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HIV infection results in clonal expansions containing integrations within pathogenesis-related biological pathways
Kevin G. Haworth, … , Jennifer E. Adair, Hans-Peter Kiem
Kevin G. Haworth, … , Jennifer E. Adair, Hans-Peter Kiem
Published July 12, 2018
Citation Information: JCI Insight. 2018;3(13):e99127. https://doi.org/10.1172/jci.insight.99127.
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Research Article AIDS/HIV Virology

HIV infection results in clonal expansions containing integrations within pathogenesis-related biological pathways

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Abstract

The genomic integration of HIV into cells results in long-term persistence of virally infected cell populations. This integration event acts as a heritable mark that can be tracked to monitor infected cells that persist over time. Previous reports have documented clonal expansion in people and have linked them to proto-oncogenes; however, their significance or contribution to the latent reservoir has remained unclear. Here, we demonstrate that a directed pattern of clonal expansion occurs in vivo, specifically in gene pathways important for viral replication and persistence. These biological processes include cellular division, transcriptional regulation, RNA processing, and posttranslational modification pathways. This indicates preferential expansion when integration events occur within genes or biological pathways beneficial for HIV replication and persistence. Additionally, these expansions occur quickly during unsuppressed viral replication in vivo, reinforcing the importance of early intervention for individuals to limit reservoir seeding of clonally expanded HIV-infected cells.

Authors

Kevin G. Haworth, Lauren E. Schefter, Zachary K. Norgaard, Christina Ironside, Jennifer E. Adair, Hans-Peter Kiem

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Figure 1

Depletion of circulating human CD4+ cells in periphery of infected mice.

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Depletion of circulating human CD4+ cells in periphery of infected mice....
Neonate NSG mice were engrafted with human CD34+ cells at birth and challenged with HIV at 16 weeks of age after development of CD4+ T cells. (A) Peripheral human CD45+ engraftment in blood samples over time for 2 cohorts of mice. Each line represents a single mouse and is colored red after infection at 16 weeks, indicated by vertical dashed red line. (B) CD3+ and (C) CD4+ T cell development over time for individual mice, represented as percent of cells in total blood. Mock mice represented as black lines (n = 3) and HIV-infected mice represented as red lines (n = 8). (D) Human engraftment at time of necropsy in peripheral blood, BM, spleen, and thymus of mice as indicated on upper x axis. Bar length corresponds to total human CD45+ engraftment and is broken down into stacked boxes representing specific cell lineages. Individual animal numbers listed on y axis and horizontal dashed black line separates mock from HIV-infected mice. One mock mouse died early and was excluded from necropsy analysis.

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