Abrogation of tolerance to a chronic viral infection

This study documents failure of peripheral tolerance mechanisms in a chronic viral infection and shows that T cell tolerance to a viral Ag seen as self from fetal life can be broken despite the presence of this Ag in extrathymic tissues. Congenital infection of mice with lymphocytic choriomeningitis virus (LCMV) results in T cell tolerance to the virus. Such mice become carriers for life harboring virus in many tissues including the thymus and exhibit no LCMV-specific CTL responses. Our previous studies have documented the curing of this congenitally acquired chronic infection after adoptive transfer of CD8+ T cells from LCMV-immune mice and the presence of host-derived, LCMV-specific CTL in these "cured" carriers. In this study we have examined the mechanism by which these carriers acquired T cell competence and show that these CTL differentiated from the bone marrow after elimination of viral Ag from the thymus. These results demonstrate that even when a chronic infection has been established in utero, the adult thymus retains the ability to restore immunocompetence to the host and to provide protection against reinfection. Surprisingly, these LCMV specific CTL were acquired at a time when infectious virus and intracellular viral Ag, although cleared from the thymus, were readily detectable in organs such as the kidney, testes, and brain. In fact, active viral replication in peripheral tissues was ongoing when these mice acquired new virus-specific T cells. These results show that clearance of virus form the thymus was sufficient to abrogate tolerance to a congenitally acquired chronic infection and that Ag in peripheral tissues did not tolerize newly developing T cells. These findings suggest that mechanisms that operate on immature cells within the thymus to silence self-reactive T cells are effective in induction of tolerance to viruses, but mechanisms of tolerizing mature T cells are likely to breakdown. This has implications for virus-induced autoimmunity and for treatment of chronic infections.     

Low dynamic state of viral competition in a chronic avian hepadnavirus infection

The dynamic state of infection of 11 ducks with the duck hepatitis B virus was investigated. Chronic infections were established in newly hatched ducklings by inoculation with a mixture of wild-type virus and a mutant virus with a partial replication defect. As expected, the wild-type virus was rapidly enriched in the virus population during the spread of infection. Enrichment thereafter was correlated with normal growth of the liver, with the average mutant-to-wild-type ratio stabilizing for at least 2 months beyond the time at which the liver mass stabilized. Using experimentally determined growth rates for the mutant and wild-type viruses, we estimated that after the spread of infection, competition between the two virus strains was limited by the amount of replication required to infect new hepatocytes in the growing livers. The results suggest that, in a chronically infected liver, the selection of variants with a replication rate advantage is inefficient and that the emergence of such variants would depend on induced liver cell turnover, such as that occurring during chronic hepatitis.     

Eicosanoids mediate Galleria mellonella cellular immune response to viral infection

Nodulation is the predominant insect cellular immune response to bacterial and fungal infections and it can also be induced by some viral infections. Treating seventh instar larvae of greater wax moth Galleria mellonella with Bovine herpes simplex virus-1 (BHSV-1) induced nodulation reactions in a dose-dependent manner. Because eicosanoids mediate nodulation reactions to bacterial and fungal infection, we hypothesized that eicosanoids also mediate nodulation reactions to viral challenge. To test this idea, we injected G. mellonella larvae with indomethacin, a nonsteroidal anti-inflammatory drug immediately prior to intrahemocoelic injection of BHSV-1. Relative to vehicle-treated controls, indomethacin-treated larvae produced significantly reduced numbers of nodules following viral infection (down from approximately 190 nodules/larva to <50 nodules/larva). In addition to injection treatments, increasing dietary indomethacin dosages (from 0.01% to 1%) were associated with decreasing nodulation (by 10-fold) and phenoloxidase activity (by 3-fold) reactions to BHSV-1 injection. We infer from these findings that cyclooxygenase products, prostaglandins, mediate nodulation response to viral infection in G. mellonella.     

A chronic viral infection model with immune impairment

In this paper, a chronic viral infection model with cell-mediated immunity and immune impairment is proposed and studied, under the assumption that the presence of the antigen can both stimulate and impair immunity. It is shown that the virus persists in the host if the basic reproductive ratio of the virus is greater than 1. The immune cells persist when there is only one positive equilibrium. The system can exhibit two positive equilibria if the basic reproductive ratio of the virus is above a threshold. This allows a bistable behavior, and the immune cells persist or die out, i.e., infection will result in disease or immune control outcome, depending on the initial conditions. By theoretical analysis and numerical simulations, we show that therapy could shift the patient from a disease progression to an immune control outcome, despite that the therapy is not necessarily lifelong. This would allow the immune response to control the virus in the long term even in the absence of continued therapy.     

Rejuvenating exhausted T cells during chronic viral infection

In a recent paper in Nature, show that the immunoreceptor PD-1 is upregulated by "exhausted" T cells during the chronic phase of viral infection in mice. Remarkably, blocking the interaction between PD-1 and its ligand, PD-L1, reactivates these T cells and reduces viral load.     

Patients with chronic viral hepatitis as sources of infection

Dynamic observation on 126 foci of infection formed by patients with manifest forms of chronic hepatitis B, 41 foci of chronic hepatitis of unknown etiology, and 37 foci formed by chronic "healthy" carriers was made. In the foci of type 1 the epidemic process developed intensively and was manifested mainly by HBsAg carriership in persons having had contacts with the patients. During the period of observation 43.0% of new cases of infection were detected. In the foci of types 2 and 3 the frequency of contacting infection was not different from that in the control group of the population.     

