The case for immunomodulatory approaches in treating HSV encephalitis - PubMed (original) (raw)

The case for immunomodulatory approaches in treating HSV encephalitis

Chandran Ramakrishna et al. Future Virol. 2013.

Abstract

HSV encephalitis (HSE) is the most prevalent sporadic viral encephalitis. Although safe and effective antiviral therapies and greatly improved noninvasive diagnostic procedures have significantly improved outcomes, mortality (~20%) and debilitating neurological sequelae in survivors remain unacceptably high. An encouraging new development is that the focus is now shifting away from the virus exclusively, to include consideration of the host immune response to infection in the pathology underlying development of HSE. In this article, the authors discuss results from recent studies in experimental mouse models, as well as clinical reports that demonstrate a role for exaggerated host inflammatory responses in the brain in the development of HSE that is motivating researchers and clinicians to consider new therapeutic approaches for treating HSE. The authors also discuss results from a few studies that have shown that immunomodulatory drugs can be highly protective against HSE, which supports a role for deleterious host inflammatory responses in HSE. The impressive outcomes of some immunomodulatory approaches in mouse models of HSE emphasize the urgent need for clinical trials to rigorously evaluate combination antiviral and immunomodulatory therapy in comparison with standard antiviral therapy for treatment of HSE, and support for such an initiative is gaining momentum.

Keywords: acyclovir; encephalitis; herpesvirus; immune pathology; immunomodulation; inflammation; innate immunity; intravenous immunoglobulin; reactive oxygen species.

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Conflict of interest statement

Financial & competing interests disclosure

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Figures

Figure 1

Figure 1. EEG (left) and brain MRI (right) fluid-attenuated inversion recovery in a 46-year-old man who developed abrupt confusion 8 months after allogeneic hematopoietic cell transplantation for acute myelogenous leukemia

EEG showed right-sided periodic sharp waves and MRI showed increased signal in the right hippocampus. Cerebrospinal fluid had 44 white blood cells/µl (87% lymphocytes) and 11 red blood cells/µl. HSV-1 was cultured from the cerebrospinal fluid. Despite treatment with acyclovir and then foscarnet, the patient became amnesic, unable to form new memory traces. L: Left; R: Right. Reproduced with permission from [7].

Figure 2

Figure 2. Hematopoietic cells control decisions on survival

Irradiated 129 Rag-knockout mice received B6 BM while nonirradiated 129 Rag-knockout recipients were transferred with splenocytes isolated from either C57BL/6 (B6) or 129 WT mice. Mice were infected with 3200 PFU HSV 17+ and observed for mortality. n = 6–10; ***p < 0.0005 for B6 versus 129. BM: Bone marrow; pi: Postinfection; WT: Wild-type.

Figure 3

Figure 3. Increased inflammation in susceptible 129 mice

(A) 129 mice are highly susceptible to HSV 17+ infection compared with B6 mice. (B) Type I IFN transcripts were measured by RT-PCR in BS (BS IFN-α) or protein in sera by ELISA (sera IFN-α) at day 4 pi. CD45hi inflammatory cells in the BS were detected by flow cytometry (BS CD45hi cells) at days 4 and 8 pi. ****p < 0.0001. BS: Brainstem; FACS: Fluorescence-activated cell sorting; pi: Postinfection; RT-PCR: Real-time PCR; WT: Wild-type.

Figure 4

Figure 4. Acyclovir administered early but not late is protective

A 7-day ACV course of treatment was started 48 h (D2), 72–80 h (D3) or 96 h (D4) pi after inoculation of mice with HSV 17+; mice were monitored daily for mortality and symptoms of HSV-1 encephalitis necessitating euthanasia. CTRLs: phosphate-buffered saline; n = 12–20 129S6 mice. ACV-D4 versus CTRL = NS. *p = 0.032; **p = 0.002; ****p < 0.00001. ACV: Acyclovir; CTRL: Control; D: Day; NS: Nonsignificant; pi: Postinfection.

Figure 5

Figure 5. HSV pathogenesis in mice

Susceptible mice: increased inflammation in BS (lesion hyperintensity in MRI – yellow arrow) and virus spread to cerebrum and spinal cord. Resistant mice: reduced inflammation in BS (no lesion hyperintensity in MRI – yellow box) and limited spread to cerebrum and spinal cord. BS: Brainstem. MRI image reproduced with permission from [31] © American Society for Microbiology (2008).

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