SARS-CoV-2 Uses CD4 to Infect T Helper Lymphocytes

Davanzo, G. G.; Codo, A. C.; Brunetti, N. S.; Boldrini, V. O.; Knittel, T. L.; Monterio, L. B.; de Moraes, D.; Ferrari, A. J. R.; de Souza, G. F.; Muraro, S. P.; Profeta, G. . S.; Wassano, N. S.; Santos, L. N.; Carregari, V. . C.; Dias, A. . H. S.; Virgilio-da-Silva, J. V.; Castro, I.; Silva-Costa, L. . C.; Palma, A.; Mansour, E.; Ulaf, R. G.; Bernardes, A. F.; Nunes, T. A.; Ribeiro, L. C.; Agrela, M. V.; Moretti, M. L.; Buscaratti, L. I.; Crunfli, F.; Ludwig, R. . G.; Gerhardt, J. A.; Seste-Costa, R.; Forato, J.; Amorin, M. . R.; Texeira, D. A. T.; Parise, P. L.; Martini, M. C.; Bispo-dos-San,

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the agent of a major global outbreak of respiratory tract disease known as coronavirus disease-2019 (COVID-19). SARS-CoV-2 infects the 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 not fully understood. Here we show that SARS-CoV-2 infects human CD4+ T helper cells, but not CD8+ 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 in a mechanism that also requires ACE2 and TMPRSS2. Once inside T helper cells, SARS-CoV-2 assembles viral factories, impairs cell function and may cause cell death. SARS-CoV-2 infected T helper cells express higher amounts of IL-10, which is associated with viral persistence and disease severity. Thus, CD4-mediated SARS-CoV-2 infection of T helper cells may explain the poor adaptive immune response of many COVID- 19 patients.