HHV-6 Induced Immune Suppression

Two review papers on HHV-6 & beta herpesvirus induced immunosuppression are:

• A review of HHV-6 induced immunosuppression by Paolo Lusso of the San Rafaele Institute in Milan (Lusso 2006)
• A review of beta herpesvirus immunosuppression by the researchers at the Hutchinson Cancer Center (Boeckh 2003)

Recent evidence demonstrates that HHV-6 (especially HHV-6A) can cause selective immunosuppression in otherwise in immunocompetent adults. HHV-6 infection can result in the following:

• Depletion of CD4 T lymphocytes via direct infection and induction of apoptosis (Grivel 2003, Lusso, 1988 )
• Lytic infection of cytotoxic effector cells -CD8+, NK cells (Lusso 1991A, 1992, 1995)
• Functional impairment and delay in maturation of dendritic cells and macrophages (Kakimoto 2002, Smith 2005)
• Suppression of the ability of macrophages and dendritic cells  to produce IL-12p70  upon stimulation with interferon gamma. (Smith 2003, 2005)
• Suppression of IL-2 secretion (Flamand 1995)
• Disturbance of key immune activation pathways and cytokine networks including an upregulation of TNF alpha, TNF- alpha, RANTES, IL-1beta and IL-10. (Flamand,1991, Arena 1999, Grivel 2000)   
• Downregulation of complement activity through the CD46 receptor and downregulation of Il-2. (Russell 2004)
• Modification on monocytes that favor immune evasion including reduced levels of CD14, CD64 and HLA-DR antigen on their surface while CD32 expression is unaffected. (Janelle 2006)
• Dysregulation of monocyte-mediated antifungal defenses (Cermelli 2006)
• HHV-6 specific IL-10 producing CD4+ T cells and CD4+ Th1 responses in HHV-6 infected individuals are selectively impaired. (Wang 2006)
• Generalized loss of CD46 expression in lymphoid tissue (Lusso 2006)
• Delayed immune response after acute HHV-6 infection. (Kumagai 2006)
• Downmodulation of the CD3/T-cell receptor complex. (Lusso 1991, Sullivan 2007)
• Suppression of IFN-beta gene induction by IE proteins from HHV-6, interfering with innate antiviral response  (Jaworska 2007)

HHV-6A was shown to dramatically accelerate progression from HIV to full blown AIDS in macaques, by causing an early depletion in both CD4+ and CD8+ cells. (Lusso 2007) HHV-6A may cause more of the destruction of lymphoid tissue and apoptosis of immune cells than HIV. Bob Gallo spoke on this subject at the last HHV-6 conference in Barcelona, telling the group that HHV-6A is an important progression factor in AIDS and has been wrongly ignored

Of note, HIV can not invade CD8 cells until HHV-6A has first infected the cell to induce the CD4+ receptor. (Lusso 1991) HHV-6A induces de novo expression of CD4 messenger RNA and protein in normal mature CD8+ T lymphocytes, rendering them susceptible to infection with HIV.