Project Details
Description
Herpes simplex virus type 2 (HSV-2) is a major driver of the HIV epidemic, but the underlying
biological mechanisms have not been delineated. Recurrent HSV-2 shedding, which occurs
more often in HIV-infected persons, is characterized by the recruitment and persistence of
CD4+ T cells and other immune cells at sites of HSV-2 reactivation as well as an increase in
activated CD4+ T cells in the peripheral blood. These findings prompted us to test the
hypothesis that HSV-2 induces transcriptional changes in CD4+ T cells that promote HIV
replication and/or reactivation. We exposed primary CD4+ T cells or a latently HIV-infected T
cell line to HSV-2 and, using RNA sequencing, identified significant transcriptional changes
both in the HSV-2 infected and bystander cells. Importantly, the transcriptional changes were
associated with an increase in HIV replication and reactivation. One of the most significant
responses we observed in both HSV-2 infected and bystander cells was an increase in
expression of the long noncoding RNA, MALAT1. MALAT1 impacts the expression of multiple
transcripts including the HIV long terminal repeat (LTR) through interactions with the
Polycomb Repressive Complex 2 (PRC2). We knocked out MALAT1 in an HIV-latently
infected cell line and showed that HIV latency reversal was significantly reduced but not
abolished when the knockout compared to the parental cells were infected with HSV-2.
Building on this foundation, we propose to further define MALAT1-mediated and identify
MALAT1-independent mechanisms by which HSV-2 promotes HIV replication and
reactivation. We will take advantage of a longitudinal biorepository of peripheral blood
mononuclear cells from people living with HIV and compare the responses to HSV-2 during
periods of HIV viremia and viral suppression. We will expose the cells to HSV-2 and conduct
single cell RNA sequencing, proteomic and histone analyses and determine how the cellular
responses to HSV-2 enhance HIV replication and promote HIV latency reversal. We will then
focus on changes at the site of HSV-2 reactivation using genital skin biopsies collected at the
time of an HSV outbreak (lesion and unaffected tissue) and after resolution in HIV-infected
and uninfected individuals. This will also allow us to assess interactions between different cell
types including epithelial cells, which are primary targets of HSV replication. We will use
cutting-edge high resolution spatial technologies to identify gene and protein expression in
the tissue. Results of these studies have great translational relevance and will identify new
targets to promote or prevent HIV latency reversal that can ultimately lead to HIV eradication.
Status | Active |
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Effective start/end date | 12/5/17 → 12/31/24 |
Funding
- National Institute of Allergy and Infectious Diseases: $488,089.00
- National Institute of Allergy and Infectious Diseases: $483,050.00
- National Institute of Allergy and Infectious Diseases: $494,568.00
- National Institute of Allergy and Infectious Diseases: $518,436.00
- National Institute of Allergy and Infectious Diseases: $2,743.00
- National Institute of Allergy and Infectious Diseases: $509,551.00
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