Treatment of HSV-1 infection with immunoglobulin or acyclovir: comparison of their effects on viral spread, latency, and reactivation.
(65/2054)
We compared immunoglobulin (IgG) and acyclovir (ACV) therapies on the establishment, maintenance, and reactivation from latency of HSV-1(McKrae) in a mouse ocular infection model. Mice were given one intraperitoneal (IP) dose of human IgG 24 h after infection (Day 1 p. i.) or ACV in the drinking water from Days 1 to 7 p.i. Both treatments allowed similar percentages of mice to survive the infection and decreased ocular virus shedding as compared with untreated controls. At most time points, there were no differences between IgG- and ACV-treated animals with respect to tissue virus titers or in the rates of virus reactivation during explant cocultivation. However, after ultraviolet exposure, HSV reactivated in 30% of ACV-treated mice compared with 90% of IgG-treated mice (P = 0.02). Also by quantitative PCR, we found more latent HSV-1 DNA copies in IgG-treated mice compared with those given ACV (P = 0.02). IgG treatment protects mice from HSV-1 infection essentially as well as ACV does. Nonetheless, it permits higher levels of latent infection and subsequent in vivo reactivation. These studies have implications for the mechanism by which IgG functions to attenuate HSV infections and for its potential value as a therapeutic agent in humans. (+info)
Type I interferons and IRF-1 play a critical role in the control of a gammaherpesvirus infection.
(66/2054)
The murine gammaherpesvirus 68 (MHV-68) is an ideal model system for the study of interactions between gammaherpesviruses and their hosts. Intranasal infection of mice with MHV-68 results in replication of the virus in the lung epithelium followed by latent infection of B cells. Resolution of productive MHV-68 infection depends on the adaptive immune system, but little is known about the role of innate immune mechanisms and the early interaction between the host and the virus. In this report, we have used mice that are deficient in components of the early defence system, the common type I interferon (IFN) receptor (IFN R), the transcriptional activator IRF-1, and the inducible nitric oxide synthase, to investigate the contribution of these mechanisms to control of MHV-68 infection. We show that while wild-type mice are highly resistant to infection with MHV-68, mice unresponsive to type I IFNs (IFN-alpha/beta R(-/-) ) are highly susceptible to the virus. At high multiplicities of infection (m.o.i. ; 4 x 10(6) PFU), 80-90% of IFN-alpha/beta R(-/-) mice succumb to infection, and at low m.o.i. (4 x 10(3) PFU), 50% mortality rates occur. Both high and low doses of virus lead to 100- to 1000-fold higher lung virus titres in IFN-alpha/beta R(-/-) mice than are found in wild-type mice and result in systemic dissemination of the virus. Latently infected cells are detectable in the spleens of IFN-alpha/beta R(-/-) mice earlier than in wild-type mice, and the numbers of latently infected cells are 10-fold higher in the IFN-alpha/beta R(-/-) mice during the acute phase of infection. We find IRF-1 has a critical role in protection from fatal disease, whereas inducible nitric oxide synthase does not appear to be important. The results indicate that innate immune mechanisms are critical for the early control of MHV-68 and may play a role in the establishment of latency. (+info)
Latent reservoirs of HIV: obstacles to the eradication of virus.
(67/2054)
The use of highly active antiretroviral therapy (HAART) in the treatment of HIV-1-infected individuals has provided a considerable amount of information regarding the dynamics of viral replication and has resulted in enormous advances in HIV therapeutics. The profound suppression of plasma viremia in HIV-infected individuals receiving HAART has resulted in a highly beneficial clinical effect and a dramatic decrease in the death rate attributable to AIDS. Nonetheless, the persistance of reservoirs of HIV, including latently infected, resting CD4+ T cells that can give rise to infectious HIV upon stimulation in vitro, has posed a sobering challenge to the long-term control or eradication of HIV in infected individuals receiving HAART. Although a recent study has demonstrated th at the size of the pool of latently infected, resting CD4+ T cells can be markedly diminished with intermittent interleukin (IL-2) and continuous HAART, complete eradication of HiV in infected individuals remains extremely problematic. Here we discuss recent developments in studies of the latent reservoir of HIV in patients receiving HAART and implications for the long-term treatment of infected individuals and eradication of the infection. (+info)
An anti-CD45RO immunotoxin eliminates T cells latently infected with HIV-1 in vitro.
