The pathogenesis of simian varicella virus in cynomolgus monkeys.

The MLM herpesvirus is infectious for cynomolgus monkeys. The disease in this species, possibly modulated by preinoculation antibody resembles human varicella. Virus has been recovered from blood during the early incubation period, and from liver, lymph nodes, kidney, bladder and urine during the eruptive period of infection. The major target organs were skin and liver; specific pathological changes developed in both. Appropriate antibody responses, including those to Herpesvirus varicellae followed infections mounted by parenteral inoculation of cynomolgus monkeys.     

Naturally acquired simian varicella virus infection in African green monkeys

Simian varicella virus (SVV) infection of primates shares clinical, pathological, immunological, and virological features with varicella-zoster virus infection of humans. Natural varicella infection was simulated by exposing four SVV-seronegative monkeys to monkeys inoculated intratracheally with SVV, in which viral DNA and RNA persist in multiple tissues for more than 1 year (T. M. White, R. Mahalingam, V. Traina-Dorge, and D. H. Gilden, J. Neurovirol. 8:191-205, 2002). The four naturally exposed monkeys developed mild varicella 10 to 14 days later, and skin scrapings taken at the time of the rash contained SVV DNA. Analysis of multiple ganglia, liver, and lung tissues from the four naturally exposed monkeys sacrificed 6 to 8 weeks after resolution of the rash revealed SVV DNA in ganglia at multiple levels of the neuraxis but not in the lung or liver tissue of any of the four monkeys. This animal model provides an experimental system to gain information about varicella latency with direct relevance to the human disease.     

Experimental simian varicella virus infection of St. Kitts vervet monkeys

Experimental simian varicella virus (SVV) infection of St. Kitts vervet monkeys was evaluated as an animal model to investigate human varicella-zoster virus (VZV) infections. During the incubation period, viremia disseminated infectious virus throughout the body via infected peripheral blood lymphocytes (PBLs). A vesicular skin rash in the inguinal area, and on the abdomen, extremities, and face appeared on day 7–10 postinfection. Necrosis and hemorrhage in lung and liver tissues from acutely infected monkeys were evident upon histologic analysis. Recovery from simian varicella was accompanied by a rise in the serum neutralizing antibody response to the virus. SVV latency was established in trigeminal ganglia of monkeys which resolved the acute infection. This study indicates that experimental SVV infection of St. Kitts vervets is a useful animal model to investigate SVV and VZV pathogenesis and to evaluate potential antiviral agents and vaccines.     

Disseminated simian varicella virus infection in an irradiated rhesus macaque (Macaca mulatta)

We describe correlative clinicopathological/virological findings from a simian varicella virus (SVV)-seronegative monkey that developed disseminated varicella 105 days after gamma-irradiation. Twelve other monkeys in the colony were also irradiated, none of which developed varicella. Before irradiation, sera from the monkey that developed disseminated infection and one asymptomatic monkey were available. Analysis indicated that subclinical reactivation of latent SVV from an asymptomatic irradiated monkey likely led to disseminated varicella in the seronegative irradiated monkey. These findings parallel those from humans with disseminated varicella infection and support the usefulness of SVV infection as a model for human varicella-zoster virus infection, particularly virus reactivation after gamma-irradiation.     

The transforming proteins of simian virus 40

Simian virus 40 (SV40) is a small DNA tumor virus whose early gene products, large T and small t antigens, efficiently immortalize and transform primary rodent cells, transform rodent cell lines and extend the lifespan of primary human cells. Mutational analysis has revealed that the transforming and lifespan extension properties of large T antigen correlate with binding to and disruption of the normal functions of the human tumor suppressor proteins pRb and p53. Small t antigen contributes to cell proliferation through inactivation of protein phosphatase 2A and subsequent activation of the MAP kinase pathway. By disrupting key cell growth control mechanisms, SV40 transforming proteins provide a valuable system for analysis of cellular growth control mechanisms.     

