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SARS-CoV-2 infects mainly lungs and may cause several immune-related complications, such as lymphocytopenia and cytokine storm, which are associated with the severity of the disease and predict mortality. The mechanism by which SARS-CoV-2 infection may result in immune system dysfunction is still not fully understood. Here, we show that SARS-CoV-2 infects human CD4\n                    <jats:sup>+<\/jats:sup>\n                    T helper cells, but not CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells, and is present in blood and bronchoalveolar lavage T helper cells of severe COVID-19 patients. We demonstrated that SARS-CoV-2 spike glycoprotein (S) directly binds to the CD4 molecule, which in turn mediates the entry of SARS- CoV-2 in T helper cells. This leads to impaired CD4 T cell function and may cause cell death. SARS-CoV-2-infected T helper cells express higher levels of IL-10, which is associated with viral persistence and disease severity. Thus, CD4-mediated SARS-CoV-2 infection of T helper cells may contribute to a poor immune response in COVID-19 patients.\n                  <\/jats:p>","DOI":"10.7554\/elife.84790","type":"journal-article","created":{"date-parts":[[2023,7,14]],"date-time":"2023-07-14T07:15:16Z","timestamp":1689318916000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.84790","source":"Crossref","is-referenced-by-count":31,"title":["SARS-CoV-2 uses CD4 to infect T helper lymphocytes"],"prefix":"10.7554","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2803-3763","authenticated-orcid":true,"given":"Natalia S","family":"Brunetti","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04wffgt70","id-type":"ROR","asserted-by":"publisher"}],"name":"Autoimmune Research Laboratory, Department of Genetics, Microbiology and Immunology, Institute of Biology, University of Campinas (UNICAMP)","place":["Campinas, 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