Joseph H Brewer

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Section of Infectious Disease - St. Luke's Hospital and Plaza Infectious Disease, 4320 Wornall Road, Suite 440, Kansas City, MO 64111, USA

Introduction

The potential therapeutic approaches for human herpesvirus-6 (HHV-6) infections include antiviral therapy and immune therapies. Several experimental therapy approaches have possible benefits for such infection based on theoretical grounds as well as clinical studies. These therapies may alter viral infection via immune-mediated mechanisms, which relate to either humoral immunity or cell-mediated immune function. There may also be direct or indirect antiviral effects. Herein, these therapy alternatives are reviewed in terms of experimental and clinical data. Most of the clinical studies regarding these therapies that have implications for patients with HHV-6 infection have generally been done in groups of patients with disease states or syndromes that are possibly associated with HHV-6 infection. The main examples of such clinical syndromes that are addressed in this section are chronic fatigue syndrome (CFS) and multiple sclerosis (MS).

Immunoglobulin

Several commercially available intravenous immunoglobulin (IVIG) preparations have been studied (Krause et al., 2002) to evaluate antimicrobial activity against various microbial pathogens. High antibody titers were found for several of the herpes viruses including HHV-6. The relative importance of humoral immunity (immunoglobulin) for the control of herpes infections, including HHV-6, is not entirely clear. If indeed immunoglobulin represents an important aspect of controlling HHV-6, then it is intuitive that IVIG may be a potentially effective therapy for HHV-6-associated infection. On the other hand, if cell-mediated immunity is the dominant mechanism for immune control for HHV-6, then immunoglobulin may be of limited value.

Several clinical studies have been done in patients with CFS utilizing IVIG compared to placebo. One double-blind, placebo-controlled study of 30 CFS patients (Peterson et al., 1990) did not demonstrate the benefit of IVIG in terms of symptom amelioration or improvement in functional status. A similar study of 99 CFS patients from Australia (Vollmer-Conna, 1997) also showed lack of statistically significant benefit of IVIG as compared to albumen. However, another randomized, double, blind study (Lloyd et al., 1990) comparing monthly high-dose IVIG (2g/kg) versus placebo, demonstrated improvement in several parameters including decrease in symptoms, increased functional status and improved immu-nologic measures. The reason for the difference in outcomes in these studies remains unclear.

A study of relapsing remitting MS patients (Fazekas et al., 1997) compared IVIG at smaller doses (0.15-0.2 mg/kg) to placebo. In this study of 150 patients, benefits were noted in the IVIG group in terms of disability status (Kurtzke expanded disability status score).

The potential role of IVIG for the treatment of HHV-6-related infection remains conjectural. IVIG is quite expensive and has a variety of adverse effects that are not uncommonly associated with the infusions.

Interferon

HHV-6 infection induces production of various cytokines from infected macrophages including interferon (Inoue et al., 1993). These cytokines, including interferon, play a role in controlling and containing the viral infection. Since interferon has broad antiviral properties, recombinant interferon may be potentially useful in the treatment of infection with HHV-6. With regard to interferon therapy, there is very little information regarding the treatment of HHV-6 with any of the three types of interferon. Alpha interferon has been studied in CFS patients showing improvement in the quality of life scores (See & Tilles, 1996). Interferon beta has been used in the treatment of MS for over 20 years. Interferon beta has been shown to be effective in decreasing progression of MS and reducing disability (Fillipini, 2003), particularly with relapsing and remitting MS. Albeit the mechanism is widely held to be immune modulation, the antiviral effects of interferon beta may be involved, as well.

It has been shown (Hong et al., 2002) in vitro that interferon beta at concentrations of 0.5 mg/ml reduced the replication of HHV-6 in a susceptible line of T cells. Additionally, this group examined the sera of MS patients treated with interferon beta compared to control patients not on treatment for cell-free detection of HHV-6 DNA and IgM antibody reactivity to HHV-6. The sera of patients treated with interferon beta had reduced levels of HHV-6 DNA detected and lower levels of IgM antibody reactivity. They also looked at paired sera of seven patients before and after treatment with interferon beta. The sera obtained after treatment showed decreased levels of HHV-6 DNA as compared to the pretreatment sera. Another study (Alvarez-Lafuente, 2004) evaluated relapsing remitting MS patients treated with interferon beta (n — 105) compared to similar patients who were not being treated (n — 84). Utilizing a quantitative real time PCR for HHV-6, the HHV-6 viral load was twice as high in the untreated patients versus the treated cases. These effects were only seen during relapse. No differences were seen when patients were in remission. All of these cases, interestingly, were HHV-6 variant A. Thus, interferon beta may exert at least some of the effects in the treatment of MS related to the antiviral properties of these agents for HHV-6.

Interferon therapy is associated with numerous adverse effects including fever, fatigue, myalgia, nausea and headache, among others (Fillipini, 2003).

Ampligen

Ampligen is a chain of nucleic acids, which is mismatched double-stranded RNA, poly(I): poly(C12U), that has been shown to have antiviral activity. In vitro studies (Ablashi et al., 1994) have demonstrated activity against HHV-6. In a study of HSB-2 cells (a B cell line) infected with the HHV-6 variant A (GS strain), ampligen was effective at blocking viral infection at concentrations of 100 and 200pg/ml (Ablashi et al., 1994). In this study, when cells were pretreated with ampligen, there was a 98% inhibition of infection. If the cells were infected first and then treated with ampligen, there was still a 95% inhibition of infection. When the ampligen was removed from the virus-infected cell culture, HHV-6 infection reappeared slowly but never reached the same level as before. No toxicity to uninfected HSB-2 cells was noted. Ampligen inhibited HHV-6 DNA polymerase activity.

