Table 2.

Other host factors inhibitors (part 1) and (part 2).

OTHERS HOST INHIBITORS		MECHANISM OF ACTION	PMID
P300	LTK14	➢Derivative of the natural product garcinol. ➢Selective inhibitor of histone acetyltransferase p300 (5-7µM). ➢Inhibit acute infection in a CD4+ T cell line at high µM concentrations, without toxicity (>50 µM). ➢No evidence in latency models.	17584612, 30351168
NFAT	Cyclosporin A (CSA)	➢Inhibits NFAT-mediated HIV-1 transcription in primary CD4+ T cells. ➢Prevents the dephosphorylation of NFAT, which is essential for NFAT’s nuclear translocation and activation, resulting in disruption of T cell activation. ➢Suppresses proliferation of cytotoxic T cells and inhibits the production of T cell-derived mediators such as interleukin-2 (IL-2). ➢Used in conjunction with ART as an immune-modulatory agent in clinical trials, with low toxicity. ➢Inhibits Ca2+/calmodulin-dependent protein phosphatase (IC50 of 65 nM), cholecystokinin-(100 pM), or carbamylcholine- (10 µM), induced amylase release. ➢Nephrotoxic effects.	10692237, 30351168, 7515049, 7542793
	Fujimycine FK506	➢Calcium dependent protein phosphatase calcineurin, responsible for the dephosphorylation of NFAT. ➢Inhibits antigen and mitogen triggered T cell activation. ➢Up to 100-fold more potent than CSA in various models. ➢Partially inhibits the Ca2+/calmodulin-dependent protein phosphatase activity but did not significantly inhibit amylase secretion at concentrations up to 1 µM. ➢Nephrotoxic effects.	7542793, 1381509, 30351168
NF-kB	ACHP	➢Inhibits IκB kinase β (IKKβ, IC50 = 8.5 nM ) and IKKα (IC50 = 250 nM). ➢Reduces the constitutive phosphorylation of IκBα and NF-κB p65 in myeloma cells at 50 µM. ➢Prevents HIV-1 reactivation induced by TNF-α in HIV latently infected cells (IC50 = 0.56 µM).	15225717, 16436709, 12617920,
	Noraris-teromycin	➢Inhibits IKKα and weakly IKKβ phosphorylation and degradation upon cellular reactivation with TNF-α treatment. ➢Prevents p65 phosphorylation. ➢Suppresses HIV-1 viral replication upon cellular reactivation with TNF-α treatment of HIV cell models of latency (OM10.1 and Molt4/IIIB, IC50~100 nM, CC50 > 10 µM).	18713798
mTOR	PP242 Torkinib	➢Competes with ATP for its binding site and inhibits both mTORC1 and mTORC2 with an IC50 of 8 nM in in vitro assays; with >10- and 100-fold selectivity for mTOR than PI3Kδ or PI3Kα/β/γ, respectively. ➢Suppresses HIV reactivation of latent HIV upon T-cell stimulants both in the Bcl-2 HIV latency primary cell model and in CD4+ T cells from HIV suppressed individuals under ART, without affecting cellular viability. ➢Abrogated Tat-independent and -dependent transactivation of the HIV promoter; and at doses (200 nM–1000 nM) reduces CDK9 phosphorylation in CD3/CD28-stimulated CD4+ T cells from uninfected donors.	27978436, 19209957, 18849971, 30351168
	Torin	➢Competes with ATP and inhibits both mTORC1 and mTORC2, with IC50 values between 2 and 10 nM. Exhibits 1000-fold selectivity for mTOR over PI3K (IC50: 1800 nM) and 100-fold binding selectivity relative to 450 other kinases. ➢Suppresses HIV reactivation of latent HIV upon T-cell stimulants both in the Bcl-2 HIV latency primary cell model and in CD4+ T cells from HIV suppressed individuals under ART, without affecting cellular viability. ➢Abrogated Tat-independent and -dependent transactivation of the HIV promoter.	27978436, 20860370, 21651476, 22125084, 30351168
	Rapamycin AY-22989, Rapamune, Sirolimus, NSC-2260804	➢Forms a complex with FKBP12 and binds to mTORC1 causing its inhibition. mTORC2 is insensitive to Rapamycin. ➢Suppresses HIV reactivation upon T-cell stimulants in the Bcl-2 HIV latency primary cell model, but with less potency than Torin and PP242, and a a slight decrease of viability. ➢Abrogated Tat-independent transactivation of the HIV promoter in a dose-dependent manner.	27978436, 17350953
TFIIH	Spironolactone (SP) SC9420	➢Aldosterone antagonist approved for clinical use, degrades the XPB cellular helicase, a TFIIH component. ➢Inhibits HIV-1 and HIV-2 infection of permissive T cells. ➢Blocks Tat-dependent transactivation of the HIV promoter. ➢Inhibits HIV-1 replication and reactivation in HIV latent cell models, primary CD4+ T cells, and HIV suppressed individuals under ART, with variable toxicity levels. ➢Reduces RNAPII recruitment to the HIV-1 genome. ➢Long-term treatment with SP does not result in epigenetic suppression of HIV since HIV rebounds upon SP treatment interruption. ➢Long-term treatment with SP does not lead to significant global dysregulation of cellular transcripts.	28842263, 30351168, 27681137, 33239456, 32573496
PI3K/Akt pathway	BPRHIV001	➢Represses the phosphorylation of PDPK1, resulting in the repression of the phosphorylation of Akt. Akt is then not able to protect p300 from degradation. P300 known to modulate Tat function through acetylation, its decrease results in subsequent inhibition of HIV-1 Tat-Mediated Transcription (IC50: 1.3 nM in HeK293T cells). ➢No evidence in latency models or in vivo.	21697490
