Liu-Meng Yang

Gut-associated lymph nodes (GALNs) constitute an important anatomical reservoir during early and chronic human immunodeficiency virus (HIV)/simian immunodeficiency virus (SIV) infection, but the fate of this compartment during terminal AIDS remains unclear. This study investigated viral persistence and lymph node injury in a rhesus macaque with long-term SIVmac239 infection and end-stage AIDS, characterized by profound CD4+ T cell depletion (30 cells/μL) and persistent viremia (1192 copies/mL). At necropsy, GALNs, including mesenteric, paracolic, and ileocecal lymph nodes, and non-gut-associated lymph nodes (NGALNs), including hepatic hilar, common iliac, and inguinal lymph nodes, were collected for viral RNA/DNA quantification, histopathology, immunofluorescence, and transcriptomics. SIV DNA was markedly lower in GALNs than in NGALNs, whereas SIV RNA was detectable only in NGALNs. GALNs exhibited extensive fibrotic remodeling, paracortical collapse, severe CD4+ T cell loss across B cell and paracortical regions, and pronounced CD8+ T cell accumulation within B cell zones. Transcriptomic profiling further revealed an exhaustion signature in GALNs, with reduced DNA replication and repair, impaired cell-cycle activity, and suppressed RNA processing, accompanied by activation of innate immune programs and attenuation of adaptive immune responses. These findings indicate that, during terminal AIDS, GALNs no longer serve as the predominant viral reservoir but instead undergo preferential and severe structural and functional exhaustion. This case highlights marked anatomical heterogeneity in lymph node vulnerability during advanced disease and supports a model in which collapse of the gut-associated immune barrier contributes to disease progression toward terminal AIDS.

Gut‑associated lymph nodes (GALNs) constitute an important anatomical reservoir during early and chronic human immunodeficiency virus (HIV)/simian immunodeficiency virus (SIV) infection, but the fate of this compartment during terminal AIDS remains unclear. This study investigated viral persistence and lymph node injury in a rhesus macaque with long‑term SIVmac239 infection and end-stage AIDS, characterized by profound CD4+ T cell depletion (30 cells/μL) and persistent viremia (1 192 copies/mL). At necropsy, GALNs, including mesenteric, paracolic, and ileocecal lymph nodes, and non‑gut‑associated lymph nodes (NGALNs), including hepatic hilar, common iliac, and inguinal lymph nodes, were collected for viral RNA/DNA quantification, histopathology, immunofluorescence, and transcriptomics. SIV DNA was markedly lower in GALNs than in NGALNs, whereas SIV RNA was detectable only in NGALNs. GALNs exhibited extensive fibrotic remodeling, paracortical collapse, severe CD4+ T cell loss across B cell and paracortical regions, and pronounced CD8+ T cell accumulation within B cell zones. Transcriptomic profiling further revealed an exhaustion signature in GALNs, with reduced DNA replication and repair, impaired cell-cycle activity, and suppressed RNA processing, accompanied by activation of innate immune programs and attenuation of adaptive immune responses. These findings indicate that, during terminal AIDS, GALNs no longer serve as the predominant viral reservoir but instead undergo preferential and severe structural and functional exhaustion. This case highlights marked anatomical heterogeneity in lymph node vulnerability during advanced disease and supports a model in which collapse of the gut‑associated immune barrier contributes to disease progression toward terminal AIDS.

HIV-1 integrase strand transfer inhibitors (INSTIs) are pivotal to antiretroviral therapy. However, the emergence of drug-resistant mutations necessitates the development of new agents. Here, we present ACC017 as a novel INSTI candidate. ACC017 demonstrated potent activity against the laboratory-adapted HIV-1_IIIB strain (EC₅₀ = 0.59 nM; SI > 34,525) and maintained efficacy against a panel of drug-resistant strains (EC₅₀ range from 0.34 to 9.12 nM) and clinical isolated strains (EC₅₀ range from 0.11 to 1.78 nM). Mechanism of action studies confirmed its ability to inhibit the integrase enzyme (IC₅₀ = 9.19 nM) and effectively block viral genome integration. Notably, in vitro resistance selection primarily yielded D232N and R263K mutations, without the emergence of G140S/A/C/R or Q148H/R/K. This promising profile, combined with synergistic interactions with other antiretroviral drugs, positions ACC017 as a potential therapeutic option.

