While CD134 remains the more important receptor for HHV-6B, HHV-6B can use the CD46 receptor when a T cell has the C1 isoform of CD46.
CD46 is well established as the receptor for HHV-6A and also can be used by HHV-6B in some T cells. CD46 is ubiquitously expressed by many cell types, is the complement receptor, and serves as a receptor for other infectious agents, as well, including Neisseria meningitidis, Neisseria gonorrhoeae, Streptococcus pyogenes, measles morbillivirus and some species of mastadenovirus.
The most commonly expressed isoforms of CD46 are distinguished by a BC domain or a C domain. Investigators from Aarhus University in Denmark used CRISPR-Cas9 to create cell lines that preferentially express the specific isoforms, BC1 or C1 in SupT1 T cells. Then they infected these cells either with HHV-6AGS or HHV-6BZ29.
The experiments demonstrated that HHV-6A prefers the BC isoform to infect T cells whereas HHV-6B prefers the C isoform. In addition, infection with HHV-6A occurs mainly by clathrin-mediated endocytosis whereas, in contrast, infection with HHV-6B occurs mainly by fusion-from-without: endocytosis inhibitors did not reduce the ability of HHV-6B infection to infect the SupT1C1 cells.
The isoform differences also affected the production of progeny virus. Levels of viral mRNA and DNA were measured at various time points in supernatants from SupT1BC1 and SupT1C1 cells infected with virus. Each virus could infect each of the two cell lines, but the levels of virus production showed that HHV-6AGS proliferated better in cells with the BC1 isoform, whereas HHV-6BZ29 proliferated better in cells with the C1 isoform (see Figure).
This report confirms that HHV-6B can use the CD46 receptor, particularly when a T cell has the C1 isoform of CD46. It also demonstrates that HHV-6A prefers the BC isoform while HHV-6B prefers the C isoform.
Read the full paper: Rossen 2022