Search

Background: Kenema Government Hospital (KGH) has developed an advanced clinical and laboratory research capacity to manage the threat of Lassa fever, a viral hemorrhagic fever (VHF). The 2013-2016 Ebola virus (EBOV) disease (EVD) outbreak is the first to have occurred in an area close to a facility with established clinical and laboratory capacity for study of VHFs., Methods: Because of its proximity to the epicenter of the EVD outbreak, which began in Guinea in March 2014, the KGH Lassa fever Team mobilized to establish EBOV surveillance and diagnostic capabilities., Results: Augustine Goba, director of the KGH Lassa laboratory, diagnosed the first documented case of EVD in Sierra Leone, on 25 May 2014. Thereafter, KGH received and cared for numbers of patients with EVD that quickly overwhelmed the capacity for safe management. Numerous healthcare workers contracted and lost their lives to EVD. The vast majority of subsequent EVD cases in West Africa can be traced back to a single transmission chain that includes this first diagnosed case., Conclusions: Responding to the challenges of confronting 2 hemorrhagic fever viruses will require continued investments in the development of countermeasures (vaccines, therapeutic agents, and diagnostic assays), infrastructure, and human resources., (© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.)

The hallmarks of persistent viral infections are exhaustion of virus-specific T cells, elevated production of interleukin 10 (IL-10) and programmed death-1 (PD-1) the dominant negative regulators of the immune system and disruption of secondary lymphoid tissues. Within the first 12-24 hours after mice are infected with lymphocytic choriomeningitis virus (LCMV) clone 13, which is used as a model of persistent virus infection, we note generation of high titers of type 1 interferon. Blockade of type 1 interferon significantly lessens IL-10 and PD-1/PD-L1, allows normal secondary lymphoid architecture and re-establishes antiviral T-cell function, thus eradicating the virus and clearing the infection. Hence, type 1 interferon is a master reostat for establishing persistent viral infection., (© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Since the licensure and generalization of an effective measles virus (MV) vaccine 41 years ago, antibody levels have been used as correlates of immunity. The long-lived MV-specific antibody response has been studied intensely, but the dynamics of MV-specific T cell immunity over time have not been well characterized. We thus characterized the profiles of MV vaccine-induced antigen-specific T cells over time since vaccination. In a cross-sectional study of healthy subjects with a history of MV vaccination, we found that MV-specific CD4 and CD8 T cells could be detected up to 34 years after vaccination. The levels of MV-specific CD8 T cells and MV-specific IgG remained stable, whereas the level of MV-specific CD4 T cells decreased significantly in subjects who had been vaccinated >21 years earlier. These results show that MV-specific T cell immunity after vaccination is long lasting and reveal different dynamics between CD4 and CD8 cells after vaccination., (Copyright 2004 Infectious Diseases Society of America)

The central nervous system (CNS) is considered an "immunoprivileged" site with restricted access and a unique microenvironment that profoundly affects the capacity of T cells to exert their functions. The lymphocytic choriomeningitis virus model offers a unique system in which to evaluate the contrasting roles of specific T cells in causing lethal CNS disease or curing pervasive and life-long CNS infection. Specific T cell kinetics in the periphery is briefly discussed. The T cell-mediated mechanisms leading to fatal choriomeningitis are reviewed as are recent methodologic advances that will facilitate the study of antigen-specific T cells in disease pathogenesis. Understanding the specific constraints imposed by the CNS on local T cell activity has important consequences for the design of therapeutic strategies aimed at preventing or curing CNS infection.

Realising that viruses could persist and thereby cause chronic disease has been one of the major accomplishments in virology. In this review we will discuss the principles by which viruses can persist and how such persistence can lead to disease. Our focus will be on the ability of certain viruses to interfere subtly with the cell's ability to produce specific differentiated products as hormones, neurotransmitters, cytokines and immunoglobulins, etc., in the absence of their ability to lyse the cell they infect. By this means viruses can replicate in histologically normal appearing cells and tissues. Despite viral replication the infected cell maintains its normal anatomic architecture and yet the virus disorders the differentiated or luxury function of the cell leading to disturbances in homeostasis and disease. Viruses by this means likely underline a wide variety of clinical illnesses, currently of unknown aetiology, that affect the endocrine, immune, nervous and other differentiated systems.

