Table 1.

Association of human herpes virus-6A (HHV-6A) and age-related macular degeneration (AMD) with AIDS, Hashimoto’s thyroiditis (HT), and multiple sclerosis (MS).

Disease	Association with HHV-6A	Association with AMD
AIDS	HIV-1 infection is epidemiologically associated with HHV-6A infection (63, 64). Particularly, HHV-6 is found in demyelinating lesions in AIDS patients with cerebral involvement (65) and HIV-1 and HHV-6 antigens and transcripts are found in the retina of patients with AIDS (66)	Persons with AIDS appear to have an approximately 4-fold increased prevalence of intermediate-stage AMD when compared to a similarly aged human immunodeficiency virus (HIV)-uninfected population (67)
HT	The most frequent cause of hypothyroidism is HT. In a study examining thyroid fine needle aspirates (FNA) and peripheral blood mononuclear cells, HHV-6 DNA prevalence was much higher in HT (82%) than in controls (10%). and viral load was significantly increased in FNA from HT patients, and thyrocytes from HT FNA displayed a 100-fold higher HHV-6 DNA load compared to infiltrating lymphocytes (68). Variant analysis performed in 10 HT samples showed that all samples harbored HHV-6A. In vitro infection of thyrocytes with HHV-6A induces modulation of miRNAs considered markers of autoimmune thyroid disease in vivo. These alterations were not seen thyrocytes infected with HHV-6B or HHV-7 (69)	The association of AMD with thyroid function is somewhat controversial. In a study with 356 people with AMD 21% reported to have hypothyroidism compared to 11% of those 9,321 without AMD giving an odds ratio of 2.33 (70). On the other side, in a prospective population-based cohort study with 5,573 participants of age ≥55 years, higher free thyroxine (FT4) values were associated with a higher risk of AMD, odds ratio albeit being very small (1.35 for the highest quartile of FT4 levels) (71). However, participants with AMD at baseline (N = 567) were excluded from the study. Interestingly, another study found that thyroxine substitution, which can be considered a surrogate marker for hypothyroidism, also correlated with AMD (72).In a smaller study with 114 patients, an association of AMD with not further specified thyroidopathy was found (73).
MS	There is abundant evidence that HHV-6A has an etiopathologic role in MS [for review, see Ref. (74)]. HHV-6A infects astrocytes via the CD46, thereby interfering with complement regulation (13, 14), in much the same way as is proposed here for RPE cells. Furthermore, it has recently been postulated that HHV-6A also interacts with Epstein–Barr virus in the CNS of MS patients leading to B-cell transformation and production of oligoclonal immunoglobulins that are typical for MS (12)	Although there are no epidemiologic studies directly examining a possible association between MS and AMD, ocular pathology has been studied in MS patients (75). MS cases with variable clinical severity demonstrated evidence of retinal atrophy and prominent inflammation