Speaker
Description
The short period of time prior to the establishment of a large and systemically replicating HIV-1 population provides a narrow window of time when the virus is at its most vulnerable to eradication. However, our understanding of these earliest stages of infection remains incomplete. To resolve these early dynamics, we used a non-human primate model to track the replication of clonal but genetically discriminable viral lineages across tissues and plasma.
Six animals were infected intravenously and necropsied at 4-5 days post-infection, with ~200 anatomical sites collected from each animal, spanning the gastrointestinal (GI) tract, GI-associated lymph nodes, peripheral lymph nodes, spleen, and additional organs. Viral DNA and RNA were quantified per site using qPCR, and next-generation sequencing was used to determine the proportions of individual barcoded lineages in each DNA-positive sample.
We developed a statistical framework to determine the sites of initial infection for individual lineages based on their replicative differences across tissues, identifying the putative tissue founder site for over 250 lineages. Replication at the initial site of infection varied widely, even among lineages originating within the same tissue sample, but did not differ significantly between tissue groups, indicating strong microenvironmental effects. Once a lineage expanded sufficiently at its origin site, dissemination was rapid and widespread, although early spread frequently followed local anatomical relationships.
Replicative success at the founder site was predictive of a lineage’s ultimate contribution to plasma viremia, with predominant plasma lineages originating from all tissue groups. Interestingly, in one animal, infection was overwhelmingly driven by a single GI-origin lineage that expanded far beyond all others highlighting how local inflammatory or target-cell conditions can amplify early stochastic differences. Together, our findings underline the importance of the earliest events in setting the course of the infection.
| Expedited Notification | No thanks, I do not require Expedited Notification |
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