Bone marrow stromal cell antigen 2 (BST-2) is a restriction factor for human immunodeficiency virus type I (HIV-1) and plays an important role in regulating the release of viral particles. However, the antiviral efficacy of BST-2 is antagonized by the HIV-1-encoded accessory protein Vpu, which facilitates the degradation of BST-2 by recruiting E3 ubiquitin ligase β-TrCP. The involvement of deubiquitinases (DUBs) in counteracting BST-2 ubiquitination and influencing its stability during HIV-1 infection remains inadequately explored. In this study, we conducted a small interfering RNA (siRNA) screening of human DUBs and determined that OTUD1 interacts with BST-2, leading to a reduction in its K48- and K63-linked ubiquitination. This reduction increases BST-2 protein stability, and subsequently inhibits HIV-1 release. Our findings reveal a novel regulatory mechanism by which DUBs influence the stability of the HIV-1 restriction factor BST-2 to dampen viral release, providing a potential therapeutic target for HIV-1 antiviral intervention.

Latent reservoir persistence remains a major obstacle for curing human immunodeficiency virus type 1 (HIV-1) infection. Thus, strategies for the elimination of latent HIV-1 are urgently needed. As a bromodomain and extra-terminal (BET) inhibitor, BMS-986158 has been used in clinical trials for advanced solid tumors and hematological malignancies. Here, we found that BMS-986158 reactivated latent HIV-1 in three types of HIV-1 latency cells in vitro, and in combination antiretroviral therapy (cART)-treated patient-derived peripheral blood mononuclear cells ex vivo, without influencing global immune cell activation. BMS-986158 reactivated latent HIV-1 by increasing phosphorylation of CDK9 at Thr186 and promoting recruitment of CDK9 and RNA polymerase II to the HIV-1 long terminal repeat in J-Lat cells. Furthermore, BMS-986158 exerted strong synergism in reactivating latent HIV-1 when combined with prostratin and vorinostat and enhanced the antiviral activity of anti-HIV-1 drugs. Finally, BMS-986158 showed antiviral activity in an HIV-1 acute infection model, possibly by arresting the cell cycle in infected cells. Thus, these results suggest that BMS-986158 is a potential candidate for AIDS/HIV-1 therapy.

APOBEC3G is a member of the human cytidine deaminase family that restricts Vif-deficient viruses by being packaged with progeny virions and inducing the G to A mutation during the synthesis of HIV-1 viral DNA when the progeny virus infects new cells. HIV-1 Vif protein resists the activity of A3G by mediating A3G degradation. Phorbol esters are plant-derived organic compounds belonging to the tigliane family of diterpenes and could activate the PKC pathway. In this study, we identified an inhibitor 12-O-tricosanoylphorbol-20-acetate (hop-8), a novel ester of phorbol which was isolated from Ostodes katharinae of the family Euphorbiaceae, that inhibited the replication of wild-type HIV-1 and HIV-2 strains and drug-resistant strains broadly both in C8166 cells and PBMCs with low cytotoxicity and the EC₅₀ values ranged from 0.106 μM to 7.987 μM. One of the main mechanisms of hop-8 is to stimulate A3G expressing in HIV-1 producing cells and upregulate the A3G level in progeny virions, which results in reducing the infectivity of the progeny virus. This novel mechanism of hop-8 inhibition of HIV replication might represents a promising approach for developing new therapeutics for HIV infection.

The search for new molecular constructs that resemble the critical two-metal binding pharmacophore and the halo-substituted phenyl functionality required for HIV-1 integrase (IN) inhibition represents a vibrant area of research within drug discovery. As reported herein, we have modified our recently disclosed 1-[2-(4-fluorophenyl)ethyl]-pyrrole-2,5-dione scaffolds to design 35 novel compounds with improved biological activities against HIV-1. These new compounds show single-digit micromolar antiviral potencies against HIV-1 and low toxicity. Among of them, compound 9g and 15i had potent anti-HIV-1 activities (EC₅₀ < 5 μM) and excellent therapeutic index (TI, CC₅₀/EC₅₀ > 100). These two compounds have potential as lead compounds for further optimization into clinical anti-HIV-1 agents.

Three new unusual 23-spirocholestane derivatives, ypsilanogenin (1), ypsilanogenin 3-O-β-D-glucopyranoside (2), and 4′-acetylypsilanogenin 3-O-β-D-glucopyranoside (3), were isolated from the whole plants of Ypsilandra thibetica. The structures of compounds 1–3 were deduced by spectroscopic and chemical methods, and the structure of 1 was further confirmed by a single-crystal diffraction analysis. All isolates were evaluated for their inhibitory activities against HIV-1.