Abstract
Combination anti-retroviral therapy (cART) has drastically improved the clinical outcome of HIV-1 infection. Nonetheless, despite effective cART, HIV-1 persists indefinitely in infected individuals. Clonal expansion of HIV-1-infected cells in peripheral blood has been reported recently. cART is effective in stopping the retroviral replication cycle, but not in inhibiting clonal expansion of the infected host cells. Thus, the proliferation of HIV-1-infected cells may play a role in viral persistence, but little is known about the kinetics of the generation, the tissue distribution or the underlying mechanism of clonal expansion in vivo. Here we analyzed the clonality of HIV-1-infected cells using high-throughput integration site analysis in a hematopoietic stem cell-transplanted humanized mouse model. Clonally expanded, HIV-1-infected cells were detectable at two weeks post infection, their abundance increased with time, and certain clones were present in multiple organs. Expansion of HIV-1-infected clones was significantly more frequent when the provirus was integrated near host genes in specific gene ontological classes, including cell activation and chromatin regulation. These results identify potential drivers of clonal expansion of HIV-1-infected cells in vivo.
Highlights
Human immunodeficiency virus type 1 (HIV-1) is an exogenous retrovirus with worldwide distribution
The estimated proviral load (PVL) was much higher than that typically observed in peripheral blood mononuclear cells (PBMCs) of infected individuals (Fig. 1D)[25], and there was no significant difference in PVL between different tissues (Fig. 1E)
The high-throughput sequencing of randomly-sheared DNA has made it possible to comprehensively quantify the clonality of retrovirus-infected cells[16, 17], and the approach has led to recent reports of clonal expansion of HIV-1–infected cells in the peripheral blood of infected individuals[12, 14, 15]
Summary
Human immunodeficiency virus type 1 (HIV-1) is an exogenous retrovirus with worldwide distribution. CART does not eradicate the virus: a reservoir of HIV-1-infected cells persists despite prolonged therapy[2], and infected individuals cannot interrupt treatment[3]. When infected individuals are treated with cART, the plasma viral RNA typically becomes undetectable by standard assays In this situation, HIV-1 proviral DNA contributes to the maintenance of the viral reservoir, and much effort has been recently dedicated to study the distribution of HIV-1 proviral integration sites and the mechanisms of proviral reactivation[6,7,8]. It has been reported recently that HIV-1-infected cells can undergo clonal expansion, as observed in infection with the related retrovirus human T-cell leukemia virus type 1 (HTLV-1)[12, 14, 15]. One can study CD4+ T-cell dynamics in the humanized mouse model, including generation, differentiation, activation, and homeostasis[23]
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