Pathogenic Mechanisms of Meningitis/Encephalitis Caused by Human Herpesvirus-6 in Immunocompetent Adult Patients

SIR—Two recent articles in Clinical Infectious Diseases by Birnbaum et al. [1] and Isaacson et al. [2], along with the editorial commentary by Whitley and Lakeman [3], highlighted the role of human herpesvirus–6 (HHV-6) in meningitis/encephalitis in immunocompetent adult patients. These investigators raised several concerns about the association of HHV-6 with meningitis/encephalitis in immunocompetent adult patients. The major concern is whether reactivation of HHV-6 infection may be considered the pathogenic mechanism in immunocompetent adults with meningitis/encephalitis, inasmuch as reactivation of HHV-6 infection has been widely reported in immunocompromised patients, including HIV-1–infected patients, bone marrow transplant recipients, and patients who have undergone liver or renal transplantation [4]. However, we cannot rule out the possibility that meningitis/encephalitis in adult immunocompetent patients may represent primary infection with HHV-6. In fact, a few reports, including the article by Isaacson et al. [2], described immunocompetent adults with meningitis/encephalitis due to HHV-6 who did not have preexisting IgM and IgG antibodies [5, 6]. In contrast, most patients who had meningitis/encephalitis caused by HHV-6 had preexisting IgG antibodies [6–9]. In a previous study, we highlighted the role of HHV-6 in reactivation of latent infection in an immunocompetent adult with meningoencephalitis [10]. In fact, in our case report, the presence of HHV-6 was detected in CSF specimens but not in PBMC specimens. In immunocompromised patients—particularly HIV-1–infected patients and organ transplant recipients—HHV-6 reinfection and reactivation of HHV-6 infection have been widely reported; thus, HHV-6 may be considered an important opportunistic pathogen [2]. In addition, concurrent infections with HHV-6 and other pathogens, including measles virus, herpes simplex virus, cytomegalovirus, Epstein-Barr virus, parvovirus B19, coxsackievirus B, and varicella-zoster virus, have been reported [4, 11]. It is interesting to note that these viral infections concurrent with HHV-6 infection have not been specifically associated with an immunosuppressive effect. On the other hand, reinfection or reactivation of HHV-6 infection is trickier to demonstrate in immunocompetent adults with meningitis/encephalitis than in others, even though HHV-6 seems to be a resident virus of the human brain and is able to cause a restricted or minimally productive infection of brain cells, including microglial cells, astrocytes, and oligodendrocytes [12]. In our opinion, however, the pathogenic mechanism involved in HHV-6 meningitis/encephalitis in immunocompetent adults may be related to the ability of HHV-6 to evade host immune responses through (1) induction of CD4 lymphocyte depletion via apoptosis [13], (2) down-regulation of CD3 expression on in vitro–infected T cell clones [14], (3) decrease of peripheral blood lymphocyte proliferation by HHV-6 via transcriptional down-regulation of IL-2 [15], and (4) decreased generation of reactive oxygen intermediates from monocytes that were infected with HHV-6 in vitro [16]. In addition, a transient immunocompromission of T cell immune response—particularly of natural killer cell activity and of IFN-α production—cannot be ruled out in adult immunocompetent patients with meningitis/encephalitis [4]. In conclusion, in adult immunocompetent patients, HHV-6 may behave as an immunosuppressive pathogen, to evade host immune responses, and in immunocompromised patients, it also behaves as an opportunistic pathogen. Thus, the ability of HHV-6 infection to remain latent or to be reactivated in certain conditions, along with the ability of HHV-6 to evade host immune responses through various mechanisms, render it an opportunistic and serious pathogen in immunocompromised patients as well in adult immunocompetent patients with meningitis/encephalitis. Potential conflicts of interest. All authors: no conflicts.