study, we have identified two coterminal transcripts of 2.7 and 3.6 kb and a 21-kilodalton (kDa) protein (pUL138) that are derived from the UL138 locus with early-late gene kinetics during productive infection. The UL138 transcripts and protein are detected in both fibroblasts and HPCs. A recombinant virus, FIX-UL138(STOP), that synthesizes the UL138 transcripts but not the protein exhibited a partial loss-of-latency phenotype in HPCs, similar to the phenotype observed for the UL138-null recombinant virus. This finding suggests that the UL138 protein is required for latency, but it does not exclude the possibility that the UL138 transcripts or other ORFs also contribute to latency. The mechanisms by which pUL138 contributes to latency remain unknown. While the 86- and 72-kDa immediate-early proteins were not detected in HPCs infected with HCMV in vitro, pUL138 did not function directly to suppress expression from the major immediate-early promoter in reporter assays. Interestingly, pUL138 localizes to the Golgi apparatus in infected cells but is not incorporated into virus particles. The localization of pUL138 to the Golgi apparatus suggests that pUL138 contributes to HCMV latency by a novel mechanism. pUL138 is the first HCMV protein demonstrated to promote an infection with the hallmarks of latency in CD34(+) HPCs.
- Thomas, M. A., Broughton, R. S., Goodrum, F. D., & Ornelles, D. A. (2009). E4orf1 limits the oncolytic potential of the E1B-55K deletion mutant adenovirus. Journal of virology, 83(6), 2406-16.More infoClinical trials have shown oncolytic adenoviruses to be tumor selective with minimal toxicity toward normal tissue. The virus ONYX-015, in which the gene encoding the early region 1B 55-kDa (E1B-55K) protein is deleted, has been most effective when used in combination with either chemotherapy or radiation therapy. Therefore, improving the oncolytic nature of tumor-selective adenoviruses remains an important objective for improving this form of cancer therapy. Cells infected during the G(1) phase of the cell cycle with the E1B-55K deletion mutant virus exhibit a reduced rate of viral late protein synthesis, produce fewer viral progeny, and are less efficiently killed than cells infected during the S phase. Here we demonstrate that the G(1) restriction imposed on the E1B-55K deletion mutant virus is due to the viral oncogene encoded by open reading frame 1 of early region 4 (E4orf1). E4orf1 has been reported to signal through the phosphatidylinositol 3'-kinase pathway leading to the activation of Akt, mTOR, and p70 S6K. Evidence presented here shows that E4orf1 may also induce the phosphorylation of Akt and p70 S6K in a manner that depends on Rac1 and its guanine nucleotide exchange factor Tiam1. Accordingly, agents that have been reported to disrupt the Tiam1-Rac1 interaction or to prevent phosphorylation of the ribosomal S6 kinase partially alleviated the E4orf1 restriction to late viral protein synthesis and enhanced tumor cell killing by the E1B-55K mutant virus. These results demonstrate that E4orf1 limits the oncolytic nature of a conditionally replicating adenovirus such as ONYX-015. The therapeutic value of similar oncolytic adenoviruses may be improved by abrogating E4orf1 function.
- Goodrum, F., Reeves, M., Sinclair, J., High, K., & Shenk, T. (2007). Human cytomegalovirus sequences expressed in latently infected individuals promote a latent infection in vitro. Blood, 110(3), 937-45.More infoLatency enables human cytomegalovirus (HCMV) to persist in the hematopoietic cells of infected individuals indefinitely and prevents clearance of the pathogen. Despite its critical importance to the viral infectious cycle, viral mechanisms that contribute to latency have not been identified. We compared the ability of low-passage clinical and laboratory-adapted strains of HCMV to establish a latent infection in primary human CD34(+) cells. The low-passage strains, Toledo and FIX, established an infection with the hallmarks of latency, whereas the laboratory strains, AD169 and Towne, replicated producing progeny virus. We hypothesized that ULb' region of the genome, which is unique to low-passage strains, may encode a latency-promoting activity. We created and analyzed recombinant viruses lacking segments or individual open reading frames (ORFs) in the ULb' region. One 5-kb segment, and more specifically the UL138 ORF, was required for HCMV to establish and/or maintain a latent infection in hematopoietic progenitor cells infected in vitro. This is the first functional demonstration of a virus-coded sequence required for HCMV latency. Importantly, UL138 RNA was expressed in CD34(+) cells and monocytes from HCMV-seropositive, healthy individuals. UL138 might be a target for antivirals against latent virus.
