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PubMed1992

Herpes simplex virus type 2 and pseudorabies virus associated growth factors and their role in the latency in vitro.

A putative herpes simplex virus type 2 (HSV-2) growth factor (HSGF-2) was detected in a crude extract from virus infected mouse embryo cells. This factor, similar to previously described pseudorabies virus (PRV) associated growth factor (PRGF) was shown to have ability to morphologically transform non-transformed cells and to repress the transformed phenotype of transformed cells. Both activities could be neutralized with two, out of seven monoclonal antibodies directed against glycoprotein B of HSV-2. Both PRGF and HSGF-2 were detected in human embryo lung cells latently infected with PRV or HSV-2 either at 41 degrees C, or in the presence of phosphonoacetic acid. Human alpha-2 interferon, when present in medium of latently infected cells enhanced the production of both HSGF and PRGF. On the contrary, when latently infected cells were treated with 5-azacytidine the synthesis of both PRGF and HSGF-2 was completely blocked and the virus reactivated from latency replicated to higher titers than in non-treated cells. The role of PRGF and HSGF-2 in the establishment, maintenance and reactivation of latency, as well as in cellular transformation is discussed.

Animals↗
PubMed1975

Effect of host age, virus dose, and route of inoculation on tumor incidence, latency, and morphology in Syrian hamsters inoculated intravenously with oncogenic DNA simian virus 40.

Three-week-old to 12-month-old male Syrian hamsters were inoculated iv with 10(8.5) median tissue culture infective dose of simian virus 40 (SV40). Three-week-old hamsters were similarly inoculated with aliquots of SV40 of progressively decreasing titers. The tumor incidence and, to a lesser extent, the tumor latency were directly dependent on the age of the animals at the time of virus exposure and on the dose of the virus. However, this age-dose dependence was not of the magnitude usually observed in hamsters inoculated with SV40 sc or im. Moreover, the wide morphologic spectrum of neoplasms induced, i.e., lymphosarcoma, reticulum cell sarcoma, and osteogenic sarcoma, by iv route of inoculation, contrasted sharply with the anaplastic and spindle-cell sarcomas which were the only types of malignant tumors resulting when other routes were used.

Age Factors↗
PubMed1979

Acylovir in oral and ganglionic herpes simplex virus infections.

The local and trigeminal ganglionic therapeutic efficacy of two topical and systemic antiviral drugs was studied in mouse lips inoculated with herpes simplex virus type 1 after thermal injury. Application of topical 3% acylovir (acycloguanosine) ointment three times daily for four days completely blocked the replication of virus in the lips, and the healing process was greatly accelerated compared with that in placebo-treated infected controls. However, neither the healing process nor the viral replication was influenced by similar therapy with 3% vidarabine ointment. When given systemically for four days, starting one day after inoculation, acyclovir (40-60 mg/kg per day) and vidarabine (50 mg/kg per day) significantly reduced the clinical manifestations on the lips and viral titers of cultures obtained from the lips. Establishment of viral latency in the trigeminal ganglion was significnatly inhibited by systemic acyclovir (60 mg/kg per day), whereas systemic vidarabine (50 mg/kg per day) was ineffective. These data suggest that acyclovir may be one of the most promising antiviral agents for the management of oral herpes viral infections and trigeminal ganglionic latency of virus as demonstrated in the mouse model.

Animals↗
PubMed2025

Unidirectional recruitment between MeCP2 and KSHV-encoded LANA revealed by CRISPR/Cas9 recruitment assay.

