HIV-associated salivary gland disease: a role for BK birus

HIV-associated salivary gland disease (HIV-SGD) is disfiguring and causes significant morbidity in the HIV population. Evidence detailing the epidemiology of HIV-SGD suggests the involvement of a viral opportunist in its pathogenesis, yet the specific etiology of HIV-SGD remains unclear. To determine the role for an opportunistic virus as the etiologic agent of HIV-SGD, we hypothesized that HIV-SGD was a manifestation of primary infection or reactivation with a DNA tumor virus, BKV, during immune suppression. The central hypothesis of this work is that viral pathogenesis is essential to the development of salivary gland disease. Results show for the first time that polyomavirus, BKV, is associated with HIV-SGD. BKV DNA, RNA, and protein were consistently detected in salivary gland biopsies and in the peripheral blood and oral fluids from HIV-SGD patients and not in control subjects

BK virus has tropism for human salivary gland cells in vitro: Implications for transmission

BACKGROUND: In this study, it was determined that BKV is shed in saliva and an in vitro model system was developed whereby BKV can productively infect both submandibular (HSG) and parotid (HSY) salivary gland cell lines. RESULTS: BKV was detected in oral fluids using quantitative real-time PCR (QRTPCR). BKV infection was determined using quantitative RT-PCR, immunofluorescence and immunoblotting assays. The infectivity of BKV was inhibited by pre-incubation of the virus with gangliosides that saturated the major capsid protein, VP1, halting receptor mediated BKV entry into salivary gland cells. Examination of infected cultures by transmission electron microscopy revealed 45-50 nm BK virions clearly visible within the cells. Subsequent to infection, encapsidated BK virus was detected in the supernatant. CONCLUSION: We thus demonstrated that BKV was detected in oral fluids and that BK infection and replication occur in vitro in salivary gland cells. These data collectively suggest the potential for BKV oral route of transmission and oral pathogenesis

Viral infections associated with oral cancers and diseases in the context of HIV: a workshop report

Human herpesviruses (HHVs) and Human papillomaviruses (HPV) are common in the general population and, in immunocompetent people, are mostly carried asymptomatically. However, once an individual becomes immunocompromised by age, illness, or HIV infection these dormant viruses can manifest themselves and produce disease. In HIV-positive patients there is an increased risk of disease caused by HHVs and HPV infections and cancers caused by the oncoviruses EBV, HHV-8, and HPV. This workshop examined four questions regarding the viruses associated with oral cancers disease in the HIV-positive and -negative populations, the immune response, and biomarkers useful for accurate diagnostics of these infections and their sequalae. Each presenter identified a number of key areas where further research is required

HIV-associated salivary gland disease: a role for BK birus

HIV-associated salivary gland disease (HIV-SGD) is disfiguring and causes significant morbidity in the HIV population. Evidence detailing the epidemiology of HIV-SGD suggests the involvement of a viral opportunist in its pathogenesis, yet the specific etiology of HIV-SGD remains unclear. To determine the role for an opportunistic virus as the etiologic agent of HIV-SGD, we hypothesized that HIV-SGD was a manifestation of primary infection or reactivation with a DNA tumor virus, BKV, during immune suppression. The central hypothesis of this work is that viral pathogenesis is essential to the development of salivary gland disease. Results show for the first time that polyomavirus, BKV, is associated with HIV-SGD. BKV DNA, RNA, and protein were consistently detected in salivary gland biopsies and in the peripheral blood and oral fluids from HIV-SGD patients and not in control subjects

Polymicrobial Infection and Bacterium-Mediated Epigenetic Modification of DNA Tumor Viruses Contribute to Pathogenesis

ABSTRACTThe human body plays host to a wide variety of microbes, commensal and pathogenic. In addition to interacting with their host, different microbes, such as bacteria and viruses, interact with each other, sometimes in ways that exacerbate disease. In particular, gene expression of a number of viruses, including Kaposi’s sarcoma-associated herpesvirus (KSHV), Epstein-Barr virus (EBV), and human immunodeficiency virus (HIV), is known to be regulated by epigenetic modifications induced by bacteria. These viruses establish latent infection in their host cells and can be reactivated by bacterial products. Viral reactivation has been suggested to contribute to periodontal disease and AIDS. In addition, bacterium-virus interactions may play a role in cancers, such as Kaposi’s sarcoma, gastric cancer, and head and neck cancer. It is important to consider the effects of coexisting bacterial infections when studying viral diseases in vivo

