NIH grant: Deciphering the role of HLA-F and KIR3DS1 on NK function and HIV pathogenesis (1R56AI203554-01)

retained text

NIH grant 1R56AI203554-01: Deciphering the role of HLA-F and KIR3DS1 on NK function and HIV pathogenesis
Institute: {'code': 'AI', 'abbreviation': 'NIAID', 'name': 'National Institute of Allergy and Infectious Diseases', 'admin_org_id': '12500003', 'admin_funding_url': ''}. PI: Alberto  Bosque. Award: $781999.
Start: 2026-08-07T00:00:00.
PROJECT SUMMARY
HIV infection is the second leading cause of viral infection-related mortality in the United States. Furthermore,
the inability of the immune system to clear the virus renders this chronic infection a major driver of inflammation-
associated co-morbidities, including cardiovascular disease and neurological disorders. This emphasizes the
need to understand mechanisms that contribute to immune-mediated control of infection and how these could
be exploited to develop cure strategies. Natural Killer (NK) cells help control infection by killing infected cells;
their function is tightly regulated by a balance of activating and inhibitory receptors present on both the NK cell
and the target cell. NK cell killer-cell immunoglobulin-like receptors (KIRs) interact with different members of
MHC-I proteins and regulate the activation or inhibition of NK cytotoxic activity. Population studies have identified
combinations of KIR and MHC-I alleles associated with slower HIV disease progression. Among them, KIR3DS1
(whose sequence is relatively conserved compared to other KIRs) was the first to be associated with delayed
disease progression. KIR3DS1 interacts with the nonclassical MHC-I molecule, HLA-F, which is also relatively
conserved compared to classical MHC-I molecules that bind to KIR2 and KIR3 proteins. This interaction triggers
NK cytotoxicity towards HIV-infected cells. Our recently published work suggests that this KIR3DS1/HLA-F
interaction can be augmented by IL-15 and retinoids. While these are clinically approved for cancer therapy and
are safe in ART-suppressed people with HIV, the mechanisms that contribute to this augmentation, with the
potential for further manipulation are unknown. The overall goal of this proposal is to decipher the mechanisms
that regulate the HLA-F/KIR3DS1 interaction in the context of infection, cytokines, and retinoids. Our central
hypothesis is that the pathways that regulate the KIR3DS1/HLA-F interaction can be exploited to enhance NK
cell-mediated control of infection in vitro and in vivo. In Aim 1, we will evaluate the contribution of human genetic
polymorphisms, viral subtype, and HIV accessory genes on HLA-F expression. In addition, we will assess the
effects of various cytokines and new retinoids on HLA-F expression. In Aim 2, we will evaluate the interplay of
KIR3DS1 and HLA-F in controlling HIV infection in vitro. This will include assessing the effects of the cytokines
and retinoids described in Aim 1 on NK cell phenotype and function. In addition, a custom CITE-Seq panel and
single cell metabolomic profiling will be used for a comprehensive analysis of KIR3DS1-expressing vs non-
expressing NK cells to determine whether pathway differences between these populations could be exploited to
expand or enhance the function of KIR3DS1+ NK cells. In Aim 3, using samples from two clinical trials, we will
assess the in vivo effects of the IL-15 superagonist, N-803 (ACTG A5386), and the retinoid, isotretinoin (ACTG
A5323), on CD4+ T cell HLA-F expression, NK cell phenotype/metabolomic, and whether these associate with
reservoir dynamics. Together, our studies will yield insights into the pathways that modulate the KIR3DS1/HLA-
F interaction that could help develop cure strategies with FDA-approved biologics and small molecule inhibitors.

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