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Humanized mice are critical for HIV-1 research, but humanized mice generated from cord blood are inefficient at mucosal HIV-1 transmission. Most mucosal HIV-1 transmission studies in mice require fetal tissue-engraftment, the use of which is highly restricted or prohibited. We present a fetal tissue-independent model called CD34T+ with enhanced human leukocyte levels in the blood and improved T cell homing to the gut-associated lymphoid tissue. CD34T+ mice are highly permissive to intra-rectal HIV-1 infection and also show normal env diversification in vivo despite high viral replication. Moreover, mucosal infection in CD34T+ mice can be prevented by infusion of broadly neutralizing antibodies. CD34T+ mice can be rapidly and easily generated using only cord blood cells and do not require any complicated surgical procedures for the humanization process. Therefore, CD34T+ mice provide a novel platform for mucosal HIV-1 transmission studies as well as rapid in vivo testing of novel prevention molecules against HIV-1.

The immune system of most SARS-CoV-2 infected individuals limits viral spread to the upper airways without pulmonary involvement. This prevents the development of pneumonic COVID-19. However, the protective immunological responses causative of successful viral containment in the upper airways remain unclear. Here, we combine longitudinal single-cell RNA sequencing, proteomic profiling, multidimensional flow cytometry, RNA-Seq of FACS-sorted leukocyte subsets and multiplex plasma interferon profiling to uncover temporally resolved protective immune signatures in non-pneumonic and ambulatory SARS-CoV-2 infected patients.We compare host responses in a high-risk patient population infected with SARS-CoV-2 but without pulmonary involvement to patients with COVID-19 pneumonia. Our data reveal a distinct immunological signature of successful viral containment, characterized by an early prominent interferon stimulated gene (ISG) upregulation across immune cell subsets. In addition, reduced cytotoxic potential of Natural Killer (NK) and T cells, as well as a monocyte phenotype with immune-modulatory potential are hallmarks of protective immunity. Temporal resolution across disease trajectories highlights ISG upregulation as particularly prominent early in the disease and confirms increased expression also in comparison to healthy controls.We validate this distinct temporal ISG signature by in-depth RNA-seq of FACS-sorted leukocyte subsets in a large prospective ambulatory SARS-CoV-2 infected cohort confirming early and robust ISG upregulation particularly in monocytes and T cells. In vitro experiments show that Stimulator of Interferon Genes (STING) agonist treatment of PBMCs recapitulates the identified protective immunological signature and might therefore offer a novel therapeutic approach in early disease, without being affected by previously described anti-interferon antibodies. In conclusion, our data demonstrate a protective ISG phenotype in patients with successful containment of SARS-CoV-2 infection without progression to COVID-19. This early protective interferon response might be exploited as a therapeutic approach and for disease course prediction. Funding: This study was supported by the Deutsche Herzstiftung e.V., Frankfurt a.M. [LN],Deutsche Forschungsgemeinschaft (DFG) SFB 914 (S.M. [B02 and Z01], K.S. [B02]), the DFG SFB 1123 (S.M. [B06], K.S. [A07]), M.J and R.Z [Z02]), the DFG FOR 2033 (S.M.), the DGF SFB1243 (W.E., L.E.W. [A14], the DGF EN 1093/2-1 (W.E., A.J.), the German Centre for Cardiovascular Research (DZHK) (Clinician Scientist Programme [L.N.], MHA 1.4VD [S.M.]), DZIF MD student programme (TI 07.003_Deak [F.D.]), FP7 program (project 260309, PRESTIGE [S.M.]), FoFoLe project 1015/1009 (L.N.), and the DFG Clinician Scientist Programme PRIME (413635475, K.P., R.K.). The work was also supported by the European Research Council (ERC 2018-ADG “IMMUNOTHROMBOSIS” [S.M.] and ERC- “T-MEMORE” [K.S.])The CORKUM cohort study was supported by LMUexcellent, funded by the Federal Ministry of Education and Research (BMBF) and the Free State of Bavaria under the Excellence Strategy of the Federal Government and the Lander.The Koco19-Immu Study is funded by Bavarian State Ministry of Science and the Arts, University Hospital, LMU Munich, Helmholtz Centre Munich, University of Bonn, University of Bielefeld, German Ministry for Education and Research (Project No.: 01KI20271). Conflict of Interest: The authors declare no conflict of interest. Ethical Approval: In accordance with the Declaration of Helsinki, and with the approval of the Ethics Committee of Ludwig-Maximilian University Munich, informed consent of the patients or their guardians was obtained. COVID-19 patients are part of the COVID-19 Registry of the LMU University Hospital Munich (CORKUM, WHO trial ID DRKS00021225). Pseudonymizeddata was used for analysis, the CORKUM and KocoImmu studies were approved by the ethics committee of LMUMunich (No: 20-245 & No: 20-371 respectively).

Humanized mice have been critical for HIV-1 research, but are inefficient at mucosal HIV-1 transmission. We present a fetal tissue-independent model called CD34T+ with enhanced human leukocyte levels in the blood and improved T cell homing to the gut-associated lymphoid tissue. CD34T+ mice are highly permissive to intra-rectal HIV-1 infection, which can be prevented by infusion of broadly neutralizing antibodies. Therefore, CD34T+ mice provide a novel platform for mucosal HIV-1 transmission and prevention studies.