Selective suppression of IL-12 production by human herpesvirus 6

Abstract

Human herpesvirus 6 (HHV-6) is a potentially immunosuppressive agent that has been suggested to act as a cofactor in the progression of HIV disease. Exposure of human macrophages to HHV-6A or HHV-6B profoundly impaired their ability to produce interleukin 12 (IL-12) upon stimulation with interferon-␥ (IFN-␥) and lipopolysaccharide (LPS). By contrast, the production of tumor necrosis factor-␣ (TNF-␣); regulated on activation, normal T-cell expressed and secreted (RANTES); and macrophage inflammatory protein 1␤ (MIP-1␤) was not negatively affected. To exclude the involvement of IL-12-suppressive cytokines, such as IL-10 and TNF-␣, the viral stocks were fractionated by ultracentrifugation. The bulk of the suppressive activity was recovered within the virion-rich pelleted fraction that was virtually devoid of such cytokines. IL-12 suppression was independent of viral replication, and the effect was not abrogated upon ultraviolet-light inactivation of the viral inoculum. The mechanism of HHV-6-mediated IL-12 suppression was investigated by RNase protection assays, which demonstrated unaltered levels of IL-12 p35 mRNA and only a modest reduction in p40 mRNA, which was insufficient to account for the near-complete loss of both extracellular and intracellular IL-12 protein. Moreover, both the IFN-␥ and the LPS signaling pathways were intact in HHV-6-treated cells. These data suggest that HHV-6 can dramatically affect the generation of effective cellular immune responses, providing a novel potential mechanism of HHV-6-mediated immunosuppression. ( IntroductionHuman herpesvirus 6 (HHV-6) is a member of the betaherpetovirinae subfamily, 1 along with HHV-7 and human cytomegalovirus (hCMV, or HHV-5). HHV-6 isolates can be divided into 2 major subgroups, A and B, that exhibit significant genetic, immunologic, and biologic divergence, albeit insufficient for classification as different viral species. Subgroup B is extremely diffused in the human population and is usually acquired within the first 2 years of life. Primary infection with this subgroup has been linked to exanthema subitum, a benign childhood disease. 2 Subgroup A is apparently less prevalent, with reported identifications being predominantly from severely immunosuppressed patients, [3][4][5] although an association with febrile episodes in early infancy has been documented in Central Africa. 6 Like other herpesviruses, HHV-6 is able to induce latent infection and may persist almost indefinitely in the host. In immunocompromised patients, HHV-6 reactivation or reinfection may cause severe opportunistic diseases, including encephalitis, pneumonitis, hepatitis, and retinitis, as well as bone marrow graft failure. 7 Moreover, in patients who have received transplants, HHV-6 infection has been fingered as a cofactor in hCMV disease. 8 Multiple lines of clinical and experimental evidence suggest that HHV-6, besides causing opportunistic infections, may be an immunosuppressive agent in its own right. In vitro, HHV-6 shows a predominant tropism for CD4 ϩ T lymphocytes, ...

Human herpesvirus 6 infection in adult living related liver transplant recipients

“…As a result of several in vitro analyses, HHV-6 has been demonstrated to have immunomodulatory effects such as impaired T cell activation, decreased cytokine synthesis, and impaired dendritic cell functions. [37][38][39][40] Although several investigators have suggested that HHV-6 infection is positively associated with CMV disease 15,17,18 and fungal infection 7 in liver transplant recipients, a definitive association between HHV-6 infection and these opportunistic infections remains unclear. This study showed no association between HHV-6 reactivation and CMV antigenemia or fungal infection.…”

Human herpes virus 6 infection is a hallmark of cord blood transplant in adults and may participate to delayed engraftment: a comparison with matched unrelated donors as stem cell source

“…[1][2][3][4]6 The role of HHV6 in delayed engraftment raises logically the question of HHV6 prophylaxis in CB transplant. If anti-CD46 antibodies may be envisaged, 38 other therapeutic agents are already available in prophylaxis such as ganciclovir or foscarnet. 39 Finally, two cases consistent with chromosomally integrated HHV6 were also observed, which is in accordance with the prevalence of 0.2-0.8% observed in the general population.…”

Increased IL-23 secretion and altered chemokine production by dendritic cells upon CD46 activation in patients with multiple sclerosis

“…A role of CD46 in IL-12p40 and p70 expression have been previously reported (Karp et al, 1996; KuritaTaniguchi et al, 2000;Schnorr et al, 1997;Smith et al, 2003). Hence, we analyzed the role of CD46 in both IL-12 and IL-23 inductions.…”

“…Production of IL-12p70 by APC can be modulated by cross-linking of CD46 at their surface, either increasing or decreasing IL-12 depending on the cell type and stimulus used. An inhibition of IL-12 production by monocytes is observed after CD46 ligation by antibodies or C3b binding (Karp et al, 1996), and a posttranscriptional inhibition of IL-12p70 was also observed when CD46 was triggered by HHV6 (Smith et al, 2003). On the other hand, IL-12p40 was increased by CD46 ligation on GM-CSF treated monocytes (KuritaTaniguchi et al, 2000), and infection of dendritic cells by measles virus led to an increase in IL-12p40 (Schnorr et al, 1997).…”

“…The engagement of CD46 at the surface of APC has been shown to modulate the production of IL-12 (p70) and/or p40 subunit, either increasing or decreasing their expression depending on the cell type and stimulus used (Karp et al, 1996;Kurita-Taniguchi et al, 2000;Schnorr et al, 1997;Smith et al, 2003). CD46 is a widely expressed transmembrane protein initially identified as a complement regulatory protein (Seya et al, 1986).…”