Kaposi's sarcoma-associated herpesvirus (KSHV, HHV-8) is associated with several human malignancies. During latency, the viral genomes reside in the nucleus of infected cells as large non-integrated plasmids, known as episomes. To ensure episome maintenance, the latency protein LANA tethers the viral episomes to the cell chromosomes during cell division. Directional recruitment of protein complexes is critical for the proper function of many nuclear processes. To test for recruitment directionality between LANA and cellular proteins, we directed LANA via catalytically inactive Cas9 (dCas9) to a repeat sequence to obtain easily detectable dots. Then, the recruitment of nuclear proteins to these dots can be evaluated. We termed this assay CRISPR-PITA for Protein Interaction and Telomere Recruitment Assay. Using this protein recruitment assay, we found that LANA recruits its known interactors ORC2 and SIN3A. Interestingly, LANA was unable to recruit MeCP2, but MeCP2 recruited LANA. Both LANA and histone deacetylase 1 (HDAC1) interact with the transcriptional-repression domain (TRD) and the methyl-CpG-binding domain (MBD) of MeCP2. Similar to LANA, HDAC1 was unable to recruit MeCP2. While heterochromatin protein 1 (HP1), which interacts with the N-terminal of MeCP2, can recruit MeCP2. We propose that available interacting domains force this recruitment directionality. We hypothesized that the tandem repeats in the SunTag may force MeCP2 dimerization and mimic the form of DNA-bound MeCP2. Indeed, providing only the tandem epitopes of SunTag allows LANA to recruit MeCP2 in infected cells. Therefore, CRISPR-PITA revealed the rules of unidirectional recruitment and allowed us to break this directionality.

Humans↗
PubMed2025

Modulation of Cell Cycle Kinases by Kaposi's Sarcoma-Associated Herpesvirus.

The cell cycle is governed by kinase activity that coordinates progression through a series of regulatory checkpoints, preventing the division of damaged cells. The Kaposi's sarcoma-associated herpesvirus (KSHV) encodes multiple genes that modulate or co-opt the activity of these kinases, shaping the cellular environment to promote viral persistence. By advancing the cell cycle, KSHV facilitates latent replication and subsequent transmission of viral genomes to daughter cells, while also contributing to the establishment of multiple cancer types. Conversely, during viral lytic replication, KSHV extends the resting phase of the cell cycle to prevent cellular DNA synthesis that would otherwise compete for essential replication precursors. This review will examine the mechanisms KSHV has evolved to control the kinase activity regulating host cell cycle progression.

Herpesvirus 8, Human↗
PubMed2025

Tracking HIV persistence across T cell lineages during early ART-treated HIV-1-infection using a reservoir-marking humanized mouse model.

Human immunodeficiency virus (HIV) infection depletes CD4 T-cells, and long-term persistence of latent virus prevents full clearance of HIV even in the presence of effective antiretroviral therapy (ART), Here we present the HIV-1-induced lineage tracing (HILT) system, a model that irreversibly marks infected cells within a humanized mouse model, which detects rare latently infected cells. Immunodeficient mice transplanted with genetically modified hematopoietic stem cells develop a human immune system, in which CD4 T-cells contain a genetic switch that permanently labels cells infected by HIV-1 expressing cre-recombinase. Through single-cell RNA sequencing of HILT-marked cells during acute infection and post-ART treatment, we identify distinct CD4+ T-cell transcriptional lineages enriched in either active or latent infections. Comparative gene expression analysis highlights common pathways modulated in both states, including EIF2, Sirtuin, and protein ubiquitination. Critical regulators of these pathways, including JUN, BCL2, and MDM2, change to opposite directions in the two states, highlighting gene expression programs that may support HIV persistence across T-cell lineages and states.

Animals↗
PubMed1975

Immunology of herpes simplex virus in fection.

The accompanying inflammation seen in ocular HSV infection-the result of interactions between viruses and the immune response-can be both beneficial and potentially harmful to the host. An understanding of the interaction of virus-immune cells is just evolving from current advances in basic research. Based on our studies on HSV keratitis [11], the control of ocular HSV infection appears to involve an early inflammatory phase with macrophage reactivity and elaboration of MIF. Transient virus-specific lymphocytes with effector reactivity, as well as neutrophils with chemotactic activity, occur during the stromal keratitis. Finally, antibody-dependent complement-mediated lysis provides another phase of restriction of infection. Thus, a rationale for effective management and therapy of occular HSV disease must be based on an understanding of (1) the immunological and immunopathological mechanisms of corneal inflammatory disease initiated by the virus; (2) the immunological mechanisms in recovery from the disease; and (3) the host's humoral and cellular immune status during virus persistence (latency) and during recurrent episodes of infection. We hope that new information obtained from assessment of roles of the humoral and cellular immune responses in recovery from disease and in recurrent disease will provide new approaches to the management of ocular HSV infections.

Antibodies, Viral↗
PubMed2026

The brain as an HIV reservoir: Recent findings using autopsy tissues from people with HIV.

