About

Professor Dirk Dittmer leads research focused on understanding viral tumorigenesis, with a particular emphasis on cancers caused by Kaposi's sarcoma-associated herpesvirus (KSHV/HHV-8). KSHV is a double-stranded DNA virus from the Rhadinovirus family of human herpesviruses, discovered in 1994. It is associated with Kaposi's sarcoma (KS) and B-cell cancers such as primary effusion lymphoma (PEL) and multicentric Castleman's disease (MCD). These diseases primarily affect internal organs and are ultimately fatal. They are most commonly observed in immunosuppressed individuals in the United States, including those who are HIV-positive and transplant patients. Professor Dittmer's lab aims to elucidate the mechanisms by which viral infections contribute to cancer development, addressing a significant health concern given that approximately 20% of all human cancers have a viral origin or require viral infection as an essential cofactor.

Research topics

• Medicine
• Internal medicine
• Immunology
• Oncology
• Family medicine
• Pathology
• Gerontology
• Demography
• Environmental health
• Virology
• Pediatrics

Selected publications

• Human cytomegalovirus terminase inhibitors letermovir, tomeglovir, and the halogenated benzimidazoles modify DNA cleavage/packaging to generate a super-genomic DNA species by cleavage site skipping

  SSRN Electronic Journal · 2026-01-01

  preprintOpen access
  PublisherDOI

• Simian Immunodeficiency Virus-Derived Extracellular Vesicles Induce a Chronic Inflammatory Phenotype in Healthy Astrocytes Unresolved by Anti-Retroviral Therapy

  Pharmaceutics · 2025-10-24

  articleOpen access

  Background/Objectives: Extracellular vesicles (EVs) are key mediators of intercellular communication and are implicated in the neuropathogenesis of HIV-associated brain injury (HABI). However, their direct effects on glial cells, particularly in the context of antiretroviral therapy (ART), remain incompletely understood. Methods: In this study, we investigated how EVs from naïve, Simian Immunodeficiency Virus (SIV)-infected, and SIV-infected ART-treated rhesus macaques impact primary mixed glial cultures. Results: Through multiple, sequential applications mimicking chronic exposure, we found that EVs from SIV-infected animals significantly reduced glial expansion and induced a simplified, reactive astrocyte morphology indicative of neuroinflammatory stress. In contrast, EVs from naïve animals supported glial health. EVs derived from ART-treated animals provided partial protection from SIV-induced effects, yet still suppressed glial proliferation and failed to fully restore normal morphology. Furthermore, cytokine profiling revealed that both SIV and SIV + ART EVs induced a sustained proinflammatory secretory phenotype, characterized by elevated IL-6, IL-8, and IFN-γ. Conclusions: Our findings demonstrate that systemically circulating EVs in SIV infection are potential drivers of glial dysfunction. The persistence of these pathogenic EV effects despite ART suggests a vesicle-mediated mechanism that may contribute to chronic neuroinflammation and cognitive impairment in virally suppressed individuals.

  PublisherOA PDFDOI

• Intra-Host Evolution Provides for the Continuous Emergence of SARS-CoV-2 Variants

  UNC Libraries · 2025-03-19

  articleOpen access

  Variants of concern (VOC) in SARS-CoV-2 refer to viruses whose viral genomes differ from the ancestor virus by &ge;3 single-nucleotide variants (SNVs) and that show the potential for higher transmissibility and/or worse clinical progression. VOC have the potential to disrupt ongoing public health measures and vaccine efforts. Still, too little is known regarding how frequently new viral variants emerge and under what circumstances. We report a study to determine the degree of SARS-CoV-2 sequence evolution in 94 patients and to estimate the frequency at which highly diverse variants emerge. Two cases accumulated &ge;9 SNVs over a 2-week period and one case accumulated 23 SNVs over 3 weeks, including three nonsynonymous mutations in the spike protein (D138H, E554D, D614G). The remainder of the infected patients did not show signs of intra-host evolution. We estimate that in as much as 2% of hospitalized COVID-19 cases, variants with multiple mutations in the spike glycoprotein emerge in as little as 1 month of persistent intra-host virus replication. This suggests the continued local emergence of variants with multiple nonsynonymous SNVs, even in patients without overt immune deficiency. Surveillance by sequencing for (i) viremic COVID-19 patients, (ii) patients suspected of reinfection, and (iii) patients with diminished immune function may offer broad public health benefits. <strong>IMPORTANCE</strong> New SARS-CoV-2 variants can potentially disrupt ongoing public health measures and vaccine efforts. Still, little is known regarding how frequently new viral variants emerge and under what circumstances. Based on this study, we estimate that in hospitalized COVID-19 cases, variants with multiple mutations may emerge locally in as little as 1 month, even in patients without overt immune deficiency. Surveillance by sequencing for continuously shedding patients, patients suspected of reinfection, and patients with diminished immune function may offer broad public health benefits.

