Brain microglia (MG) may serve as a human immunodeficiency virus 1 (HIV) reservoir and ignite rebound viremia following cessation of antiretroviral therapy (ART), but they have yet to be proven to harbor replication-competent HIV. Here, we isolated brain myeloid cells (BrMCs) from nonhuman primates and rapid autopsy of people with HIV (PWH) on ART and sought evidence of persistent viral infection. BrMCs predominantly displayed microglial markers, in which up to 99.9% of the BrMCs were TMEM119⁺ MG. Total and integrated SIV or HIV DNA was detectable in the MG, with low levels of cell-associated viral RNA. Provirus in MG was highly sensitive to epigenetic inhibition. Outgrowth virus from parietal cortex MG in an individual with HIV productively infected both MG and PBMCs. This inducible, replication-competent virus and virus from basal ganglia proviral DNA were closely related but highly divergent from variants in peripheral compartments. Phenotyping studies characterized brain-derived virus as macrophage tropic based on the ability of the virus to infect cells expressing low levels of CD4. The lack of genetic diversity in virus from the brain suggests that this macrophage-tropic lineage quickly colonized brain regions. These data demonstrate that MG harbor replication-competent HIV and serve as a persistent reservoir in the brain.

Pathological obesity can result from genetic predisposition, obesogenic diet, and circadian rhythm disruption. Obesity compromises function of muscle, which accounts for a majority of body mass. Behavioral intervention that can counteract obesity arising from genetic, diet or circadian disruption and can improve muscle function holds untapped potential to combat the obesity epidemic. Here we show thatDrosophila melanogaster(fruit fly) subject to obesogenic challenges exhibits metabolic disease phenotypes in skeletal muscle; sarcomere disorganization, mitochondrial deformation, upregulation of Phospho-AKT level, aberrant intramuscular lipid infiltration, and insulin resistance. Imposing time-restricted feeding (TRF) paradigm in which flies were fed for 12 h during the day counteracts obesity-induced dysmetabolism and improves muscle performance by suppressing intramuscular fat deposits, Phospho-AKT level, mitochondrial aberrations, and markers of insulin resistance. Importantly, TRF was effective even in an irregular lighting schedule mimicking shiftwork. Hence, TRF is an effective dietary intervention for combating metabolic dysfunction arising from multiple causes.

This study reports on the synthesis and biological evaluation of Re(i) picolinic acid complexes as inhibitors of the SARS-CoV-2 main protease.

One inhibitor of the main SARS-CoV-2 protease has been approved recently by the FDA, yet it targets only SARS-CoV-2 main protease (Mpro). Here, we discovered inhibitors containing thiuram disulfide or dithiobis-(thioformate) tested against three key proteases involved in SARS-CoV-2 replication, including Mpro, SARS-CoV-2 papain-like protease (PLpro), and human cathepsin L. The use of thiuram disulfide and dithiobis-(thioformate) covalent inhibitor warheads was inspired by an idea to find a better alternative than disulfiram, an approved treatment for chronic alcoholism that is currently in phase 2 clinical trials against SARS-CoV-2. Our goal was to find more potent inhibitors that target both viral proteases and one essential human protease to reduce the dosage, improve the efficacy, and minimize the adverse effects associated with these agents. We found that compounds coded as RI175, RI173, and RI172 were the most potent inhibitors in an enzymatic assay against SARS-CoV-2 Mpro, SARS-CoV-2 PLpro, and human cathepsin L, with IC₅₀s of 300, 200, and 200 nM, which is about 5-, 19-, and 11-fold more potent than disulfiram, respectively. In addition, RI173 was tested against SARS-CoV-2 in a cell-based and toxicity assay and was shown to have a greater antiviral effect than disulfiram. The identified compounds demonstrated the promising potential of thiuram disulfide or dithiobis-(thioformate) as a reactive functional group in small molecules that could be further developed for treatment of the COVID-19 virus or related variants.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Background: Antiretroviral therapy (ART) suppresses HIV replication and partially restores immune function, but immunologic abnormalities often persist. Methods: We performed longitudinal multiparametric flow cytometry on peripheral blood mononuclear cells from 79 people with HIV-1 (51 women, 28 men) who were virologically suppressed and followed over a median 6 years of ART. We assessed T-cell counts and expression of activation (CD38⁺HLA-DR⁺), cycling (Ki67⁺), exhaustion (TIGIT⁺PD-1⁺), cytotoxicity (CD107a⁺), and regulatory (FoxP3⁺CD25⁺) markers across memory subsets, and we examined associations with sex and HIV reservoir size and activity. Results: CD4⁺ T-cell counts increased and CD8⁺ T-cell counts declined over time, improving CD4/CD8 ratios. Immune activation and cycling markers decreased in both T-cell compartments. TIGIT/PD-1 expression declined significantly in CD4⁺ memory subsets but not in CD8⁺ T cells, while CD107a expression remained elevated in effector memory CD8⁺ and CD4⁺ T cells. Regulatory CD4⁺ T cells declined over time, and no significant associations were observed between T-cell phenotypes and HIV reservoir measures or between sexes. Conclusions: Long-term ART promotes partial immune normalization, including reduced activation and reversal of CD4⁺ T-cell exhaustion. However, persistent expression of CD8⁺ T-cell surrogate markers of exhaustion and stable cytotoxic profiles suggest ongoing antigenic stimulation, potentially driven by HIV or chronic coinfections.