FACT	Curaxin CBL0100	➢Inhibits acute HIV-1 replication in a CD4+ T cell line (IC50 = 0.055 μM, CC50 > 0.2 µM) and PBMCs. ➢Reduces HIV-1 reactivation in latency cell lines and primary CD4+ T cell model of HIV-1 latency. ➢Suppresses HIV-1 transcriptional elongation by reducing the HIV promoter occupancy of RNAP II and FACT. ➢Proposed mechanism: HIV-1 Tat associates with FACT recruits it in the proximity to nuc-1. FACT facilitates the disassembly/reassembly of the nuc-1 to allow the RNAP II transcriptional elongation. CBL0100 intercalates into chromatins and blocks the FACT accessibility/association with nuc-1, preventing the subsequent steps.	29089933, 30351168
BRD4	ZL0580	➢Structurally close analog to ZL0590. Suppresses HIV by selectively binding to BD1 domain of BRD4. Mechanistically different from the BET/BRD4 pan-inhibitor JQ1, which non selectively binds to BD1 and BD2 domains of all BET proteins. ➢Suppresses acute and latent HIV replication and reactivation at micromolar range in in vitro and ex vivo HIV cell models. ➢Inhibits transcription elongation and induces a repressive chromatin environment at the HIV promoter. ➢PBMCs of aviremic HIV-infected individuals treated both with ART and ZL0580 accelerated HIV suppression during ART and delayed viral rebound after ART cessation.	31329163, 31936859, 31733396
JAK/STAT	Ruxolitinib INCB018424	➢FDA approved for rheumatoid arthritis and a potent and selective ATP-competitive inhibitor of JAK 1, 2, and 3 with an IC50 value of 2.7, 4.5, and 322 nM, respectively. ➢Sub micromolar inhibition of HIV-1, HIV-2, and SIV, RT-SHIV, across primary human or rhesus macaque lymphocytes and macrophages, with no significant cytotoxicity at 2 to 3 logs above their effective antiviral concentration. ➢Inhibits reactivation of latent HIV at low-micromolar concentrations across the J-Lat T cell latency models and in primary human central memory lymphocytes, with variable toxicity levels. ➢Decreases the frequency of cells harboring HIV integrated DNA in cultures of T cells activated by TCR in the presence or absence of ART with doses of Ruxolitinib as low as 0.01 μM. ➢Significantly blocks IL-2, IL-7, and IL-15 induced HIV reactivation upon γ-C cytokines stimulation in in vitro and ex vivo CD4 T cell cultures. ➢Clinical trial phase 2 using 10 mg of Ruxolitinib twice daily in combination with ART for 5 weeks vs ART alone, in, aviremic HIV-infected individuals showed well-tolerated treatment, no significant reduction of IL-6 and decrease of markers of immune activation known to be associated with poor HIV outcomes.	33693561, 24419350, 29267399, 22422826, 31936859, 32573496
	Tofacitinib CP-690550, Tasocitinib, Xeljanz	➢FDA approved drug for myelofibrosis and JAK3 and 1 inhibitor. ➢Potent inhibitor of inflammatory cytokines with resultant immunosuppressive and anti-inflammatory activity. ➢Very similar activities to Ruxolitinib: with 1) submicromolar inhibition of infection with HIV-1, HIV-2, and SIV, RT-SHIV, across primary human or rhesus macaque lymphocytes and macrophages, with no significant cytotoxicity at 2 to 3 logs above their effective antiviral concentration; 2) inhibited reactivation of latent HIV-1 at low-micromolar concentrations across the J-Lat T cell latency models and in primary human central memory lymphocytes, with variable toxicity levels; 3) decreases the frequency of cells harboring HIV integrated DNA in cultures of T cells activated by TCR in the presence or absence of ART; 4) significantly blocks IL-2, IL-7, and IL-15 induced HIV reactivation upon γ-C cytokines stimulation in in vitro and ex vivo CD4+ T cell cultures.	24419350, 29267399, 31936859
	Filgotinib GLPG0634	➢Selective JAK inhibitor with IC50 of 10 nM, 28 nM, 810 nM, and 116 nM for JAK1, JAK2, JAK3, and TYK2. ➢Suppresses HIV replication in CD4+ T cells from aviremic HIV-infected individuals and cell lines at µM range. ➢Suppresses HIV-1 splicing mRNA while Ruxolitinib reduces unspliced mRNAs. ➢Reduces T cell activation from virally suppressed ART treated individuals. ➢Suppresses HIV driven aberrant cancer-related gene expression at the integration site in cell line. ➢Significantly reduces the frequency of cells harboring inducible HIV in a T cell line. ➢Transcriptome analysis revealed that Filgotinib suppresses T cell activation via the JAK/STAT signaling pathway, alters RNA processing and chromatin organization.	32573496
PP1	1H4	➢Targets the “RVxF”-binding cavity of PP1 to disrupt the interaction of PP1 with Tat and inhibit HIV replication. ➢Inhibits HIV transcription and replication with IC50 10 µM, CC50 > 25 µM in a T cell line. ➢Prevents the translocation of PP1 to the nucleus.	22768081
	1E7-03 Compound 7C	➢Acts like 1H4 but with an IC50 5-fold lower than 1H4, with no toxicity and a plasma half-life greater than 8 h in mice. ➢Enhances trans-endothelial migration of HIV-Tg macrophages in vitro, decreased lung neutrophil infiltration in vivo, and increases lung macrophage levels in HIV-Tg mice. Moreover, it reduces levels of inflammatory IL-6 cytokine, improves bleeding score and decreases lung injury.	25073485