Salt-stable association of simian virus 40 capsid with simian virus 40 DNA

In 8 M CsCl, a fraction of the wild-type previrions and tsB228 nucleoprotein complexes lose their core histones but retain their capsid. These histone-depleted complexes appear in the electron microscope as a protein shell attached to supercoiled DNA. Consistent with this result, we find that in 1 M NaCl, the wild-type previrions dissociate into two populations of nucleoprotein complexes. One population sediments between 50 and 140 S and morphologically resembles the shell-DNA complexes isolated in CsCl gradients. The other population is comprised primarily of nucleoproteins which sediment at 40 S.     

The simian virus 40 large tumor antigen

In this review, I hope to achieve the following: (a) to document the presence of a lysosome-like proton pump ATPase in many different membrane systems of animal, plant and microbial origin; (b) to glean from the diverse data common characteristics of these ATPases, especially as regards their similarities and differences with mitochondrial-type F1F0 proton pump ATPases; and (c) to consider questions of synthesis and regulation of a cellular proton pump system with such a widespread distribution.     

Specific association of simian virus 40 tumor antigen with simian virus 40 chromatin

Simian virus 40 tumor antigen (SV40 T antigen) was bound to both replicating and fully replicated SV40 chromatin extracted with a low-salt buffer from the nuclei of infected cells, and at least a part of the association was tight specific. T antigen cosedimented on sucrose gradients with SV40 chromatin, and T antigen-chromatin complexes could be precipitated from the nuclear extract specifically with anti-T serum. From 10 to 20% of viral DNA labeled to steady state with [3H]thymidine for 12 h late in infection or 40 to 50% of replicating viral DNA pulse-labeled for 5 min was associated with T antigen in such immunoprecipitates. After reaction with antibody, most of the T antigen-chromatin complex was stable to washing with 0.5 M NaCl, but only about 20% of the DNA label remained in the precipitate after washing with 0.5 M NaCl-0.4% Sarkosyl. This tightly bound class of T antigen was associated preferentially with a subfraction of pulse-labeled replicating DNA which comigrated with an SV40 form I marker. A tight binding site for T antigen was identified tentatively by removing the histones with dextran sulfate and heparin from immunoprecipitated chromatin labeled with [32P]phosphate to steady state and then digesting the DNA with restriction endonucleases HinfI and HpaII. The site was within the fragment spanning the origin of replication, 0.641 to 0.725 on the SV40 map.     

A simian varicella virus (SVV) homolog to varicella-zoster virus gene 21 is expressed in monkey ganglia latently infected with SVV.

We have sequenced a simian varicella virus (SVV) open reading frame (ORF), 3,123 bp in length, whose product has 51% amino acid homology with the sequence encoded by the ORF of varicella-zoster virus gene 21. Several regions are highly conserved between the two ORFs, with homologies of approximately 80%. The SVV gene is transcribed in tissue culture cells productively infected with SVV and in monkey ganglia latently infected with SVV.     

Increased cellular immune responses and CD4+ T-cell proliferation correlate with reduced plasma viral load in SIV challenged recombinant simian varicella virus - simian immunodeficiency virus (rSVV-SIV) vaccinated rhesus macaques

ABSTRACT: BACKGROUND: An effective AIDS vaccine remains one of the highest priorities in HIV-research. Our recent study showed that vaccination of rhesus macaques with recombinant simian varicella virus (rSVV) vector -- simian immunodeficiency virus (SIV) envelope and gag genes, induced neutralizing antibodies and cellular immune responses to SIV and also significantly reduced plasma viral loads following intravenous pathogenic challenge with SIVMAC251/CX1. FINDINGS: The purpose of this study was to define cellular immunological correlates of protection in rSVV-SIV vaccinated and SIV challenged animals. Immunofluorescent staining and multifunctional assessment of SIV-specific T-cell responses were evaluated in both Experimental and Control vaccinated animal groups. Significant increases in the proliferating CD4+ T-cell population and polyfunctional T-cell responses were observed in all Experimental-vaccinated animals compared with the Control-vaccinated animals. CONCLUSIONS: Increased CD4+ T-cell proliferation was significantly and inversely correlated with plasma viral load. Increased SIV-specific polyfunctional cytokine responses and increased proliferation of CD4+ T-cell may be crucial to control plasma viral loads in vaccinated and SIVMAC251/CX1 challenged macaques.     