The possible role of viruses as the cause of some thyroid disorders was evaluated in three strains of mice neonatally infected with lymphocytic choriomeningitis virus. We report the first definitive evidence that viruses can persist in the thyroid gland, particularly thyroid epithelial cells in which thyroglobulin is synthesized. Concomitant with the infection of these cells was a significant reduction in the level of thyroglobulin mRNA and circulating thyroid hormones. Another virus that causes persistent infection but does not replicate in the thyroid gland failed to alter serum levels of thyroid hormones, indicating the thyroid dysfunction was not a generalized result of stress accompanying a persistent infection. This alteration in thyroid homeostasis during persistent infection with lymphocytic choriomeningitis virus is not caused by autoantibodies to the thyroid. Moreover, despite infection of the thyroid gland, neither necrosis nor inflammation occurs. Thyroid dysfunction was noted both when persistence was initiated at birth and in utero during congenital infection. These observations in an experimental model raise the issue that viruses may play a role in the pathogenesis of some thyroid disorders in man.

Immune complexes occurred in a large proportion of mice with syngeneic neuroblastomas. Circulating immune complexes formed in all mice, whereas almost 50% had deposits of host IgG and complement in a granular pattern along the mesangia and basement membranes of the renal glomeruli. The bound IgG was eluted and recovered from the glomeruli and demonstrated immunologic specificity to neuroblastoma cell-surface antigens.

A virus can replicate in differentiated cells, thereby altering their ability to make specialized products such as endocrine hormones, neurotransmitters, and lymphokines. Systemically, the outcome can be an imbalance in homeostasis, resulting in diseases of the endocrine, nervous, immune, or other systems, frequently in the absence of detectable cell destruction.

A patient suffered recurrent episodes of aseptic lymphocytic meningitis for many years and then developed amyotrophic lateral sclerosis (ALS). Immune-complexes were deposited in the renal glomerular basement membrane and mesangia. The necropsy study revealed both lymphocytic meningitis and ALS. Study of the motor neurons with the electron microscope revealed proliferation of endoplasmic reticulum, small cytoplasmolytic areas and focal neurofibrillar accumulations in axons. Interwoven, serpentine 10-15 nm. tubules first appeared with ER proliferation and, presumably at a later stage, were sometimes present in large masses. These tubules might be virus material but virus cultures, including tissue culture, and animal inoculations have thus far been negative.

Human cytomegalovirus (HCMV) infections are commonly associated with immunosuppression. A direct effect of this virus on lymphocyte functions in vitro, however, has not been shown. We have been investigating the effects of low-passage, fresh isolates of HCMV (cell-free and cell-associated) on natural killer cell (NK) activity and T cell proliferation. Cell-associated, low-passage isolates of HCMV markedly depressed NK activity. Suppression of NK activity was clearly manifested only after seven days of culture and could not be correlated with titer of virus or cell viability. Addition of interferon-alpha (IFN-alpha) but not interleukin-2 (IL-2) partially reconstituted the response, whereas depletion of infected monocytes prevented inhibition of NK-mediated lysis. The effects of cell-free and cell-associated isolates of HCMV on T cell proliferation differed in several respects from suppression of NK activity. Both cell-associated and cell-free isolates of HCMV completely abrogated antigen-specific and mitogen responses. This effect was apparent after only three days of culture with virus and was not reversed by either IFN or IL-2. Cell-associated strain AD169 also induced suppression but to a lesser extent. From observations reported here and other data, we suggest that HCMV can cause direct suppression of lymphocyte functions.

