HSV-2 triggers upregulation of MALAT1 in CD4+ T cells and promotes HIV latency reversal
Carl A. Pierce, … , Kevan C. Herold, Betsy C. Herold
Carl A. Pierce, … , Kevan C. Herold, Betsy C. Herold
Published April 20, 2023
Citation Information: J Clin Invest. 2023;133(11):e164317. https://doi.org/10.1172/JCI164317.
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Research Article AIDS/HIV Virology Article has an altmetric score of 5

HSV-2 triggers upregulation of MALAT1 in CD4+ T cells and promotes HIV latency reversal

Abstract

Herpes simplex virus type 2 (HSV-2) coinfection is associated with increased HIV-1 viral loads and expanded tissue reservoirs, but the mechanisms are not well defined. HSV-2 recurrences result in an influx of activated CD4+ T cells to sites of viral replication and an increase in activated CD4+ T cells in peripheral blood. We hypothesized that HSV-2 induces changes in these cells that facilitate HIV-1 reactivation and replication and tested this hypothesis in human CD4+ T cells and 2D10 cells, a model of HIV-1 latency. HSV-2 promoted latency reversal in HSV-2–infected and bystander 2D10 cells. Bulk and single-cell RNA-Seq studies of activated primary human CD4+ T cells identified decreased expression of HIV-1 restriction factors and increased expression of transcripts including MALAT1 that could drive HIV replication in both the HSV-2–infected and bystander cells. Transfection of 2D10 cells with VP16, an HSV-2 protein that regulates transcription, significantly upregulated MALAT1 expression, decreased trimethylation of lysine 27 on histone H3 protein, and triggered HIV latency reversal. Knockout of MALAT1 from 2D10 cells abrogated the response to VP16 and reduced the response to HSV-2 infection. These results demonstrate that HSV-2 contributes to HIV-1 reactivation through diverse mechanisms, including upregulation of MALAT1 to release epigenetic silencing.

Authors

Carl A. Pierce, Lip Nam Loh, Holly R. Steach, Natalia Cheshenko, Paula Preston-Hurlburt, Fengrui Zhang, Stephanie Stransky, Leah Kravets, Simone Sidoli, William Philbrick, Michel Nassar, Smita Krishnaswamy, Kevan C. Herold, Betsy C. Herold

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Figure 6

scRNA-Seq reveals shared and divergent gene expression features of HSV-2–infected and bystander cells.

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scRNA-Seq reveals shared and divergent gene expression features of HSV-2...
(A) Multiscale PHATE visualization of sample likelihood score calculated with MELD for each experimental time point. Purple, green, and red color schemes correspond to mock, 6 hpi, and 24 hpi, respectively, and the size of a dot is proportional to the number of cells represented. (B) Multiscale PHATE visualization of UL15 expression, where color intensity denotes gene expression. (C and D) Box plots showing relative gene expression of cells at 24 hpi within Multiscale PHATE clusters for genes involved in HIV reactivation (C) and general antiviral immune responses (D). Values represent normalized and denoised gene expression levels for individual cells relative to average expression in mock-infected cells (**P < 0.01, ***P < 0.001, Welch’s t test). At 24 hpi, cells in the early cluster are mock-like, cells in the mid cluster are defined as bystanders, and those in the late are productively HSV-2–infected.