Subcellular localization of the simian virus 40 agnoprotein

The intracellular distribution of the simian virus 40 agnoprotein in infected cells was determined by indirect immunofluorescence and biochemical fractionation followed by indirect immunoprecipitation. The specific antibodies used in these studies were directed against either purified agnoprotein or a synthetic oligopeptide homologous to the N-terminus of the processed protein. Both procedures showed predominant localization of the agnoprotein to the cytosol and to the perinuclear region in association with the outer nuclear membrane. A minor but detectable fraction of the protein was also found in the nucleus. The definition of its subcellular distribution, as well as its high lability in vivo and affinity for nucleic acid, provide a basis for speculation on the function of this gene product.     

Genetic diversity of simian immunodeficiency virus

We have demonstrated that the genetic diversity of simian immunodeficiency virus from African green monkeys (SIVagm) is much greater than that observed previously for individual HIV-1, HIV-2, or SIVmac isolates. Extensive genetic variation among SIVagm isolates and the high prevalence of green monkey infection without disease suggest that the virus has been in the green monkey population for a long time. We have also demonstrated that SIV from a sooty mangabey monkey (isolate SMM-7) is closer to SIVmac and HIV-2 than to HIV-1 and SIVagm. The extensive genetic diversity of SIVagm and the relatedness of SIVsmm to HIV-2 warrant continued examination of SIVagm and SIVsmm isolates from dispersed geographic regions. SIV strains much more closely related to HIV-1, HIV-2, or SIVmac may be found which would be reasonable candidates for recent cross-species transmission.     

Novel simian homologues of Epstein-Barr virus

Thirty different lymphocryptoviruses (LCV), 26 of them novel, were detected in primates by a panherpesvirus PCR assay. Nineteen LCV from chimpanzees, bonobos, gorillas, and other Old World primates were closely related to Epstein-Barr virus (EBV), the type species of the genus lymphocryptovirus. Seven LCV originating from New World primates were related to callitrichine herpesvirus 3 (CalHV-3), the first recognized New World LCV. Importantly, a second LCV from gorillas and three LCV from orangutans and gibbons were only distantly related to EBV and CalHV-3. They were tentatively assigned to a novel genogroup of Old World primate LCV. The work described in the paper may also help identify an as yet unknown human LCV.     

The simian origins of the pathogenic human T-cell lymphotropic virus type I

At least four, and possibly six, molecular subtypes of human T-cell lymphotropic virus type I (HTLV-I) exist: one is confined to Melanesia/Australia, one is ubiquitous, and the others are found only in Africa. Molecular epidemiology suggests that all subtypes arose from separate interspecies transmissions from simians to humans.     

Association of simian virus 40 T antigen with replicating nucleoprotein complexes of simian virus 40.

An immunoprecipitation assay was established for simian virus 40 T-antigen-bound nucleoprotein complexes by means of precipitation with sera from hamsters bearing simian virus 40-induced tumors. About 80% of simian virus 40 replicating nucleoprotein complexes in various stages of replication were immunoprecipitated. In contrast, less than 21% of mature nucleoprotein complexes were immunoprecipitated. Pulse-chase experiments showed that T antigen was lost from most of the nucleoprotein complexes concurrently with completion of DNA replication. T antigen induced by dl-940, a mutant with a deletion in the region coding for small T antigen, was also associated with most of the replicating nucleoprotein complexes. Once bound with replicating nucleoprotein complexes at the permissive temperature, thermolabile T antigen induced by tsA900 remained associated with the complexes during elongation of the replicating DNA chain at the restrictive temperature. These results suggest that simian virus 40 T antigen (probably large T antigen) associates with nucleoprotein complexes at or before initiation of DNA replication and that the majority of the T antigen dissociates from the nucleoprotein complexes simultaneously with completion of DNA replication.