- Ornelles, D. A., Broughton-Shepard, R. N., & Goodrum, F. D. (2007). Analysis of adenovirus infections in synchronized cells. Methods in molecular medicine, 131, 83-101.More infoAdenoviruses (Ads) are small DNA tumor viruses that have played a pivotal role in understanding eukaryotic cell biology and viral oncogenesis. Among other cellular pathways, Ad usurps cell cycle progression following infection. Likewise, progression of the viral infection is influenced by the host cell cycle. We describe here methods developed for synchronizing dividing cell populations and for analysis of cell cycle synchrony by flow cytometry. Furthermore, three methods used to evaluate the outcome of Ad infection in synchronized cell populations are described. These include two assays for infectious centers and an assay for analyzing production of progeny virus by transmission electron microscopy. These methods have been used to demonstrate that Ads that fail to direct synthesis of the E1B 55-kDa or E4orf6 proteins replicate most effectively upon infecting cells in S phase.
- Goodrum, F., Jordan, C. T., Terhune, S. S., High, K., & Shenk, T. (2004). Differential outcomes of human cytomegalovirus infection in primitive hematopoietic cell subpopulations. Blood, 104(3), 687-95.More infoThe cellular reservoir for latent human cytomegalovirus (HCMV) in the hematopoietic compartment, and the mechanisms governing a latent infection and reactivation from latency are unknown. Previous work has demonstrated that HCMV infects CD34+ progenitors and expresses a limited subset of viral genes. The outcome of HCMV infection may depend on the cell subpopulations infected within the heterogeneous CD34+ compartment. We compared HCMV infection in well-defined CD34+ cell subpopulations. HCMV infection inhibited hematopoietic colony formation from CD34+/CD38- but not CD34+/c-kit+ cells. CD34+/CD38- cells transiently expressed a large subset of HCMV genes that were not expressed in CD34+/c-kit+ cells or cells expressing more mature cell surface phenotypes. Although viral genomes were present in infected cells, viral gene expression was undetectable by 10 days after infection. Importantly, viral replication could be reactivated by coculture with permissive fibroblasts only from the CD34+/CD38- population. Strikingly, a subpopulation of CD34+/CD38- cells expressing a stem cell phenotype (lineage-/Thy-1+) supported a productive HCMV infection. These studies demonstrate that the outcome of HCMV infection in the hematopoietic compartment is dependent on the nature of the cell subpopulations infected and that CD34+/CD38- cells support an HCMV infection with the hallmarks of latency.
- Goodrum, F. D., Jordan, C. T., High, K., & Shenk, T. (2002). Human cytomegalovirus gene expression during infection of primary hematopoietic progenitor cells: a model for latency. Proceedings of the National Academy of Sciences of the United States of America, 99(25), 16255-60.More infoHuman cytomegalovirus (HCMV) resides latently in hematopoietic cells of the bone marrow. Although viral genomes can be found in CD14+ monocytes and CD34+ progenitor cells, the primary reservoir for latent cytomegalovirus is unknown. We analyzed human hematopoietic subpopulations infected in vitro with a recombinant virus that expresses a green fluorescent protein marker gene. Although many hematopoietic cell subsets were infected in vitro, CD14+ monocytes and various CD34+ subpopulations were infected with the greatest efficiency. We have developed an in vitro system in which to study HCMV infection and latency in CD34+ cells cultured with irradiated stromal cells. Marker gene expression was substantially reduced by 4 days postinfection, and infectious virus was not made during the culture period. However, viral DNA sequences were maintained in infected CD34+ cells for >20 days in culture, and, importantly, virus replication could be reactivated by coculture with human fibroblasts. Using an HCMV gene array, we examined HCMV gene expression in CD34+ cells. The pattern of viral gene expression was distinct from that observed during productive or nonproductive infections. Some of these expressed viral genes may function in latency and are targets for further analysis. Altered gene expression in hematopoietic progenitors may be indicative of the nature and outcome of HCMV infection.