Human BK Polyomavirus—The Potential for Head and Neck Malignancy and Disease

Members of the human Polyomaviridae family are ubiquitous and pathogenic among immune-compromised individuals. While only Merkel cell polyomavirus (MCPyV) has conclusively been linked to human cancer, all members of the polyomavirus (PyV) family encode the oncoprotein T antigen and may be potentially carcinogenic. Studies focusing on PyV pathogenesis in humans have become more abundant as the number of PyV family members and the list of associated diseases has expanded. BK polyomavirus (BKPyV) in particular has emerged as a new opportunistic pathogen among HIV positive individuals, carrying harmful implications. Increasing evidence links BKPyV to HIV-associated salivary gland disease (HIVSGD). HIVSGD is associated with elevated risk of lymphoma formation and its prevalence has increased among HIV/AIDS patients. Determining the relationship between BKPyV, disease and tumorigenesis among immunosuppressed individuals is necessary and will allow for expanding effective anti-viral treatment and prevention options in the future

Impact of periodontal intervention on local inflammation, periodontitis, and HIV outcomes

Periodontal disease resolution was hypothesized to impact systemic HIV measures

A dynamic model for induced reactivation of latent virus

We develop a deterministic mathematical model to describe reactivation of latent virus by chemical inducers. This model is applied to the reactivation of latent KSHV in BCBL-1 cell cultures with butyrate as the inducing agent. Parameters for the model are first estimated from known properties of the exponentially growing, uninduced cell cultures. Additional parameters that are necessary to describe induction are determined from fits to experimental data from the literature. Our initial model provides good agreement with two independent sets of experimental data, but also points to the need for a new class of experiments which are required for further understanding of the underlying mechanisms

Signaling Cascades Triggered by Bacterial Metabolic End Products during Reactivation of Kaposi's Sarcoma-Associated Herpesvirus

The present studies explore the role of polymicrobial infection in the reactivation of Kaposi's sarcoma-associated herpesvirus (KSHV) and analyze signaling pathways activated upon this induction. We hypothesized that activation of the cellular stress-activated mitogen-activated protein kinase (MAPK) p38 pathway would play a key role in the bacterium-mediated disruption of viral latency similar to that of previously reported results obtained with other inducers of gammaherpesvirus lytic replication. KSHV within infected BCBL-1 cells was induced to replicate following exposure to metabolic end products from gram-negative or -positive bacteria that were then simultaneously exposed to specific inhibitors of signal transduction pathways. We have determined that bacterium-mediated induction of lytic KSHV infection is significantly reduced by the inhibition of the p38 MAPK pathway. In contrast, inhibition of the phosphatidylinositol 3-kinase pathway did not impair induction of lytic replication or p38 phosphorylation. Protein kinase C, though activated, was not the major pathway used for bacterium-induced viral reactivation. Furthermore, hyperacetylation of histones 3 and 4 was detected. Collectively, our results show that metabolic end products from these pathogens induce lytic replication of KSHV in BCBL-1 cells primarily via the activation of a stress-activated MAPK pathway. Importantly, we demonstrate for the first time a mechanism by which polymicrobial bacterial infections result in KSHV reactivation and pathogenesis

Bacteria-mediated reactivation of gammaherpesviruses

Significant morbidity is associated with the synergistic and inhibitory interactions of bacteria, viruses, parasites, and fungi. The oral cavity, gut, and genitourinary tract are home to many of these organisms and are the site of virus-associated malignancies that affect millions worldwide. Yet little is known with regard to the cellular and molecular interactions of viral pathogens with the normal flora as well as the interactions among pathogens themselves. Our laboratory is interested in understanding the role of factors present within the immediate environment that may influence reactivation of persistent infection and pathogenesis. Our central hypothesis is that viral-bacterial interactions foster enhanced pathogen replication and modulation of the immune response in the mouth, GI tract, and genito-urinary tract. The detection of replicating virus in these tissues has incited investigation into the relationship between bacterial infection and herpesviral reactivation. We hypothesized that bacterial end-products including short chain fatty acids (SCFA), lipopolysaccharide (LPS), and lipoteichoic acid (LTA) secreted by oral bacteria initiate viral reactivation from latency. Latently infected EBV, KSHV, and MHV 68 cell lines were incubated with crude spent media containing secreted SCFA, and components of bacterial pathogens (E. faecalis, Bacteriodes, Prevotella, Porphomonas, and Fusiobacterium Nucleatum). Cells were then assayed for viral promoter activation, promoter-protein interactions, and state of infection. Following incubation with crude spent media, viral immediate early promoters were activated, the viral early genes were upregulated as determined by RT PCR and western blot, and linear genomes were detected. HDAC inhibition activity as well as protein kinase C activity increased significantly following treatment with bacterial spent media. KSHV and EBV were consistently reactivated by bacterial metabolites but the mechanism of reactivation was both bacteria, virus, and cell type specific. Interestingly, EBV was preferentially reactivated following toll like receptor stimulation while KSHV and HSV-1 reactivation occurred following HDAC inhibition. In conclusion, these studies provide significant insights to gammaherpesreactivation that may occur in vivo via pathogen-pathogen interaction