HIV persistence within anatomical reservoirs remains the primary barrier to achieving an HIV cure. While antiretroviral therapy effectively suppresses plasma viremia, it does not eliminate integrated proviral genomes that persist in long-lived cellular compartments. The central nervous system (CNS) is a clinically important HIV reservoir, characterized by immune privilege and the persistence of tissue-resident infection despite effective antiretroviral therapy (ART). Evidence from postmortem studies reveals that HIV DNA, RNA, and even intact replication-competent proviruses remain detectable in brain tissue from virally suppressed people with HIV. Evidence derived primarily from in situ approaches and viable-cell studies supports myeloid-lineage reservoirs, particularly microglia and CNS-associated macrophages, as key cellular sources of persistence, while the extent and biological relevance of astrocyte infection remains debated. These reservoirs exhibit transcriptional activity and are associated with chronic neuroinflammation, which may contribute to HIV-associated neurocognitive disorders, despite systemic viral suppression. Here, we synthesize recent findings from autopsy brain studies, including work enabled by major biorepositories, such as the National NeuroHIV Tissue Consortium and rapid-autopsy programs, including the Last Gift, both of which are essential for studying HIV reservoirs in the CNS. We summarize methodologies for detecting and characterizing HIV in brain tissue, highlight heterogeneous patterns of regional distribution and compartmentalization, and review emerging links between CNS persistence and neuroinflammation. We conclude with priorities for harmonized tissue processing, multi-modal single-cell and spatial profiling, and coordinated cross-cohort analyses to clarify the contribution of CNS reservoirs to neuroHIV pathogenesis and systemic rebound.

Humans↗
PubMed1975

Latency of Herpes Simiae (B virus) in rabbits.

When small doses of herpes simplex virus (HSV) were given to rabbits a significant degree of protection was afforded against later infection with herpes simiae (B virus). Only 12/47 rabbits died within 3 weeks of receiving B virus dosages that would normally have proved lethal. B virus became latent in survivors and was recovered from brain and spinal cord suspensions from rabbits which died within 6 months and from dorsal root ganglia of rabbits which had survived for more than 2 years without overt signs of infection. A minority of the survivors tested also yielded HSV. Rabbits with latent B virus in the ganglia showed little or no detectable neutralizing antibody to B virus. The possibility is discussed that human populations having a high frequency occurrence of HSV antibody may include carriers of latent B virus.

Animals↗
PubMed1975

Acute and recurrent infection with herpes simplex virus in the mouse: a model for studying latency and recurrent disease.

Nineteen recent isolated and three laboratory strains of herpes simplex virus types 1 and 2 were tested for their ability to produce clinical signs in mice following intradermal inoculation in the ear. All viruses produced erythema at the inoculation site; this was the most sensitive clinical sign of infection. Virus multiplication in the ear tissue was similar for both types 1 and 2 up to the fifth day after inoculation but type 2 viruses persisted for longer. Latent infection was demonstrated in cervical dorsal root ganglia. Type 1 viruses required a much higher dose than type 2 to produce neurological signs and death after intradermal inoculation but the difference was less after intracerebral inoculation. Erythema of the inoculated ear recurred sporadically during several months observation in about half the mice that survived intradermal infection with a selected type 1 isolate. The presence of virus in the ear tissue during such recurrences was confirmed by electron microscopy and isolation of infectious virus. The system of ear infection in the mouse is presented as a new model for studying neurovirulence, and latent and recurrent infection with herpes simplex virus.

Animals↗
PubMed1978

Herpes simplex virus vaccine: protection from stomatitis, ganglionitis, encephalitis and latency.

A mouse model system was developed for studying the pathogenesis of oral infection with herpes simplex virus type 1 and the protection offered by prior immunization with a nucleic acid-free vaccine. Of non-immunized mice, 95-100% developed ulcerative lesions 3-5 days following application of virus to abraded oral epithelial surfaces. Infection of the ipsilateral sensory (trigeminal) ganglion and the cerebellum occurred by day 2 and sequentially progressed to the contralateral ganglion by day 4 and to the cerebrum by day 5. Prior immunization of mice with an inactivated virus vaccine, and most importantly, with a vaccine free of nucleic acid, protected mice from subsequent oral virus infection. Protection was demonstrated by: (i) reduction in the incidence and severity of primary oral lesions; (ii) a decrease in the number of mice with acute ganglionic infection or dying of encephalitis; and (iii) a reduction in the incidence of latent trigeminal ganglionic infection.