  PublisherDOI

• Kinome profiling of non-Hodgkin lymphoma identifies Tyro3 as a therapeutic target in primary effusion lymphoma

  UNC Libraries · 2025-10-10

  articleOpen access

  Non-Hodgkin lymphomas (NHLs) make up the majority of lymphoma diagnoses and represent a very diverse set of malignancies. We sought to identify kinases uniquely up-regulated in different NHL subtypes. Using multiplexed inhibitor bead-mass spectrometry (MIB/MS), we found Tyro3 was uniquely up-regulated and important for cell survival in primary effusion lymphoma (PEL), which is a viral lymphoma infected with Kaposi's sarcoma-associated herpesvirus (KSHV). Tyro3 was also highly expressed in PEL cell lines as well as in primary PEL exudates. Based on this discovery, we developed an inhibitor against Tyro3 named UNC3810A, which hindered cell growth in PEL, but not in other NHL subtypes where Tyro3 was not highly expressed. UNC3810A also significantly inhibited tumor progression in a PEL xenograft mouse model that was not seen in a non-PEL NHL model. Taken together, our data suggest Tyro3 is a therapeutic target for PEL.

  PublisherDOI

• KSHV and HPV modulate epithelial-to-mesenchymal transition in oral epithelial cells

  mBio · 2025-08-15 · 3 citations

  articleOpen access

  Most oral viral infections that manifest as oral diseases or cancers are caused by oncogenic human papillomavirus and herpesviruses. However, the mechanisms involved in the association between oral cancer and oncogenic virus infection are not well understood. In this study, we used telomerase (hTERT) -immortalized normal oral gingival keratinocytes (NOKs) and generated latent Kaposi's sarcoma-associated herpesvirus (KSHV)- and human papillomavirus 31 (HPV31)-infected NOKs. NOKs either stably maintaining HPV episomes or latently infected with KSHV acquired a fibroblast-like morphology and upregulated cell proliferation in both complete media and serum starvation culture conditions. Moreover, migration and invasion assays revealed that the KSHV- and HPV-infected NOKs show markedly higher migration and invasion activity compared to uninfected cells. We demonstrated that KSHV-NOK and HPV-NOK express much lower protein levels of the epithelial cell marker E-cadherin and significantly higher protein levels of mesenchymal cell marker vimentin, indicating that KSHV and HPV31 infection induces an epithelial-to-mesenchymal transition (EMT). Notably, after efficient vimentin knockdown using two different lentiviral short hairpin RNAs (shRNAs) or eribulin treatment, E-cadherin expression was restored, and phenotypic alterations (proliferation, migration, and invasion) caused by KSHV and HPV31 infection were abolished, suggesting that KSHV- and HPV31-induced EMTs play an important role in these phenotypic alterations by KSHV and HPV31. Given that changes in EMT are often associated with cancer progression, our results offer important insight into the mechanism behind KSHV and HPV infection and cancer, suggesting that EMT is a potential therapeutic target for KSHV- and HPV-driven cancers.IMPORTANCEThe oral cavity is believed to be a primary site where many viruses infect the human body. Kaposi's sarcoma-associated herpesvirus (KSHV) and human papillomavirus (HPV) are both found and cause cancers in the oral cavity. However, knowledge of how KSHV and HPV infection is connected to oral cancer (e.g., oncogenesis and metastasis) remains limited. Here, our study reveals that KSHV and high-risk HPV31 can induce epithelial-to-mesenchymal transition by upregulation of vimentin and downregulation of E-cadherin, which is vital for KSHV-normal oral gingival keratinocyte (NOK) and HPV-NOK to acquire cancer cell characteristics such as cell survival, migration, and invasion activities. For the first time, we show that knockdown of vimentin and eribulin treatment can restore E-cadherin and reverse epithelial-to-mesenchymal transition in KSHV- and HPV31-infected oral epithelial cells. These findings fill a gap in our understanding of oncogenesis and metastasis of oral cancers caused by KSHV and HPV31, revealing that vimentin may serve as a potential therapeutic molecular target for KSHV- and HPV-associated oral cancer.

