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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) primarily replicates in mucosal sites, and more information is needed about immune responses in infected tissues. Here, we used rhesus macaques to model protective primary immune responses in tissues during mild coronavirus disease 2019 (COVID-19). Viral RNA levels were highest on days 1 to 2 after infection and fell precipitously thereafter.18 F-fluorodeoxyglucose (18 FDG)–avid lung abnormalities and interferon (IFN)–activated monocytes and macrophages in the bronchoalveolar lavage (BAL) were found on days 3 to 4 after infection. Virus-specific effector CD8+ and CD4+ T cells became detectable in the BAL and lung tissue on days 7 to 10 after viral RNA, radiologic evidence of lung inflammation, and IFN-activated myeloid cells had substantially declined. SARS-CoV-2–specific T cells were not detectable in the nasal turbinates, salivary glands, and tonsils on day 10 after infection. Thus, SARS-CoV-2 replication wanes in the lungs, as well as the nasal and oral mucosa, of rhesus macaques before antigen-specific effector T cells arrive at those sites, suggesting that innate immunity efficiently restricts viral replication during mild COVID-19.

Mild SARS-CoV-2 infection in rhesus macaques is associated with viral control prior to antigen-specific T cell responses in tissues