Animals↗
PubMed2025

Viral Enhancers Orchestrate Kaposi's Sarcoma-Associated Herpesvirus Transcription.

Kaposi's sarcoma-associated herpesvirus (KSHV), the etiological agent of Kaposi's sarcoma and other lymphoproliferative disorders, presents a delicate balance between host cell manipulation, and orchestrating its transcriptional repertoire. Like all herpes viruses, the virus can reside in latency, expressing only a handful of proteins or launch a lytic program that expresses over 80 proteins responsible for the generation and release of new virions. Enhancers, as their name suggests, can enhance the transcription rate from a promoter depending on the cellular environment and tissue. While the promoters in KSHV have been extensively studied, the enhancers were only recently identified. Here we will describe our current view on KSHV enhancers.

Herpesvirus 8, Human↗
PubMed1978

Incidence, latency, and morphologic types of neoplasms induced by simian virus 40 inoculated intravenously into hamsters of three inbred strains and one outbred stock.

The incidence, latency, and morphologic types of neoplasms induced in hamsters of the three inbred strains LSH/SsLak, LHC/Lak, and MHA/SsLak, inocuated iv at 3 weeks of age with 10(7.5) median tissue culture infective dose (TCID50) of simian virus 40 (SV40). were determined and compared with those of the outbred stock LVG/Lak. Although the incidence and latency were approximately the same in hamsters of the three inbred strains, hamsters of the outbred stock exhibited almost complete resistance to tumor induction under identical experimental conditions. The morphologic types of neoplasms, i.e., lymphocytic leukemia, reticulum cell sarcoma, osteogenic sarcoma, and anaplastic sarcoma, induced in inbred hamsters were similar to those induced in outbred hamsters inoculated iv with 10(8.5) TCID50 SV40. The lymphocytic leukemias that developed in the 2 LSH/SsLak inbred hamsters were established as tumor transplants in vivo and as permanent cell lines in vitro.

Animals↗
PubMed1979

Transplacental transmission and neonatal infection with swine influenza virus (Hsw1N1) in swine.

To study the question of chronicity or latency of swine influenza virus (Hsw1N1) infections in swine, newborn pigs were exposed to the virus in two experiments, and pregnant gilts were exposed in another experiment. Of five pigs exposed at 5 days of age, virus was isolated from throat swab samples of all (up to 10 postexposure days (PED) in one pig) and from a blood sample from one pig on PED 1 and 3. Virus was not isolated from urine, tissues, or explants of organs from pigs euthanatized PED 20 to 67, and disease was not evident. Of 11 pigs exposed within 2 hours of birth (before consuming colostrum), virus was shed for longer periods (for 10 and 11 days in four pigs) and severe respiratory tract pathologic changes developed. However, there was no evidence of chronic or latent infections. There was evidence of transplacental transmission of virus in one of ten pigs born to pregnant gilts that were exposed 10, 24, and 39 days before parturition, respectively.

Animals↗
PubMed1978

A biological perspective of slow virus infection and chronic disease.

Sequential events characterize the interaction of viruses with parenchymal cells, and acute lytic infections of tissues and organs have broad biological attributes. A knowledge of these permits a keener understanding of persistent, intermittent herpesvirus infections and persistent, continuous respiratory virus infections. In addition to unique biochemical mechanisms which may permit the latter chronic infections to evolve, the roles of defective and mutant strains of virus, viral interference, and the genetic, developmental and immunological expressions of the host are of considerable and provocative importance. The traditional view of viral infections embraces a broad spectrum of acute pathological and inflammatory events. The relationship of measles virus to subacute sclerosing panencephalitis, the elucidation of the latency of herpes simplex virus, and the slow unmasking of the pathogenesis of multiple sclerosis have illustrated the subtle elements of persistent viral infections of the human being. These chronic neurological diseases have provided the opportunity and stimulus for sharp dissection of the biological and biochemical processes which embellish the logical link of viral infections to other forms of chronic human illness.

Antibody Formation↗