  PublisherDOI

• Lymphotropic Virotherapy Induces DC and High Endothelial Venule Inflammation, Promoting the Antitumor Efficacy of Intratumor Virus Administration

  Cancer Immunology Research · 2025-11-21

  articleOpen access

  Tumor-draining lymph nodes are a pivotal site for antitumor T-cell priming. However, their mechanistic roles in cancer immune surveillance and immunotherapy response remain poorly defined. Intratumor (IT) virotherapy generates antitumor T-cell immunity through multifaceted engagement of innate antiviral inflammation. In this study, we identify type-I interferon (IFNI) signaling in glioma-draining cervical lymph nodes as a mediator of IT polio virotherapy. Transient IFNI signaling after IT administration was rescued by cervical perilymphatic infusion (CPLI) virotherapy, targeting cervical lymph nodes directly. Dual-site (IT plus CPLI) virotherapy induced profound inflammatory reprogramming of cervical lymph nodes, enhanced viral RNA replication and IFNI signaling in dendritic cells and high endothelial venules, augmented antiglioma efficacy in mice, and was associated with T-cell activation in patients with recurrent glioblastoma. A phase II clinical trial of IT plus CPLI polio virotherapy is ongoing (NCT06177964). This study implicates the lymphatic system as a virotherapy target and demonstrates that CPLI virotherapy has the potential to complement brain tumor immunotherapy. See related Spotlight by Kaufman, p. 182.

  PublisherOA PDFDOI

• RIG-I Detects Kaposi’s Sarcoma-Associated Herpesvirus Transcripts in a RNA Polymerase III-Independent Manner

  UNC Libraries · 2025-11-06

  articleOpen access

  Retinoic acid-inducible gene I (RIG-I) is a cytosolic pathogen recognition receptor that initiates the innate immune response against many RNA viruses. We previously showed that RIG-I restricts Kaposi's sarcoma-associated herpesvirus (KSHV) reactivation (J. A. West et al., J Virol 88:5778-5787, 2014, https://doi.org/10.1128/JVI.03226-13). In this study, we report that KSHV stimulates the RIG-I signaling pathway in a RNA polymerase (Pol) III-independent manner and subsequently induces type I interferon (IFN) responses. Knockdown or inhibition of RNA Pol III had no effect on beta interferon (IFN-&beta;) induction by KSHV. By using high-throughput sequencing of RNA isolated by cross-linking immunoprecipitation (HITS-CLIP) approach, we identified multiple KSHV regions that give rise to RNA fragments binding to RIG-I, such as ORF8_10420-10496, Repeat region (LIR1)_{119059-119204}, and ORF25_43561-43650 The sequence dissimilarity between these fragments suggests that RIG-I detects a particular structure rather than a specific sequence motif. Synthesized ORF8_10420-10496 RNA stimulated RIG-I-dependent but RNA Pol III-independent IFN-&beta; signaling. In summary, several KSHV RNAs are sensed by RIG-I in a RNA Pol III-independent manner.<strong>IMPORTANCE</strong> Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease. Innate immune responses against viral infections, especially the induction of type I interferon, are critical for limiting the replication of viruses. Retinoic acid-inducible gene I (RIG-I), a cytosolic RNA helicase sensor, plays a significant role in the induction of type I interferon responses following viral infection. Here, we identified multiple RNA regions in KSHV as potential virus ligands that bind to RIG-I and stimulate RIG-I-dependent but RNA Pol III-independent IFN-&beta; signaling. Our results expand the role of RIG-I by providing an example of a DNA virus activating a canonical RNA-sensing pathway.

