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In this study, by means of cellular depletion, the cluster of differentiation (CD) tetraspanins CD9, CD63, and CD151 were found to reduce HPV16 infection in HeLa cells by 50 to 80%. Moreover, we tested recombinant proteins or peptides of specific tetraspanin domains on their effect on the most oncogenic HPV type, HPV16, and HCMV. We found that the C-terminal tails of CD63 and CD151 significantly inhibited infections of both HPV16 and HCMV. Although CD9 was newly identified as a key cellular factor for HPV16 infection, the recombinant CD9 C-terminal peptide had no effect on infection. Based on the determined half-maximal inhibitory concentration (IC50), we classified CD63 and CD151 C-terminal peptides as moderate to potent inhibitors of HPV16 infection in HeLa and HaCaT cells, and in EA.hy926, HFF (human foreskin fibroblast) cells, and HEC-LTT (human endothelial cell-large T antigen and telomerase) cells for HCMV, respectively. These results indicate that HPV16 and HCMV share similar cellular requirements for their entry into host cells and reveal the necessity of the cytoplasmic CD151 and CD63 C-termini in virus infections. Furthermore, this highlights the suitability of these peptides for functional investigation of tetraspanin domains and as inhibitors of pathogen infections.<\/jats:p>","DOI":"10.3390\/ijms19103007","type":"journal-article","created":{"date-parts":[[2018,10,2]],"date-time":"2018-10-02T11:30:02Z","timestamp":1538479802000},"page":"3007","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Inhibition of Tetraspanin Functions Impairs Human Papillomavirus and Cytomegalovirus Infections"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4041-8917","authenticated-orcid":false,"given":"Laura A.","family":"Fast","sequence":"first","affiliation":[{"name":"Institute for Virology and Research Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg University, 55122 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Snje\u017eana","family":"Mikuli\u010di\u0107","sequence":"additional","affiliation":[{"name":"Institute for Virology and Research Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg University, 55122 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Fritzen","sequence":"additional","affiliation":[{"name":"Institute for Virology and Research Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg University, 55122 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonas","family":"Schwickert","sequence":"additional","affiliation":[{"name":"Institute for Virology and Research Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg University, 55122 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatima","family":"Boukhallouk","sequence":"additional","affiliation":[{"name":"Institute for Medical Microbiology and Hygiene, University Medical Center of the Johannes Gutenberg University, 55122 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Hochdorfer","sequence":"additional","affiliation":[{"name":"Institute of Virology, Ulm University Medical Center, 89081 Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Sinzger","sequence":"additional","affiliation":[{"name":"Institute of Virology, Ulm University Medical Center, 89081 Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henar","family":"Suarez","sequence":"additional","affiliation":[{"name":"Departamento de Biolog\u00eda Molecular, UAM, 28049 Madrid, Spain"},{"name":"Centro de Biolog\u00eda Molecular Severo Ochoa (CBM-SO), Instituto de Investigaci\u00f3n Sanitaria Princesa (IIS-IP), 28006 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4637-3059","authenticated-orcid":false,"given":"Peter N.","family":"Monk","sequence":"additional","affiliation":[{"name":"Department of Infection, Immunity and Cardiovascular Disease, School of Medicine and Biomedical Science, University of Sheffield, Sheffield S10 2RX, England, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7484-2866","authenticated-orcid":false,"given":"Mar\u00eda","family":"Y\u00e1\u00f1ez-M\u00f3","sequence":"additional","affiliation":[{"name":"Departamento de Biolog\u00eda Molecular, UAM, 28049 Madrid, Spain"},{"name":"Centro de Biolog\u00eda Molecular Severo Ochoa (CBM-SO), Instituto de Investigaci\u00f3n Sanitaria Princesa (IIS-IP), 28006 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana","family":"Lieber","sequence":"additional","affiliation":[{"name":"Institute of Virology, Ulm University Medical Center, 89081 Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4310-7329","authenticated-orcid":false,"given":"Luise","family":"Florin","sequence":"additional","affiliation":[{"name":"Institute for Virology and Research Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg University, 55122 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,10,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/j.micinf.2009.11.001","article-title":"The role of tetraspanins in the pathogenesis of infectious diseases","volume":"12","author":"Figdor","year":"2010","journal-title":"Microbes Infect."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"4","DOI":"10.2174\/187152612798994957","article-title":"Tetraspanins: Gateways for infection","volume":"12","author":"Monk","year":"2012","journal-title":"Infect. 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