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HIV Latency Affected by Host Cell Transcriptomes

NEW YORK (GenomeWeb) – Host cells' transcriptomes influence latent HIV infections, a new single-cell study has found.

Despite antiretroviral therapy, HIV can persist in patients' cells for decades, and these latently infected cells can contribute to reinfection when treatment ceases, providing a stumbling block to eliminating HIV infections.

Researchers from Duke University and the University of North Carolina at Chapel Hill applied single-cell analysis approaches to the study of viral and host gene expression within latently infected cells. As they reported in Cell Reports today, the researchers found that while HIV downregulation occurred in diverse cells, such downregulation is also associated with the expression of a particular set of host genes. Knowing which viral and host factors are involved in latency could help investigators develop therapies to fully clear HIV infections, they added.

"Therapeutic modulation of these programs may reverse or enforce HIV latency," the authors wrote.

The Duke and UNC team developed a cellular model of HIV latency by infecting activated CD4+ T cells with an HIV strain that expresses a green fluorescent protein marker. After sorting and long-term co-culture with H80 cells, they generated a population of cells with both a downregulated HIV gene and GFP expression. Upon reactivation, the cells re-expressed GFP. After confirming viral RNA expression correlated with GFP protein expression, the researchers isolated single cells at various time points for analysis of both their viral and host transcriptomes.

Cells obtained two days after infection had higher levels of viral RNA, as compared to cells analyzed 12 weeks post infection, as gauged by single-cell qPCR. This indicated to the researchers that most infected cells eventually downregulated viral gene expression. However, they also noted that the extent of downregulation varied between cells.

The researchers then used single cell RNA-seq to compare host cell gene expression patterns of infected and uninfected CD4+ T cells from two donors. In their clustering analysis, infected and uninfected cells from the same donor grouped near each other, showing that their transcriptomes were broadly similar. The cells also clustered by donor.

The researchers identified seven gene-expression-based clusters, though they noted that these clusters largely fell along a gradient rather than in distinct groups. Overall, they uncovered 12 upregulated and six downregulated genes that differed between infected and uninfected cells.

Additionally, when they folded in scRNA-seq data from a third donor, they noted 33 upregulated and 13 downregulated transcripts when comparing actively GFP-expressing versus non-expressing cells, and 87 upregulated and 42 downregulated transcripts when they compared cells with high viral RNA expression cells to those not expressing GFP.

Through a pathway analysis, the researchers found that these up- and downregulated transcripts were enriched for involvement in cell death and survival and in cellular proliferation. This suggested that although HIV transcription is downregulated in a range of cells, it occurs more often in cells that express a certain set of genes linked to greater proliferation potential.

In particular, the team noted that this transcriptional signature was more common in Tn and Tcm cells.            

The researchers argued that the cellular environment could influence viral transcriptomic latency. "Overall these findings indicate that the latent reservoir is a complex and diverse population of cells but that expression of specific host cell genes likely plays a role in the pre ferential downregulation of the HIV provirus in some T cell subtypes," the authors concluded.

They also noted that further studies are needed to tease out the mechanisms of latency and develop therapeutic approaches.

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