To study effects of herpesvirus reactivation on the nervous system, mice with latent genital herpes simplex virus type 2 (HSV-2) infections were immunosuppressed. Reactivated infection was detected ...by virus isolation or by antigen screening in histological sections of spines that contained cords, roots, and dorsal root ganglia. In ganglia, viral antigen was restricted to 2 distinct groups at T9-L2, and L6-S2 levels. In some ganglia, antigen was found in up to 4% of non-contiguous neurons, in their axons, and in endoneurial and satellite cells. Nerve roots distal to ganglia contained a few antigen-positive endoneurial cells and axons, but convincing antigen was not seen in proximal roots. Rare foci of anterior horn cells in the lower cord were the only central sites found to contain antigen. Comparison of antigen-containing ganglionic neuron counts to vaginal culture data indicate that peripheral virus shedding may depend on the number of neurons with reactivated infection. In non-immunosuppressed, latently infected mice, virus recovery was restricted to ganglionic explants from lower thoracic and lumbosacral regions; these ganglia contained no infectious virus in homogenates and no detectable antigen. These mice had an inflammatory polyradiculopathy in a similar distribution to virus found in latent and reactivated infection. The data show that genital HSV-2 infection can result in more extensive ganglionic latency and peripheral nervous system disease than has previously been recognized. Immunosuppression leads to reactivation and widespread, anatomically restricted antigen expression in many ganglia, consistent with the innervation of the genitourinary tract. Decalcified spine preparations provide a sensitive and simple way to detect virus reactivations and disease in these neural tissues.
We tested antibody titres against Epstein-Barr virus (EBV) antigens in patients suffering from chronic viral disease and compared them with those determined in sex- and age-matched healthy controls. ...Patient sera showed signs of active EBV infection antibodies against early antigen (EA) and/or viral capsid antigen (VCA) in the IgM or IgA classes significantly more frequently than the control group. Correspondingly, geometric mean titres (GMT) of antibodies against all viral antigens were elevated in the patients. The strongest association with EBV was observed in patients whose clinical symptoms closely resembled infectious mononucleosis: 92% of the subjects in this subgroup possessed anti-EA and 41 and 25% had IgM and IgA anti-VCA antibody, respectively. In patients with signs of lymphoproliferation only and in those suffering from frequent respiratory infections the association with EBV was less marked but still significant. Patients with transient defects in humoral and cellular immunity mounted higher titres against VCA in the IgG class than those without immune defects.
We previously have described a model of in vitro herpes simplex virus (HSV) latency in which latent infection was (i) established with human leukocyte interferon (IFN-alpha) in combination with ...(E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) or 9-(2-hydroxyethoxy)methylguanine (acyclovir); (ii) maintained after termination of combined inhibitor treatment by incubation at 40.5 degrees, and (iii) reactivated by either reducing the incubation temperature to 37 degrees or by superinfecting at the elevated temperature with human cytomegalovirus (HCMV). We now report the use of this system to examine the transcriptional activity of the HSV genome during establishment, maintenance, and reactivation of HSV latency in vitro. Numerous species of virus-specific polyadenylated RNAs were present during the first 3 days of combined BVDU and IFN-alpha treatment of HSV type 1 (HSV-1)-infected human fetus lung fibroblast cells. However, after 7 days of combined inhibitor treatment, only a very small quantity of virus-specific RNA could be detected utilizing the short unique region of the HSV-1 genome as probe. After terminating combined BVDU and IFN-alpha treatment and increasing the temperature from 37 to 40.5 degrees on day 7 after infection, virus-specific RNA was undetectable by RNA blot hybridization analysis; however, a small amount of HSV-specific RNA was detected in 2% of the cells by in situ hybridization. The HSV-1 transcriptional products produced after HCMV superinfection in the presence of selected inhibitors of macromolecular synthesis also were examined and demonstrated that the efficient activation of HSV-1 immediate-early gene transcription required the expression of not only immediate-early HCMV gene product(s), but also at least a subset of early-late gene products.
The reactivation of UV-irradiated SV 40 was measured in UV-irradiated CV-1 cells as a function of time between irradiation of the cells and infection. To avoid the possible bias of multiplicity ...reactivation and/or virus propagation, infection was quantitated in terms of V-antigen-positive nuclei at the end of the first lytic cycle. In irradiated cell cultures enhanced reactivation of SV 40 was observed, which indicates induction of DNA repair enzymes. Maximal reactivation was obtained when the time interval between irradiation and infection was 72 h. The UV-inducible DNA repair enzymes might represent elements of an SOS-type response in mammalian cells.
A strain of herpes simplex type 1 (HSV-1:KOS) encoding a functional thymidine kinase (tk+) gene and a thymidine kinase deficient (tk-) mutant strain (HSV-1:PTK3B) were used as probes to examine the ...repair of UV-damaged viral DNA in one tk- (143) and two tk+ (R970-5 and AC4) human cell lines. UV survival for each HSV-1 strain was similar for infection of both tk- and tk+ cells suggesting that the repair of viral DNA was not dependent on the expression of a functional cellular tk gene. In contrast, UV survival of HSV-1:PTK3B was substantially reduced compared to HSV-1:KOS when infecting all 3 human cell lines, as well as Vero monkey kidney cells and LPM1A mouse cells. These results suggest that the repair of UV-irradiated HSV-1 in lytically infected mammalian cells depends, in part at least, on the expression of the viral encoded tk.
Eighty-eight consecutive hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) positive, heterosexual patients of Caucasian origin presenting with chronic hepatitis were followed for ...1 to 15 years (mean, 5.4 years). During the study period, 45 (51%) patients cleared HBeAg and hepatitis B virus-deoxyribonucleic acid from serum and were followed for 53 +/- 29 months (mean +/- SD) after seroconversion to antibody to hepatitis B e antigen. All patients manifested biochemical improvement. During follow-up, 10 (22%) of the 45 patients experienced spontaneous reactivation of hepatitis B replication with reappearance of serum hepatitis B virus-deoxyribonucleic acid and, in 4 patients, of hepatitis B e antigen. All patients then showed biochemical exacerbation of disease. These serologic events were transient, lasting an average of 12 months, in 8 (80%) patients. All patients were asymptomatic or minimally symptomatic. Histologic findings of liver tissue from 7 patients showed progression from chronic active hepatitis to active cirrhosis in 2 (28%) patients, while in the remaining 6 cases histology remained unchanged or improved from chronic active to chronic persistent hepatitis. These data indicate that spontaneous reactivation of hepatitis B infection occurs in heterosexual patients with chronic hepatitis B and this event is usually transient and asymptomatic, although in some patients it may be the major cause of progressive hepatic damage.
Case presentation Overall, this case highlights the importance of having a high clinical suspicion of fatal VZV infections in heavily immunosuppressed SLE patients even when typical signs and ...symptoms are lacking.
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