NIH grant: Viral and Cellular microRNA Dependencies in HIV-associated Lymphomas (1R01CA314630-01)

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NIH grant 1R01CA314630-01: Viral and Cellular microRNA Dependencies in HIV-associated Lymphomas
Institute: {'code': 'CA', 'abbreviation': 'NCI', 'name': 'National Cancer Institute', 'admin_org_id': '12500008', 'admin_funding_url': ''}. PI: Eva Henriette Gottwein. Award: $644961.
Start: 2026-08-01T00:00:00.
PROJECT SUMMARY
People living with HIV (PLWH) remain at substantially increased risk for aggressive B-cell lymphomas despite
effective antiretroviral therapy. Diffuse large B-cell lymphoma (DLBCL) is the most common subtype. In contrast,
primary effusion lymphoma (PEL) is a rare but highly aggressive HIV-associated lymphoma caused by Kaposi’s
sarcoma-associated herpesvirus (KSHV). PEL has a dismal prognosis and remains incurable with current
chemotherapy-based approaches. In PEL and PEL-derived cell lines, KSHV remains predominantly latent,
expressing few proteins and approximately 17 mature microRNAs (miRNAs). Despite their identification nearly
two decades ago, the roles of the KSHV miRNAs in PEL remain poorly understood, primarily due to challenges
in achieving lasting miRNA loss-of-function. The overarching goal of this proposal is to define the contributions
of KSHV miRNAs to PEL cell survival and proliferation, with extensions to miR-155-dependent DLBCL. We
have developed improved lentiviral miRNA inhibitors to achieve stable miRNA inhibition in cultured PEL cells.
Our preliminary data suggest that at least two KSHV miRNAs, including miR-K11, a KSHV mimic of miR-155,
are essential for PEL cell viability. We hypothesize that KSHV miRNAs, and miR-K11 in particular, promote
lymphoma cell survival by silencing toxic host target genes, and that miR-K11 engages the conserved miR-155
gene regulatory network (miR-155-GRN), which is critical in HIV-associated DLBCLs. To investigate these
hypotheses, we propose two Specific Aims. In Specific Aim 1, we will use updated lentiviral miRNA inhibitors to
determine the essentiality of all KSHV miRNAs in PEL and define their effects on the cellular and viral
transcriptomes, viral lytic reactivation, apoptosis, and cell cycle progression. In Specific Aim 2, we will
determine the essential roles of the miR-155-GRN in PEL and miR-155-dependent DLBCL, using genetic
screening approaches to identify the target genes whose silencing underlies miR-155-GRN dependency.
Collectively, this work will define the essential functions of KSHV miRNAs in PEL, identify the disease-relevant
targets of miR-K11 in PEL, and test whether conserved interactions mediate miR-155-GRN dependency
across HIV-associated lymphomas. These results will provide new mechanistic insights into KSHV biology and
miRNA-driven oncogenesis in PLWH, while informing strategies to disrupt viral and cellular miRNA networks as
potential therapeutic strategies.

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