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Integrated Single-Cell Analysis of Multicellular Immune Dynamics during Hyper-Acute HIV-1 Infection

By Samuel W. Kazer, Toby P. Aicher, Daniel M. Muema, Shaina L Carroll, Jose Ordovas-Montanes, Carly Ziegler, Sarah K. Nyquist, Emily B. Wong, Nasreen Ismail, Mary Dong, Amber Moodley, Krista L Dong, Zaza M. Ndhlovu, Thumbi Ndung'u, Bruce D. Walker, Alex K Shalek

Posted 30 May 2019
bioRxiv DOI: 10.1101/654814

Cellular immunity is critical for controlling intracellular pathogens, but the dynamics and cooperativity of the evolving host response to infection are not well defined. Here, we apply single-cell RNA-sequencing to longitudinally profile pre- and immediately post-HIV infection peripheral immune responses of multiple cell types in four untreated individuals. Onset of viremia induces a strong transcriptional interferon response integrated across most cell types, with subsequent pro-inflammatory T cell differentiation, monocyte MHC-II upregulation, and cytolytic killing. With longitudinal sampling, we nominate key intra- and extracellular drivers that induce these programs, and assign their multi-cellular targets, temporal ordering, and duration in acute infection. Two individuals studied developed spontaneous viral control, associated with initial elevated frequencies of proliferating cytotoxic cells, inclusive of a previously unappreciated proliferating natural killer (NK) cell subset. Our study presents a unified framework for characterizing immune evolution during a persistent human viral infection at single-cell resolution, and highlights programs that may drive response coordination and influence clinical trajectory.

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