Properties of a persistent viral infection: possible lysogeny by an enveloped nonlytic mycoplasmavirus.

MVL2, an enveloped double-stranded DNA mycoplasmavirus, causes a nonlytic infection of Acholeplasma laidlawii leading to the establishment of a persistent infection. Persistently infected clones were found to be resistant to superinfection by homologous virus, but could be infected by heterologous virus. Cells in a persistently infected culture had the potential to produce virus and transmitted this potential as a stable heritable trait. Mitomycin C and UV light induced an increase in infectious centers in persistently infected cultures.     

Linking dynamical and population genetic models of persistent viral infection

This article develops a theoretical framework to link dynamical and population genetic models of persistent viral infection. This linkage is useful because, while the dynamical and population genetic theories have developed independently, the biological processes they describe are completely interrelated. Parameters of the dynamical models are important determinants of evolutionary processes such as natural selection and genetic drift. We develop analytical methods, based on coupled differential equations and Markov chain theory, to predict the accumulation of genetic diversity within the viral population as a function of dynamical parameters. These methods are first applied to the standard model of viral dynamics and then generalized to consider the infection of multiple host cell types by the viral population. Each cell type is characterized by specific parameter values. Inclusion of multiple cell types increases the likelihood of persistent infection and can increase the amount of genetic diversity within the viral population. However, the overall rate of gene sequence evolution may actually be reduced.     

Genetic analysis of resistance to viral infection

As machines that reprogramme eukaryotic cells to suit their own purposes, viruses present a difficult problem for multicellular hosts, and indeed, have become one of the central pre-occupations of the immune system. Unable to permanently outpace individual viruses in an evolutionary footrace, higher eukaryotes have evolved broadly active mechanisms with which to sense viruses and suppress their proliferation. These mechanisms have recently been elucidated by a combination of forward and reverse genetic methods. Some of these mechanisms are clearly ancient, whereas others are relatively new. All are remarkably adept at discriminating self from non-self, and allow the host to cope with what might seem an impossible predicament.     

Crash of a population of the marine heterotrophic flagellate Cafeteria roenbergensis by viral infection

Viruses are known as important mortality agents of marine microorganisms. Most studies focus on bacterial and algal viruses, and few reports exist on viruses infecting marine heterotrophic protists. Here we show results from several incubations initiated with a microbial assemblage from the central Indian Ocean and amended with different amounts of organic matter. Heterotrophic flagellates developed up to 30,000 cells ml(-1) in the most enriched incubation. A 18S rDNA clone library and fluorescent in situ hybridization counts with newly designed probes indicated that the peak was formed by Cafeteria roenbergensis and Caecitellus paraparvulus (90% and 10% of the cells respectively). Both taxa were below detection in the original sample, indicating a strong positive selective bias during the enrichment. During the peak, C. roenbergensis cells were observed with virus-like particles in the cytoplasm, and 4 days later this taxa could not be detected. Transmission electron microscopy confirmed the viral nature of these particles, which were large (280 nm), had double-stranded DNA, and were produced with a burst size of approximately 70. This virus was specific of C. roenbergensis as neither C. paraparvulus that was never seen infected, nor other flagellate taxa that developed in later stages of the incubation, appeared attacked. This is one of the few reports on a heterotrophic flagellate virus and the implications of this finding in the Indian Ocean are discussed.     

IL-7 knocks the socs off chronic viral infection

Chronic viral infections represent a major burden to human health, and modulation of the immune system is emerging as a novel approach to fighting such infections. Pellegrini et al. (2011) demonstrate that treatment with the cytokine IL-7 may reinvigorate the immune response to persistent infection by targeting immunosuppressive Socs3 proteins.     

Identification of the viral and cellular microRNA interactomes during SARS-CoV-2 infection

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A conserved family of immune effectors cleaves cellular ATP upon viral infection

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Typical changes of lymphocyte surface architectonics in chronic viral infection

With the use of scanning electron microscopy, lymphocyte surface architectonics has been described in cases of chronic viral persistence at tick-borne (vernal) encephalitis, hepatitis types A and B, and Herpes simplex. In lymphocytic population smooth and plicate cells in addition to cells with vesicles and outgrowths on the surface prevailed. The appearance of lymphocytes with a combined type of superficial microrelief was registered. It is supposed that despite the variety of types of lymphocyte surface architectonics and possible causes promoting their polymorphism, changes in superficial ultrastructure of immunocompetent cells for chronic viral infection have a nonspecific character.     

Highly permissive infection of microglial cells by Japanese encephalitis virus: a possible role as a viral reservoir

Japanese encephalitis virus (JEV), a mosquito-borne Flavivirus, is a major cause of acute encephalitis, and neurons have been proposed to be the principle JEV target cells in the central nervous system. However, clinically, infection with JEV leads to increased levels of cytokines and chemokines in the serum and cerebrospinal fluid (CSF) the levels of which correlate with the mortality rate of patients. This research aimed to study the role of microglial cells in JEV infection. Mouse microglial cells (BV-2) supported the replication of JEV with extracellular production of virus by 10 h post-infection, and virus titer reached a maximum (2.55 × 10¹⁰ pfu/ml) by day 3 post-infection. While apoptosis was induced in response to virus infection, no alteration in nitric oxide production was observed. Microglial cells remained productively infected with JEV for up to 16 weeks without significant morphological alterations, and the released virions were infectious to mouse neuroblastoma (NA) cells. The high virus production and long persistence of JEV in microglial cells suggests that these cells may serve as viral reservoirs for the infection of neurons in the CNS.