- Goodrum, F. D., & Ornelles, D. A. (1999). Roles for the E4 orf6, orf3, and E1B 55-kilodalton proteins in cell cycle-independent adenovirus replication. Journal of virology, 73(9), 7474-88.More infoAdenoviruses bearing lesions in the E1B 55-kDa protein (E1B 55-kDa) gene are restricted by the cell cycle such that mutant virus growth is most impaired in cells infected during G(1) and least restricted in cells infected during S phase (F. D. Goodrum and D. A. Ornelles, J. Virol. 71:548-561, 1997). A similar defect is reported here for E4 orf6-mutant viruses. An E4 orf3-mutant virus was not restricted for growth by the cell cycle. However, orf3 was required for enhanced growth of an E4 orf6-mutant virus in cells infected during S phase. The cell cycle restriction may be linked to virus-mediated mRNA transport because both E1B 55-kDa- and E4 orf6-mutant viruses are defective at regulating mRNA transport at late times of infection. Accordingly, the cytoplasmic-to-nuclear ratio of late viral mRNA was reduced in G(1) cells infected with the mutant viruses compared to that in G(1) cells infected with the wild-type virus. By contrast, this ratio was equivalent among cells infected during S phase with the wild-type or mutant viruses. Furthermore, cells infected during S phase with the E1B 55-kDa- or E4 orf6-mutant viruses synthesized more late viral protein than did cells infected during G(1). However, the total amount of cytoplasmic late viral mRNA was greater in cells infected during G(1) than in cells infected during S phase with either the wild-type or mutant viruses, indicating that enhanced transport of viral mRNA in cells infected during S phase cannot account for the difference in yields in cells infected during S phase and in cells infected during G(1). Thus, additional factors affect the cell cycle restriction. These results indicate that the E4 orf6 and orf3 proteins, in addition to the E1B 55-kDa protein, may cooperate to promote cell cycle-independent adenovirus growth.
- Goodrum, F. D., & Ornelles, D. A. (1998). p53 status does not determine outcome of E1B 55-kilodalton mutant adenovirus lytic infection. Journal of virology, 72(12), 9479-90.More infoThe ability of the adenovirus type 5 E1B 55-kDa mutants dl1520 and dl338 to replicate efficiently and independently of the cell cycle, to synthesis viral DNA, and to lyse infected cells did not correlate with the status of p53 in seven cell lines examined. Rather, cell cycle-independent replication and virus-induced cell killing correlated with permissivity to viral replication. This correlation extended to S-phase HeLa cells, which were more susceptible to virus-induced cell killing by the E1B 55-kDa mutant virus than HeLa cells infected during G1. Wild-type p53 had only a modest effect on E1B mutant virus yields in H1299 cells expressing a temperature-sensitive p53 allele. The defect in E1B 55-kDa mutant virus replication resulting from reduced temperature was as much as 10-fold greater than the defect due to p53 function. At 39 degreesC, the E1B 55-kDa mutant viruses produced wild-type yields of virus and replicated independently of the cell cycle. In addition, the E1B 55-kDa mutant viruses directed the synthesis of late viral proteins to levels equivalent to the wild-type virus level at 39 degreesC. We have previously shown that the defect in mutant virus replication can also be overcome by infecting HeLa cells during S phase. Taken together, these results indicate that the capacity of the E1B 55-kDa mutant virus to replicate independently of the cell cycle does not correlate with the status of p53 but is determined by yet unidentified mechanisms. The cold-sensitive nature of the defect of the E1B 55-kDa mutant virus in both late gene expression and cell cycle-independent replication leads us to speculate that these functions of the E1B 55-kDa protein may be linked.