  PublisherDOI

• Tetraspanin CD9 alters cellular trafficking and endocytosis of tetraspanin CD63, affecting CD63 packaging into small extracellular vesicles

  Journal of Biological Chemistry · 2025-02-03 · 20 citations

  articleOpen access

  Small extracellular vesicles (sEVs) are particles secreted from cells that play vital roles both in normal physiology and in human disease. sEVs are highly enriched in tetraspanin proteins, such as CD9 and CD63, and contain tetraspanin-enriched membrane microdomains involved in loading of sEVs with macromolecule cargoes and in sEV biogenesis. However, the precise roles of individual tetraspanins in sEV biogenesis and cargo loading remain poorly understood. Here, we report that CD9 negatively regulated CD63 trafficking to tetraspanin-enriched microdomains and its subsequent packaging into sEVs, whereas CD63 had no discernable effect on CD9 localization or packaging. Using super resolution microscopy of individual vesicles, we showed that CD9 governs the fraction of sEVs that are loaded with CD63. Interestingly, CD9-dependent suppression of CD63 packaging was rescued by pharmacological blockade of endocytosis. Together, our data support a model where CD9 contributes to the regulation and secretion of CD63 in an endocytosis-dependent manner to reprogram the contents of sEVs and tetraspanin-enriched microdomains.

  PublisherOA PDFDOI

• North Carolina CORonavirus VAriant SEQuencing (CORVASEQ): A surveillance network to monitor an evolving pandemic

  medRxiv · 2025-11-27

  preprintOpen accessSenior authorCorresponding

  When the need for comprehensive viral genomic sequencing emerged early in the SARS-CoV-2 pandemic, public health leaders in North Carolina sought to expand the state's genomic surveillance capacity. The North Carolina CORonavirus VAriant SEQuencing (CORVASEQ) network was established in the summer of 2021, drawing on institutional and local partnerships to build a statewide pathogen genomic surveillance network to conduct timely and representative genomic surveillance of SARS-CoV-2 variants. This streamlined and comprehensive network rapidly increased the number of viruses sequenced and provided representative genomic surveillance coverage of all 100 counties in North Carolina. The standardized protocols and established modes of communication developed in establishing the CORVASEQ network can help the state more rapidly mobilize in response to ongoing and emerging public health threats in North Carolina. The successes and lessons learned from the CORVASEQ network can serve as a valuable roadmap for other states or areas as they seek to build or enhance pathogen genomic surveillance networks.

  PublisherOA PDFDOI

• Whole-genome sequencing of Kaposi sarcoma-associated herpesvirus (KSHV/HHV8) reveals evidence for two African lineages

  UNC Libraries · 2025-05-06

  articleOpen accessSenior author
  PublisherDOI

Recent grants

• NIH Grant P20CA210285

  NIH · $1.0M · 2020

• NIH Grant R21CA097951

  NIH · $402k · 2005

• NIH Grant R01CA109232

  NIH · $2.5M · 2016

• Cancer Genetics Research Program

  NIH · $80.2M · 1997–2027

• Modulation of tumorigenesis by viral exosomes

  NIH · $94.0M · 1997–2027

Frequent coauthors

• Blossom Damania

  209 shared

• D. Avilov

  Syracuse University

  74 shared

• Satish Gopal

  National Cancer Institute

  71 shared

• Yuri Fedoriw

  University of North Carolina at Chapel Hill

  69 shared

• Sang‐Hoon Sin

  University of North Carolina at Chapel Hill

  63 shared

• Anthony Eason

  57 shared

• Nader Kim El‐Mallawany

  Baylor College of Medicine

  50 shared

• Richard F. Ambinder

  Johns Hopkins University

  49 shared

Education

• Ph.D., Microbiology and Immunology

  University of North Carolina at Chapel Hill

  1997

• M.S., Microbiology and Immunology

  University of North Carolina at Chapel Hill

  1993

• B.S., Microbiology and Immunology

  University of North Carolina at Chapel Hill

  1991