Studies that address the activity of ampligen in HHV-6-associated infection have been done in patients with CFS. Ampligen has been evaluated in a randomized, double-blind, placebo-controlled study (Strayer et al., 1995) of CFS patients. Efficacy was assessed by Karnofsky performance score (KPS), cognition scale (SCL-90-R), activity of daily living (ADL) scale and exercise treadmill performance. After 24 weeks of treatment, patients receiving ampligen had higher scores for global performance and perceived cognition than the placebo group. Patients on ampligen had improved KPS, increased capacity for ADL, reduced cognitive impairment and improved work on the treadmill. Patients receiving ampligen also required less medication to control their symptoms. In another study (Strayer et al., 1994), 15 patients with CFS were studied for performance (KPS), neuropsycho-logical testing, exercise capacity and HHV-6 antigen positivity in cell culture. After treatment with ampligen for 12-48 weeks, there was an improvement from baseline for KPS, cognition and exercise tolerance. In the viral analysis, there was a reduction in the expression of HHV-6. An evaluation of levels of 2,5-oligoadenylate synthetase (2-5A) and RNAase L (Suhadolnik, 1994) in 15 patients with CFS

before and after treatment with ampligen was compared to healthy controls. Patients had lower levels of 2-5A and increased levels of RNAase L activity. Also, the levels of HHV-6 replication activity in peripheral blood mononuclear cells (PBMC) were studied before and after treatment. Therapy with ampligen resulted in significant downregulation of the 2-5A/RNAase L pathway, as well as significant decrease in HHV-6 replication in PBMC.

Thus, ampligen has demonstrated in vitro activity for HHV-6 in infected cells, decreased HHV-6 replication in CFS patients and improved clinical parameters (performance, cognitive skills and symptom reduction) in patients treated with ampligen compared to placebo. Presently, it remains an investigational therapy.

Transfer factor

Transfer factor (TF) was originally described as dialyzable leukocyte extract over 40 years ago. This small dialyzable molecule can transfer cell-mediated immunity from an immune donor to a non-immune recipient (Fudenberg and Pizza, 1989). The molecular structure of TF is uncertain, however, it has been postulated to be a small ribonucleopeptide (Dwyer, 1983). TF appears to have the properties of a cytokine that can induce an immune response in the recipient, probably via the effects on T cells (Fudenberg and Pizza, 1989). TF is antigen specific but the degree of epitope specificity has not been clarified. It is not species specific and thus can be transferred from one species to another without an allergic reaction in the recipient (Fudenberg and Pizza, 1989). There are several potential sources for TF. One very accessible source for substantial amounts of TF is bovine colostrum (Jones, 2003).

TF has been used as a therapeutic modality in a variety of infections (Fudenberg and Pizza, 1989). Numerous studies (Steele et al., 1980; Jones, 2003; Viza et al., 1987) have investigated the treatment of herpes virus infections with TF including herpes simplex, varicella zoster virus, cytomegalovirus and Epstein-Barr virus. One study utilizing an oral formulation of TF derived from bovine colostrum was highly effective in controlling infection with cytomegalovirus and Epstein-Barr virus in children (Jones, 2003).

A report was published (Ablashi et al., 1996) on the treatment of two patients with CFS and active HHV-6 infection treated with a TF that was specific for HHV-6. One of these patients improved rapidly and resumed normal activities, whereas the other patient did not improve. Another study (Brewer and Wilson, 2003) was reported in CFS patients with active HHV-6 infection (HHV-6 viremia demonstrated by positive rapid viral culture) and low natural killer cell function who were treated with TF. One group of 28 patients was given a TF derived from bovine colostrum that had specific activity for HHV-6 compared to 10 patients who were given TF from colostrum devoid of activity for HHV-6. The group given the HHV-6-specific TF showed a significant improvement in symptom profile scores as well as improved NK immune function compared to the placebo group. This study, among others, has shown TF to be remarkably free of adverse effects (Fudenberg and Pizza, 1989; Brewer and Wilson, 2003).

Although, the data for TF in the treatment of HHV-6-related infection is limited, it may represent an attractive alternative that merits further investigation. It has proven to be a potentially effective therapy for various herpes virus infections including HHV-6 and has a good record of safety.

Isoprinosine

Isoprinosine (inosine pranobex) is a synthetic purine derivative licensed in 1971. It has been demonstrated to have immune modulating and antiviral properties. This compound has been used to treat immune deficiencies and various viral infections. Isoprinosine modulates T cell and NK function (Diaz-Mitoma et al., 2003), thus, the major effects relate to cell-mediated immunity. Safety studies in clinical trials and post-marketing experience have shown it to be quite free of adverse effects (Diaz-Mitoma et al., 2003). It has not been specifically studied in vitro for HHV-6 infection. However, isoprinosine has been recently studied in patients with CFS and low NK function (Diaz-Mitoma et al., 2003). In this single-blinded study, clinical improvement was noted in six out of ten patients treated with isoprinosine compared to a group receiving placebo. The clinical improvement was directly associated with improved NK function from baseline. This is the only controlled study to date evaluating this compound in any of the HHV-6-associated infections. This agent is not currently available in the US, but is sold in many other countries as an antiviral drug.

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Colour Section

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Crossmatching Incompatible Microscope

Plate 1 Peripheral blood mononuclear cells (PHA stimulated), cultured from AIDS patient with B-cell lymphoma, showing large refractile cells. (see page 4).

Plate 2 Giemsa-stained peripheral blood mononuclear cells, containing refractile cells, showing multinucleated giant cells. (see page 4).

Plate 3 Immunofluorescent staining of HHV-6-infected human cordblood mononuclear cells with patient GS serum. (see page 6).

HUMAN HERPESVIRUSES (HHV)

HHV-1 HHV-2 HHV-3

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