- Goodrum, F. D., & Ornelles, D. A. (1997). The early region 1B 55-kilodalton oncoprotein of adenovirus relieves growth restrictions imposed on viral replication by the cell cycle. Journal of virology, 71(1), 548-61.More infoThe E1B 55-kDa oncoprotein of adenovirus enables the virus to overcome restrictions imposed on viral replication by the cell cycle. Approximately 20% of HeLa cells infected with an E1B 55-kDa mutant adenovirus produced virus when evaluated by electron microscopy or by assays for infectious centers. By contrast, all HeLa cells infected with a wild-type adenovirus produced virus. The yield of E1B mutant virus from randomly cycling HeLa cells correlated with the fraction of cells in S phase at the time of infection. In synchronously growing HeLa cells, approximately 75% of the cells infected during S phase with the E1B mutant virus produced virus, whereas only 10% of the cells infected during G1 produced virus. The yield of E1B mutant virus from HeLa cells infected during S phase was sevenfold greater than that of cells infected during G1 and threefold greater than that of cells infected during asynchronous growth. Cells infected during S phase with the E1B mutant virus exhibited severe cytopathic effects, whereas cells infected with the E1B mutant virus during G1 exhibited a mild cytopathic effect. Viral DNA synthesis appeared independent of the cell cycle because equivalent amounts of viral DNA were synthesized in cells infected with either wild-type or E1B mutant virus. The inability of the E1B mutant virus to replicate was not mediated by the status of p53. These results define a novel property of the large tumor antigen of adenovirus in relieving growth restrictions imposed on viral replication by the cell cycle.
- Goodrum, F. D., Shenk, T., & Ornelles, D. A. (1996). Adenovirus early region 4 34-kilodalton protein directs the nuclear localization of the early region 1B 55-kilodalton protein in primate cells. Journal of virology, 70(9), 6323-35.More infoThe localization of the adenovirus type 5 34-kDa E4 and 55-kDa E1B proteins was determined in the absence of other adenovirus proteins. When expressed by transfection in human, monkey, hamster, rat, and mouse cell lines, the E1B protein was predominantly cytoplasmic and typically was excluded from the nucleus. When expressed by transfection, the E4 protein accumulated in the nucleus. Strikingly, when coexpressed by transfection in human, monkey, or baby hamster kidney cells, the E1B protein colocalized in the nucleus with the E4 protein. A complex of the E4 and E1B proteins was identified by coimmunoprecipitation in transfected HeLa cells. By contrast to the interaction observed in primate and baby hamster kidney cells, the E4 protein failed to direct the E1B protein to the nucleus in rat and mouse cell lines as well as CHO and V79 hamster cell lines. This failure of the E4 protein to direct the nuclear localization of the E1B protein in REF-52 rat cells was overcome by fusion with HeLa cells. Within 4 h of heterokaryon formation and with protein synthesis inhibited, a portion of the E4 protein present in the REF-52 nuclei migrated to the HeLa nuclei. Simultaneously, the previously cytoplasmic E1B protein colocalized with the E4 protein in both human and rat cell nuclei. These results suggest that a primate cell-specific factor mediates the functional interaction of the E1B and E4 proteins of adenovirus.
- Goodrum Sterling, F. D. (2016, April). Regulating Host Trafficking and Signaling for Viral Persistence. Cellular & Molecular Medicine/Molecular & Cellular Biology Joint Seminar Series. Tucson, AZ: Departments of CMM and MCB.
- Goodrum Sterling, F. D. (2016, January). Cytomegalovirus control of host trafficking and signaling. Invited Seminar. Boston, MA: Harvard University, Harvard Medical School, Department of Microbiology and Immunology.
