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

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<sup>+</sup> 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.

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Publication Details

Journal
Science Translational Medicine
Published
2025-03-12
DOI
https://doi.org/10.1126/scitranslmed.adm8961
Citations
3
Primary Topic
Cytomegalovirus and herpesvirus research
Type
article
Field-Weighted Citation Impact
4.06
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article

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

Craig N. Kreklywich, Cliburn Chan, Peter A. Barry, Daniel N. Streblow et al.
3 citations
Science Translational Medicine
Cytomegalovirus and herpesvirus research
4.06
article

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

Craig N. Kreklywich, Cliburn Chan, Peter A. Barry, Daniel N. Streblow, Chelsea M. Crooks, You‐Lin Qiao, Tabitha D. Manuel, Klaus Frueh, Amitinder Kaur, Claire Callahan, Matilda J. Moström, Sarah Valencia, Timothy F. Kowalik, Claire E. Otero, Katherine L. Knight, Sallie R. Permar, Scott G. Hansen, Roxanne M. Gilbride, Lesli Sprehe, Kimberli A. Schmidt, Husam Taher, Savannah Kendall, Anne M. Mirza, Francesco Monticolo, Elizabeth A. Scheef, Richard Barfield, Louis J. Picker, Hsuan-Yuan Wang, Daniel Malouli, Nathan Vande Burgt, Ke Zhang, Jian Shu, Alice F. Tarantal
article en
3 citations

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<sup>+</sup> 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.

Science Translational MedicineVol. 17(789)
Broad Institute (US), Tulane University (US), University of Massachusetts Chan Medical School (US), Duke University (US), Cornell University (US), Massachusetts General Hospital (US), Harvard–MIT Division of Health Sciences and Technology (US), Duke Medical Center (US), Children's Cancer Therapy Development Institute (US), Duke University Hospital (US), Weill Cornell Medicine (US), University of California, Davis (US)
Good health and well-being
Openalex Percentile: Top 7%
Cytomegalovirus and herpesvirus research
4.06
DOIOpen Access PDFOpenAlex
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