A convenient and flexible enzyme-linked immunosorbent assay system for the detection of specific antibodies to measles virus has been developed. In this system infected cells are desiccated on 96-well microtiter plates and stored at room temperature. After incubation of samples to be tested in the cell-coated plates and subsequent washing, bound antibodies are detected with a peroxidase-conjugated staphylococcal protein A probe. After another washing and the addition of the appropriate substrate, the amount of bound probe is estimated by colorimetric analysis. This technique offers several advantages. The need for a purified viral antigen source is obviated. The plates are easily prepared and can be stored for months at room temperature. Major viral epitopes, including surface glycoproteins as well as cytoplasmic viral antigens, are preserved despite desiccation. The method is more sensitive than the conventional means of virus-specific antibody detection.

Approximately one-half of autopsied acquired immune deficiency syndrome (AIDS) patients demonstrate probable human cytomegalovirus (CMV) infection of the central nervous system (CNS). Because CMV in brain tissue or cerebrospinal fluid is difficult to culture, we used antisera, and radioactive probes to diagnose CMV infection in the brain of an autopsied AIDS patient, who died of a fulminant CNS and systemic infection with CMV, suggesting a complete seeding of the ependymal regions possibly followed by a uniform ventriculofugal spread of the virus deep into the parenchyma. Cytomegalic cells were observed in optic nerve, retina, ependymal and subependymal regions of the brain and in the motor (but not sensory) root-CNS junctions. Immunocytochemistry demonstrated viral antigen predominantly in cytomegalic cells, which also stained positively for glial fibrillary acidic protein, S-100, or neuron-specific enolase, but not a common leukocyte antigen. Virions were visible in these cells examined by electron microscopy. No viral replication was observed in pineocytes, pituicytes or the choroid plexus. Morphologically normal cells that were CMV antigen-negative proved to be infected after in situ hybridization with well-defined human CMV DNA fragments. Hence, morphologically normal glia and neurons show restricted replication of CMV, indicating that such cells may be latently infected.

We mapped an immunodominant domain of the human immunodeficiency virus (HIV). We selected hydrophilic amino acid sequences encoded by conserved regions of the gag, pol, and env genes of HIV as potential antigenic domains. Eighteen peptides representing these sequences were synthesized; the peptides elicited strong antibody responses in rabbits. Sera from 53 HIV-infected patients and 50 controls were tested against the synthetic peptides. Although no antibodies to peptides from gag, pol, or env gp120 proteins were present, antibodies to four of the six peptides from env gp41 were detected. Epitope mapping using overlapping peptides showed that sera from 53 (100%) of 53 HIV-infected patients (and from none of 50 controls) reacted with peptides aa584-609 and aa598-609 from gp41, sera from 32 (60%) of 53 patients reacted with peptide aa603-614, and sera from 19 (35%) of 53 patients reacted with peptides aa609-620. Thus, amino acid sequence LeuGlyIleTrpGlyCysSerGlyLysLeuIleCys (aa598-609) from the transmembrane glycoprotein is an immunodominant domain of HIV recognized by serum antibodies from HIV-infected patients.

Defective-interfering (DI) lymphocytic choriomeningitis virus (LCMV) prevented disease in the central nervous system produced by standard LCMV. Standard LCMV injected into Lewis rats two days after birth produced a disorder distinguishable clinically by weight loss and ataxia and histologically by infiltration of mononuclear cells and necrosis of the cerebellum. Concurrent injection of DI LCMV with standard LCMV prevented the disease and markedly reduced the synthesis of standard LCMV and of viral antigens in the brain. Because inhibition of viral synthesis occurred early (day 3) after infection and because no interferon activity could be demonstrated, it was concluded that the interference effect was likely due to DI virus-mediated homologous interference. Other experiments showed that DI LCMV blocked viral antigen synthesis in culture. The curtailed production of viral antigens and cytolytic standard virus by DI virus may play a role in control of acute and persistent viral infections.