- Goodrum Sterling, F. D. (2016, July). Human Cyotmegalovirus Persistence. P01 Symposium. Chicago, IL: Northwestern University.
- Goodrum Sterling, F. D. (2016, July). Viral control of host trafficking and signaling. 42nd International Herpesvirus Workshop. Madison, WI: IHW.
- Goodrum Sterling, F. D. (2016, June). Complex roles of the UL136 gene of human cytomegalovirus in replication and latency. American Society of Virology 35th Annual Meeting. Balcksburg, VA: American Society of Virology.
- Goodrum Sterling, F. D. (2016, June). Virus control of host trafficking and signaling. Invited Seminar. Hanover, NH: Dartmouth College, Geisel School of Medicine, Department of Microbiology and Immunology.
- Goodrum Sterling, F. D. (2016, November). Opposing regulation of the EGF Receptor: A molecular switch controlling cytomegalovirus latency and reactivation. 6th International Workshop on CMV and Immunosenescence. Tucson, AZ.
- Goodrum Sterling, F. D. (2016, September). Virus control of host trafficking and signaling. Invited Seminar. Philadelphia, PA: University of Pennsylvania, Perelman School of Medicine, Department of Microbiology.
- Goodrum Sterling, F. D. (2015, April). Virus-Host Interaction Contributing to Cytomegalovirus Persistence. Invited Seminar. Ann Arbor, MI: Department of Microbiology and Immunology.
- Goodrum Sterling, F. D. (2015, December). Cytomegalovirus Persistence. Invited Seminar, Pediatric Infectious Disease Research Conference. Nashville, TN: Vanderbilt University.
- Goodrum Sterling, F. D. (2015, February). Viral Regulation of EGFR for Latency. Invited Seminar. Irvine, CA: University of California, Irvine, Department of Microbiology and Molecular Genetics.
- Goodrum Sterling, F. D. (2015, Februray). Promoter Switching and Reactivation from Latency. MicroLunch. Tucson, AZ: University of Arizona.
- Goodrum Sterling, F. D. (2015, July). Hijacking cellular trafficking pathways for viral persistence. FASEB Microbial Pathogenesis: Mechanisms of Infectious Disease. Keystone, CO: FASEB.
- Goodrum, F. D. (2015, July). Hijacking of cellular trafficking pathways for viral persistence. FASEB Microbial Pathogenesis: Mechanisms of Infectious Disease. Keystone, CO: FASEB.More infoInvited Speaker
- Goodrum Sterling, F. D. (2014, January). Questions of Viral Persistence: Switches and Gatekeepers. Invited Seminar, College of Medicine-Phoenix, Biomedical Sciences. Phoenix, AZ: College of Medicine-Phoenix, Biomedical Sciences.
- Goodrum Sterling, F. D. (2014, March). Human Cytomegalovirus Persistence. Jamie McNew Endowed Lectureship, Invited Speaker. Minneapolis, MN: University of Minnesota, Amplatz Children's Hospital.
- Goodrum Sterling, F. D. (2014, May). Biphasic Regulation of HCMV Gene Expression in Latency and Lytic Cycle Progression. MicroLunch. Tucson, AZ: University of Arizona.
- Goodrum Sterling, F. D. (2014, May). Human Cytomegalovirus Regulation of EGFR for Latency. Graduate Student Invited Seminar. Syracuse, NY: SUNY Upstate Medical University, Department of Microbiology and Immunology.
- Goodrum Sterling, F. D. (2014, October). Complexity of HCMV gene expression and its differential effects on virus replication. 3rd Annual ASM Conference on Viral Manipulation of Nuclear Processes. Washington, DC: American Society of Microbiology.
- Goodrum Sterling, F. D. (2014, October). Viral Regulation of EGFR for Latency. Plenary Speaker, 14th Annual Symposium on Virology. Lincoln, NE: University of Nebraska, Nebraska Center for Virology.
