The pentameric complex is not required for congenital CMV transmission in seronegative rhesus macaques-Reference-Cited by-同舟云学术

The pentameric complex is not required for congenital CMV transmission in seronegative rhesus macaques

Published:2025-03-12 Issue:789 Volume:17 Page:
ISSN:1946-6234
Container-title:Science Translational Medicine
language:en
Short-container-title:Sci. Transl. Med.

Author:

Wang Hsuan-Yuan¹²³^ORCID,Taher Husam³,Kreklywich Craig N.³,Schmidt Kimberli A.⁴^ORCID,Scheef Elizabeth A.⁵^ORCID,Barfield Richard⁶,Otero Claire E.¹²^ORCID,Valencia Sarah M.²^ORCID,Zhang Ke⁷⁸^ORCID,Callahan Claire⁷^ORCID,Monticolo Francesco⁷,Qiao Yueqing⁷,Gilbride Roxanne M.³^ORCID,Crooks Chelsea M.¹^ORCID,Mirza Anne⁹,Knight Kelsey¹⁰,Moström Matilda J.⁵^ORCID,Manuel Tabitha D.⁵^ORCID,Sprehe Lesli⁵,Kendall Savannah⁵,Burgt Nathan Vande³^ORCID,Kowalik Timothy F.⁹^ORCID,Barry Peter A.⁴,Hansen Scott G.³^ORCID,Shu Jian⁷⁸¹¹,Tarantal Alice F.¹²,Chan Cliburn⁶^ORCID,Streblow Daniel N.³,Picker Louis J.³^ORCID,Kaur Amitinder⁵^ORCID,Früh Klaus³^ORCID,Permar Sallie R.¹^ORCID,Malouli Daniel³^ORCID

Affiliation:

1. Department of Pediatrics, Weill Cornell Medicine, New York, NY 10065, USA.

2. Duke University Medical Center, Durham, NC 27710, USA.

3. Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR 97006, USA.

4. Department of Pathology and Laboratory Medicine, Center for Immunology and Infectious Diseases, California National Primate Research Center, University of California Davis, Davis, CA 95616, USA.

5. Division of Immunology, Tulane National Primate Research Center, Covington, LA 70433, USA.

6. Department of Biostatistics and Bioinformatics and Center for Human Systems Immunology, Duke University School of Medicine, Durham, NC 27710, USA.

7. Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.

8. Broad Institute of MIT and Harvard, Boston, MA 02142, USA.

9. Department of Microbiology, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA.

10. Infectious Disease and Immunology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA.

11. Harvard-MIT Program in Health Sciences and Technology, MIT, Cambridge, MA 02139, USA.

12. Departments of Pediatrics and Cell Biology and Human Anatomy, School of Medicine, and California National Primate Research Center, University of California Davis, Davis, CA 95616, USA.

Abstract

Congenital cytomegalovirus (cCMV) is the leading infectious cause of neonatal neurological impairment worldwide, but the viral factors enabling vertical spread across the placenta remain undetermined. The pentameric complex (PC), composed of the subunits gH/gL/UL128/UL130/UL131A, has been demonstrated to be important for entry into nonfibroblast cells in vitro. These findings link the PC to broad cell tropism and virus dissemination in vivo, denoting all subunits as potential targets for intervention strategies and vaccine development. To determine the relevance of the PC for congenital transmission in a translational nonhuman primate model, we engineered a rhesus CMV (RhCMV) mutant lacking the orthologs of UL128 and UL130, which demonstrated diminished infection of epithelial cells in vitro. However, intravenous inoculation of either CD4 + T cell–depleted or immunocompetent RhCMV-seronegative pregnant rhesus macaques (RMs) in the early second trimester with the PC-deficient mutant resulted in maternal RhCMV peak plasma viremia similar to inoculations with PC-intact RhCMV, although virus shedding in saliva and urine was limited. Infections with the PC-intact virus induced IgG responses that neutralized RhCMV entry into epithelial cells in tissue culture. These responses were reduced, but not absent, from animals infected with the PC-deficient virus, which also induced IgG responses against gH. Moreover, congenital CMV transmission was confirmed in multiple animals infected with PC-deficient virus by detecting viral DNA in the amniotic fluid, indicating that transplacental transmission in RMs is not contingent on the PC.

Publisher

American Association for the Advancement of Science (AAAS)

Link

https://www.science.org/doi/pdf/10.1126/scitranslmed.adm8961

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