A comprehensive review of the role and potential functions HHV-6A/B U94

The review covers the role the U94 gene product plays in the virus’s life cycle, replication, and latency, as well as in natural killer cell response, remyelination and angiogenesis.

The U94 gene is highly conserved and unique to HHV-6A/B. Caselli et al. of the University of Ferrara, have published a comprehensive review of the role, functions, and effects of the U94 gene product.

Role in HHV-6 life cycle:  The U94 gene is expressed at low levels during lytic infections, suggesting that it is required during productive replication. During latency, U94 is one of a few latency-associated proteins, and inhibits the replication of β-herpesviruses (HHV-6/7, HCMV) by inhibiting replication.

Role in chromosomal integration of HHV-6: U94 has been suspected to play a role in chromosomal integration of the viral DNA, since U94 has DNA binding, endonuclease, and helicase activities. However, the evidence is mixed, as a study found that viruses in which the U94 gene had been deleted nevertheless maintained the ability to integrate into the host cell genome (Wallaschek 2016). Thus, U94 may play a role in aiding integration but does not appear to be essential for integration.

Immunity and U94 gene product: Anti-U94 IgG antibodies are significantly higher in autoimmune disease processes—including multiple sclerosis, Hashimoto’s thyroiditis, and systemic sclerosis—than in healthy control subjects. Additionally, U94 also can elicit a cellular response: in these diseases, there are increased numbers of U94-specific CD8+ T-cells and CD4+ T-cells, especially CD4+ cells secreting IFNy and IL-2.

U94 is also known to impair NK cell response, particularly in female reproductive system tissues. U94 induces the production of human leukocyte antigen G (HLA-G), which is usually implicated in tolerogenic effects that allow embryo implantation in the endometrium (Rizzo 2018). HLA-G has been shown to be induced by HHV-6, leading to impairment of NK function.

Effect of U94 on Cells and Tissues:  U94 has been implicated as a possible cause of a failure of reparative remyelination in people with multiple sclerosis: it inhibits the migration of oligodendrocyte progenitor cells that lead to the production of myelin sheaths for nerves (Campbell 2017).

U94 protein also inhibits angiogenesis, following infection of endothelial cells. This antiangiogenic activity is related to U94 induction of HLA-G. The relationship of this property to tumor biology, if any, remains uncertain. U94 gene product also has interactions with proteins involved in the apoptosis pathway and inhibits the cholesterol biosynthesis pathway.

Read the full article: Caselli 2020