- Goodrum Sterling, F. D. (2013, April). Viral Determinants of Human Cytomegalovirus Latency. Post-doctoral Association Invited Speaker. Chapel Hill, NC: University of North Carolina, Chapel Hill, Department of Microbiology and Immunology.
- Goodrum Sterling, F. D. (2013, February). The Multifunctional UL135 Protein of Human Cytomegalovirus. MicroLunch. Tucson, AZ: University of Arizona.
- Goodrum Sterling, F. D. (2013, July). Endothelium Tropism Determinants of Human Cytomegalovirus. 38th International Herpesvirus Workshop. Grand Rapids, MI: International Herpesvirus Workshop.
- Goodrum Sterling, F. D. (2013, October). The Issue of Viral Persistence. Invited Seminar, Department of Pharmacology and Toxicology. Tucson, AZ: Department of Pharmacology and Toxicology.
- Goodrum Sterling, F. D. (2013, Septemeber). The Human Cytomegalovirus UL135/UL138 Switch. MicroLunch. Tucson, AZ: University of Arizona.
- Goodrum Sterling, F. D. (2017, Februrary). Viral Determinants of Cytomegalovirus Latency. Invited Seminar. St. Louis, MO: Washington University in St. Louis, School of Medicine, Department of Pathology and Immunobiology.
- Goodrum, F. D. (2013, March). The Question of Persistence. 4th International Workshop on CMV and Immunosenescence. Parma, Italy.
- Goodrum Sterling, F. D. (2012, April). Human Cytomegalovirus Latency. Invited Seminar. Winston-Salem, NC: Wake Forest University School of Medicine.
- Goodrum Sterling, F. D. (2012, December). Host-virus interactions underlying human cytomegalovirus latency. Invited Seminar. Shreveport, LA: Louisiana State University Health Sciences Center, Department of Microbiology and Immunology.
- Goodrum Sterling, F. D. (2012, March). Determinants of Virus Fate. Frontiers in Immunobiology and Immunopathogenesis Symposium. Tucson, AZ: Department of Immunobiology, University of Arizona.
- Goodrum Sterling, F. D. (2012, March). Human Cytomegalovirus Latency. Invited Seminar. Cleveland, OH: Cleveland Clinic, Department of Molecular Biology.
- Goodrum Sterling, F. D. (2012, September). The Multifunctional UL135 Protein of Human Cytomegalovirus. Immunobiology Seminar Series. Tucson, AZ: Department of Immunobiology, University of Arizona.
- Goodrum, F. D. (2012, July). Viral Mechanisms of Human Cytomegalovirus Persistence. American Society of Virology. Madison, WI: American Society of Virology.
- Goodrum, F. D. (2012, November). How many sites of latency are there?. 14th International CMV/Beta Herpesvirus Workshop. San Francisco, CA: International CMV/Beta Herpesvirus Workshop.More infopanel member
- Goodrum, F. D. (2012, November). Novel HCMV Determinants Controlling Replication in Endothelial Cells. 14th International CMV/Beta Herpesvirus Workshop. San Francisco, CA: CMV/Beta Herpesvirus Workshop.
- Goodrum Sterling, F. D. (2011, May). Viral Control of Translation. Gordon Conference on Viruses and Cells. Il Ciocco, Italy: Gordon Research Conferences.
- Goodrum, F. D. (2011, October). Viruses and the Stress Response. 2nd Manipulation of Nuclear Processes by DNA Viruses. Santa Fe, NM.
- Goodrum Sterling, F. D. (2010, July). Questions of Human Cytomegalovirus Coexistence. Inaugural Priscilla A. Schaffer Lectureship. Salt Lake City, UT: International Herpesvirus Workshop.
- Goodrum Sterling, F. D. (2010, November). Viral Determinants of Coexistence. 22nd Annual Kavli Frontiers of Science Symposium. Irvine, CA: National Academy of Sciences.
- Goodrum, F. D. (2015, July). Endothelium Tropism Determinants of Human Cytomegalovirus. 40th International Herpesvirus Workshop. Boise, ID: International Herpesvirus Workshop.