32nd International Dynamics & Evolution of Human Viruses

IN-DEPTH CHARACTERIZATION OF THE SIV TISSUE RESERVOIR DYNAMICS

Not scheduled

20m

Abbaye de Royaumont, Asnières-sur-Oise, France

Oral Within-host dynamics & adaptation

Speaker

Ramon Lorenzo-Redondo (1 Division of Infectious Diseases, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. 2 Center for Pathogen Genomics and Microbial Evolution, Northwestern University Institute for Global Health, Chicago, IL 60611, USA.)

Description

Despite the success of antiretroviral therapy (ART) in controlling viremia, HIV-1 reservoirs persist during therapy constituting the major obstacle to a functional cure. These reservoirs lead to a rapid rebound in viremia when treatment fails or is discontinued. To eliminate this viral reservoir that mostly resides in tissues, it is key to characterize its tissue microenvironment and associated viral population dynamics during ART, and after analytical treatment interruption (ATI).

We have developed immunoPET/CT-guided host transcriptomics, combined with immunofluorescence detection of viral proteins and viral sequencing using the SIV/rhesus macaque (RM) model. With this approach we can find and study foci of viral replication in tissues to understand the characteristics of the relevant reservoirs for viral persistence. RM were challenged with barcoded SIVmac239, ART initiated at week 10 after infection, and maintained for 54 weeks, followed by PET/CT-guided necropsy after early ATI (4-7 days post-ATI). 64Copper-labelled probe against viral envelope (env) efficiently detected infection sites as early as 4-days post-ATI. Using this unprecedented capacity to detect viral reservoirs, we perform whole genome long-read deep viral sequencing in tissue sections where env was detected during ART and after ATI. With the sequences obtained, viral population dynamics were analyzed using phylogenetic and phylodynamic approaches and host transcriptomics association analyses were performed.

This unique in-depth analysis of the intra-host viral population dynamics in tissue reservoirs depicts highly complex dynamics. Early after ATI, we can observe significantly different patterns of viral diversification and population structure in the tissue reservoirs, especially in areas with highest detection of viral proteins and distinct transcriptional patterns newly characterized by our groups as virus reservoir microenvironment. Amongst these, the highest viral diversity levels are consistently detected in gut and brain tissues, reflective of higher viral replication and diversification in these tissues that could constitute a key source of rebounding virus.