(68/2054)
Despite the success of highly active antiretroviral therapy (HAART) in lowering circulating HIV-1 to undetectable levels in most infected individuals, several studies have documented the presence of a small reservoir of latently infected cells in HAART patients, the majority of which are CD45RO(+) memory T cells. We previously have demonstrated that latently infected, replication-competent cells can be generated in vitro after eliminating CD25(+) cells with an immunotoxin (IT). The present study was designed to determine whether these latent cells could be eliminated by an anti-CD45RO IT. Our results indicate that the anti-CD45RO IT eliminates >99%, of either M-tropic or T-tropic virus produced by the latently infected cells after mitogen stimulation. This IT also appears to be as effective as the anti-CD25 IT in eliminating the activated, HIV-1-producing cells. In contrast, the anti-CD45RO IT does not kill CD45RA(+) naive cells. Further studies using cells from HIV-1-infected individuals on HAART will be necessary to determine the potential clinical utility of this IT. (+info)
LAT expression during an acute HSV infection in the mouse.
(69/2054)
Previous studies using cell culture systems to evaluate LAT expression demonstrated that the LAT promoter expresses at much higher levels in neuroblastoma cell lines than fibroblast lines. The high level of LAT expression in neuronal-derived cell lines correlates with the high level of LAT accumulation observed in sensory ganglia neurons during a latent infection. We have found that using LAT promoters to express reporter genes from recombinant viruses in vivo produces high levels of LAT promoter activity in the epithelium of the mouse foot. An analysis of LAT promoter activity during an acute infection in the mouse clearly demonstrates that in contrast to studies performed with selected cell lines, the LAT promoter expresses similar levels of reporter gene product in peripheral cells and in neurons. In addition, the amount of reporter gene product is higher when the LAT promoter is located within the R(L) as compared to the U(L) region, and when expression is adjusted for copy number of the reporter construct, expression is roughly the same. These results suggest the activity of the LAT promoter varies greatly according to cell type and that high levels of expression is not limited solely to neurons, especially in the in vivo setting. (+info)
HSV-1 migration in latently infected and naive rabbits after penetrating keratoplasty.
(70/2054)
PURPOSE: To investigate the migration of herpes simplex virus type 1 (HSV-1) between latently infected and naive corneal tissues and trigeminal ganglion (TG) in rabbits after penetrating keratoplasty (PKP) and transcorneal epinephrine iontophoresis. METHODS: Two mutants, genetically constructed from HSV-1 strain 17syn+, were used to inoculate rabbit corneas: 17deltaPst, a latency associated transcript (LAT) negative, low-reactivating virus and 17Pr, a high-reactivating, LAT-positive rescuant of 17deltaPst. Latently infected rabbits were given corneal allografts from naive rabbits, and naive rabbits received grafts from latently infected rabbits. Ninety days after PKP, groups of the transplanted rabbits were induced to reactivate by transcorneal epinephrine iontophoresis, but others were not induced. Viral shedding was monitored by tear film cultures. Rabbits were killed 5 days after iontophoresis. Transplanted grafts, recipient corneal rims, and corresponding TG were obtained. Nucleic acids were extracted and amplified for detection of HSV-1 DNA and viral gene transcription. RESULTS: In naive rabbits receiving grafts transplanted from rabbits latently infected with 17Pr (LAT+), 3 of 6 corneal rims contained HSV DNA after induction. In contrast, none of the 5 corneal rims from naive rabbits receiving grafts from rabbits latent with 17deltaPst (LAT-) contained viral DNA. Viral DNA and gene transcripts were detected in 2 of 6 TG from naive rabbits that received grafts from 17Pr (LAT+) latently infected rabbits. In recipient corneal rims and TG of latently infected rabbits receiving grafts from naive rabbits, viral DNA concentration was significantly greater with induced reactivation, compared with the results in noninduced rabbits. The amount of viral DNA in naive grafts transplanted into 17Pr (LAT+) latently infected rabbits was significantly higher with induction than without induction (P = 0.018). More viral DNA and viral gene transcripts were found in tissues from rabbits latently infected with 17Pr (LAT+) than in rabbits latently infected with 17deltaPst (LAT-). CONCLUSIONS: Corneas from latently infected rabbits contain HSV-1 DNA that can replicate after induced reactivation. Viral migration can occur in both anterograde and retrograde directions between the transplanted graft and the recipient corneal rim and TG. The LAT negative HSV-1 construct 17deltaPst has a significantly reduced ability to replicate and migrate. (+info)
Viral hyperinfection of the central nervous system and high mortality after hematopoietic stem cell transplantation for treatment of Theiler's murine encephalomyelitis virus-induced demyelinating disease.
