HHV-6A and 7 infection of T cells downregulates the protein tyrosine phosphatase, CD45

CD45, important in T cell receptor signaling, may be one mechanism by which roseolaviruses evade immune detection and help achieve latency.

Herpesviruses evade host detection through various mechanisms. For example, the glycoprotein gene product, U21, encoded by HHV6A/B and HHV-7 can downregulate MHC I complexes from the cell surface (Glosson 2007).

Whyte et al. (2021) of the Medical College of Wisconsin quantified the expression of N-linked glycoproteins on the cell surface of roseolovirus (HHV6A, 6B, and 7)-infected T cells using mass spectrometry, a reliable and useful way of examining the cell surface proteome during viral infection (Weekes 2014).

They found that HHV-6A and HHV-7 down-regulated the protein tyrosine phosphatase CD45 (CD45) by 87.5%. This protein is expressed on the surface of all nucleated cells of hematopoietic origin and is critical for proper immune function. Various isoforms of CD45 were strongly downregulated by HHV-6A.

HHV-6A infected cells CD45 mRNA compared to a negative control (293T) and uninfected control (JJhan). qPCR performed in two biological replicates P <0.0001.

CD45 was not internalized in an endosomal compartment, as is found with other viruses; rather, it was depleted by unclear mechanisms. (Proteasomal and lysosomal degradation of CD45 was ruled out). CD45 mRNA was greatly reduced in HHV-6A cells (tested with qRT-PCR), which suggests transcriptional downregulation.

The authors confirmed that TCR stimulation is impaired in HHV-6A infection: levels of metabolic byproducts of TCR signaling were reduced, as compared to noninfected controls.  The authors speculate that the downregulation of CD45 may be a means to inhibit activation of HHV-6A-infected T cells: that would prevent activation-induced cell death and thereby create a host cell environment conducive to harboring latent virus.

The functional consequences of CD45 down-regulation in roseolavirus-infected cells remain to be determined.

Read the full article: Whyte 2021