Divergent tropism of HHV-6AGS and HHV-6BPL1 in T cells expressing different CD46 isoform patterns

•HHV-6BPL1 entry correlates with the expression of CD46 isoform patterns.•High expression of CD46-BC2 correlates with HHV-6BPL1 infection.•Low expression of CD46-CYT-1 inversely correlates with HHV-6BPL1 infection.•Anti-CD46 antibodies block HHV-6BPL1 entry in SupT1 cells.•Heparin does not affect binding of HHV-6BPL1 to Molt3 cells.

CD46 is a receptor for HHV-6A, but its role as a receptor for HHV-6B is controversial. The significance of CD46 isoforms for HHV-6A and HHV-6B tropism is unknown. HHV-6AGS was able to initiate transcription of the viral genes U7 and U23 in the CD46+CD134- T-cell lines Peer, Jurkat, Molt3, and SupT1, whereas HHV-6BPL1 was only able to do so in Molt3 and SupT1, which expressed a CD46 isoform pattern different from Peer and Jurkat. The HHV-6BPL1-susceptible T-cell lines were characterized by low expression of the CD46 isoform BC2 and domination of isoforms containing the cytoplasmic tail, CYT-1. A HHV-6BPL1 susceptible cell line, Be13, changed over time its CD46 isoform pattern to resemble Peer and Jurkat and concomitantly lost its susceptibility to HHV-6BPL1 but not HHV-6AGS infection. We propose that isoforms of CD46 impact on HHV-6B infection and thereby in part explain the distinct tropism of HHV-6AGS and HHV-6BPL1.