(71/2054)
Theiler's murine encephalomyelitis virus (TMEV) establishes a persistent infection in the central nervous system (CNS) leading to an inflammatory demyelinating disease of the CNS in which the histology and clinical course is similar to multiple sclerosis (MS). Disease pathogenesis is primarily due to T-cell-mediated destruction of myelin, which has been attributed to cytopathic effects of the virus, but immune-mediated destruction of myelin mediated via both virus-specific and myelin-specific T cells appear to play the major role. To determine if bone marrow transplantation would be an effective therapy for a virus-initiated autoimmune disease and to better separate viral cytopathic effects from immune-mediated demyelination, we ablated the immune system of TMEV-infected animals with 1,100 cGy total body irradiation, and then the animal's immunity was reconstituted by transplantation of disease-susceptible SJL/J mice with syngeneic marrow or disease-susceptible DBA/2J with marrow from disease-resistant (C57Bl/6 x DBA/2)F1 (B6D2) donors. Hematopoietic transplant performed after onset of disease resulted in 42% mortality in SJL/J syngeneic transplants, 47% mortality in diseased DBA2 recipients restored with marrow from naive B6D2 donors, and 12% in diseased DBA2 recipients receiving marrow from B6D2 donors previously infected with TMEV. Delayed type hypersensitivity (DTH) to both virion and myelin proteins was decreased in surviving mice that underwent transplantation; however, CNS viral titers were significantly elevated compared with nontransplanted controls. We conclude that a functional immune system with appropriate T-cell responses are important in prevention of lethal cytopathic CNS effects from TMEV. Relevant to the clinical use of bone marrow transplantation, attempts to ablate the immune system in viral-mediated immune diseases or virus-initiated autoimmune disease may have acute and lethal consequences. Our results raise concern about the attempted use of autologous hematopoietic transplantation in patients with MS, an autoimmune disease with a suspected virus etiology, particularly if the graft is aggressively depleted of lymphocytes. (+info)
Expression of cell-homologous genes of human herpesvirus-8 in human immunodeficiency virus-negative lymphoproliferative diseases.
(72/2054)
Human herpesvirus-8 (HHV-8) genome encodes for genes homologous to human cellular genes such as interleukin-6 (IL-6), Cyclin-D, BCL-2, and IL-8 receptor (G-protein-coupled receptor [GCR]). We used reverse transcriptase-polymerase chain reaction to study the expression of these viral genes in lymphoproliferative disorders associated with HHV-8 infection. None of these genes was expressed in 1 case of benign, localized Castleman's disease (CD), and only viral IL-6 and viral Cyclin-D were transcribed in 2 cases of benign lymphadenopathies with giant germinal center hyperplasia and increased vascularity. In contrast, all 4 genes were transcribed in 1 case of multicentric CD of plasma cell type with aggressive clinical course and in 1 primary effusion lymphoma cell line. Our study provides the evidence that various HHV-8 genes, homologous to cellular genes involved in control of proliferation and apoptosis, may be differently expressed in different lymphoid disorders in vivo. (+info)