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Blocking Host Factors IAP and DDX3 Reverse HIV-1 Latency and Restore Apoptosis Vulnerability of the HIV-1 reservoir

ABSTRACT: Antiretroviral therapy (ART) effectively suppresses HIV-1 replication but does not purge the latent HIV-1 reservoir. Strategies aimed at HIV-1 latency reversal and subsquent elimination of infected cells are being explored. Targeting the inhibitor of apoptosis proteins (IAP) and DEAD-box polypeptide 3 (DDX3) RNA helicase reduce the HIV-1 reservoir ex vivo. However, mechanisms driving elimination of HIV-1 infected cells remain unclear. Here we uncovered the mechanism regarding latency reversal and induction of cell death specific for HIV-1 infected cells. Inhibition of IAP by second mitochondrial-derived activator of caspases mimetic (SMACm; AZD5582) resulted in activation of non-canonical NF-κB that induced HIV-1 transcription also in combination with a DDX3 inhibitor (DDX3i; FH1321). Transcriptome analysis revealed that HIV-1 actively suppressed apoptosis-related genes. SMACm treatment resulted in a broad induction of these genes irrespective of infection. Notably, DDX3 inhibition specifically restored the expression of the majority of HIV-1 suppressed genes, and when combined with SMACm restored almost all HIV-1 downregulated genes, thereby rendering HIV-1 infected cells vulnerable to apoptosis. Thus, our data strongly suggest that inhibition of host factors IAP and DDX3 not only induces latency reversal but also restores HIV-1 induced suppression of apoptotic processes in infected cells leading to reservoir elimination.

ORGANISM(S): Homo sapiens

PROVIDER: GSE303821 | GEO | 2026/02/01

REPOSITORIES: GEO

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Project description:Background: The cellular reservoir of latent HIV infection remains the main barrier to cure this virus. Elimination of this reservoir would be possible, if molecular identity of latently infected cells were fully elucidated. Biomarkers proposed previously were able to capture only a relatively small fraction of all reservoir cells. In the present study, we set out to conduct comprehensive molecular profiling, at the protein and RNA levels, of CD4+ T cells latently infected with HIV in vitro, using liquid chromatography-mass spectrometry (LC-MS) and RNA sequencing (RNA-Seq), respectively. Protein-based methods such as quantitative proteomic profiling using LC-MS may be more beneficial due to direct transferability of results to antibody-based approaches to capture latently infected cells. Integrated analysis of proteomic and transcriptomic data adds a level of validation and increases confidence in identified biomarkers. Flow cytometry and integrated HIV DNA assay were further used to enrich for latently infected cells with antibodies against selected biomarker proteins. Results: Using quantitative proteomics, we identified a total of 10,886 proteins (peptide level FDR < 0.05), of which 673 were up- and 780 down-regulated in latently infected compared to mock-infected cells in vitro (p < 0.05). Among these proteins, 21 were dysregulated at the RNA level in the same direction. Pathway analysis identified p53, mTOR, Wnt and NOTCH signaling, demonstrating that our in vitro model reflects known mechanisms of latency establishment and maintenance. Comparison of identified proteins with other proteomics studies revealed that identified molecular signatures of latency depend on technology and cell types used; however, a subset of proteins were identified both in the present, and at least one other study. Antibodies against selected protein markers, CEACAM1 and PLXNB2, could enrich for latently infected cells from mixed cell population 3-10 fold (5.8 fold average, p < 0.001). Conclusion: Two new molecules, CEACAM1 and PLXNB2, were identified as biomarkers for HIV latency. However, the level of enrichment for latently infected cells compared to biomarkers proposed previously was not improved. These results are consistent with the idea that each proposed biomarker defines only a subset of latently infected cells, and that a combined biomarker will be required to capture or target the latent HIV reservoir represented by different cell types.

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Blocking Host Factors IAP and DDX3 Reverse HIV-1 Latency and Restore Apoptosis Vulnerability of the HIV-1 reservoir

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