PMID- 35019717
OWN - NLM
STAT- MEDLINE
DCOM- 20220428
LR  - 20220910
IS  - 1098-5514 (Electronic)
IS  - 0022-538X (Print)
IS  - 0022-538X (Linking)
VI  - 96
IP  - 5
DP  - 2022 Mar 9
TI  - CD46 Isoforms Influence the Mode of Entry by Human Herpesvirus 6A/B in T Cells.
PG  - e0155721
LID - 10.1128/JVI.01557-21 [doi]
LID - e01557-21
AB  - CD46 is a receptor for human herpesvirus 6A (HHV-6A) and is in some cells also 
      important for infection with HHV-6B. CD46 has several isoforms of which the most 
      commonly expressed can be distinguished by expression of a BC domain or a C 
      domain in a serine-threonine-proline-rich (STP) extracellular region. Using a 
      SupT1 CD46 CRISPR-Cas9 knockout model system reconstituted with specific CD46 
      isoforms, we demonstrated that HHV-6A infection was more efficient when BC 
      isoforms were expressed as opposed to C isoforms, measured by higher levels of 
      intracellular viral transcripts and recovery of more progeny virus. Although the 
      B domain contains several O-glycosylations, mutations of Ser and Thr residues did 
      not prevent infection with HHV-6A. The HHV-6A infection was blocked by inhibitors 
      of clathrin-mediated endocytosis. In contrast, infection with HHV-6B was 
      preferentially promoted by C isoforms mediating fusion-from-without, and this 
      infection was less affected by inhibitors of clathrin-mediated endocytosis. Taken 
      together, HHV-6A preferred BC isoforms, mediating endocytosis, whereas HHV-6B 
      preferred C isoforms, mediating fusion-from-without. This demonstrates that the 
      STP region of CD46 is important for regulating the mode of infection in SupT1 
      cells and suggests an epigenetic regulation of the host susceptibility to HHV-6A 
      and HHV-6B infection. IMPORTANCE CD46 is the receptor used by human herpesvirus 
      6A (HHV-6A) during infection of T cells, but it is also involved in infection of 
      certain T cells by HHV-6B. The gene for CD46 allows expression of several 
      variants of CD46, known as isoforms, but whether the isoforms matter for 
      infection of T cells is unknown. We used a genetic approach to delete CD46 from T 
      cells and reconstituted them with separate isoforms to study them individually. 
      We expressed the isoforms known as BC and C, which are distinguished by the 
      potential inclusion of a B domain in the CD46 molecule. We demonstrate that 
      HHV-6A prefers the BC isoform to infect T cells, and this occurs predominantly by 
      clathrin-mediated endocytosis. In contrast, HHV-6B prefers the C isoform and 
      infects predominantly by fusion-from-without. Thus, CD46 isoforms may affect 
      susceptibility of T cells to infection with HHV-6A and HHV-6B.
FAU - Rossen, Litten Sorensen
AU  - Rossen LS
AD  - Department of Biomedicine, Aarhus Universitygrid.7048.b, Aarhus, Denmark.
FAU - Schack, Vivien R
AU  - Schack VR
AUID- ORCID: 0000-0002-1365-3938
AD  - Department of Biomedicine, Aarhus Universitygrid.7048.b, Aarhus, Denmark.
FAU - Thuesen, Katrine Kyd Holstein
AU  - Thuesen KKH
AD  - Department of Biomedicine, Aarhus Universitygrid.7048.b, Aarhus, Denmark.
FAU - Bundgaard, Bettina
AU  - Bundgaard B
AD  - Department of Biomedicine, Aarhus Universitygrid.7048.b, Aarhus, Denmark.
FAU - Hollsberg, Per
AU  - Hollsberg P
AUID- ORCID: 0000-0001-5314-5818
AD  - Department of Biomedicine, Aarhus Universitygrid.7048.b, Aarhus, Denmark.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220112
PL  - United States
TA  - J Virol
JT  - Journal of virology
JID - 0113724
RN  - 0 (CD46 protein, human)
RN  - 0 (Clathrin)
RN  - 0 (Membrane Cofactor Protein)
RN  - 0 (Protein Isoforms)
SB  - IM
MH  - Cells, Cultured
MH  - Clathrin/metabolism
MH  - Epigenesis, Genetic
MH  - Gene Deletion
MH  - *Herpesvirus 6, Human/physiology
MH  - Humans
MH  - *Membrane Cofactor Protein/genetics/metabolism
MH  - Protein Isoforms/genetics/metabolism
MH  - *T-Lymphocytes/metabolism/virology
MH  - *Virus Internalization
PMC - PMC8906420
OTO - NOTNLM
OT  - CD46
OT  - HHV-6A
OT  - HHV-6B
COIS- The authors declare no conflict of interest.
EDAT- 2022/01/13 06:00
MHDA- 2022/04/29 06:00
PMCR- 2022/09/09
CRDT- 2022/01/12 12:19
PHST- 2022/01/13 06:00 [pubmed]
PHST- 2022/04/29 06:00 [medline]
PHST- 2022/01/12 12:19 [entrez]
PHST- 2022/09/09 00:00 [pmc-release]
AID - 01557-21 [pii]
AID - jvi.01557-21 [pii]
AID - 10.1128/JVI.01557-21 [doi]
PST - ppublish
SO  - J Virol. 2022 Mar 9;96(5):e0155721. doi: 10.1128/JVI.01557-21. Epub 2022 Jan 12.