Biology subjects

Daniali, M.

Publications and source records attributed to Daniali, M..

4 recordsLinked to original sources

bioRxiv2025

Antiviral and Anti-inflammatory Effects of Cannabidiol in HIV/SIV Infection

Persistent reservoirs and chronic immune activation are hallmarks of HIV, despite the effectiveness of antiretroviral therapy (ART) in suppressing viral replication. Here, we use rhesus macaques and primary and induced pluripotent stem cell (iPSC)-derived human immune cells to evaluate the virologic and immunologic consequences of cannabidiol (CBD) exposure during HIV/SIV infection. We show that CBD, in the absence of ART, suppresses viral replication and establishment of the viral reservoir to levels comparable with first-line therapies during acute SIV infection of rhesus macaques. This antiviral effect of CBD extended to in vitro HIV infection of human macrophages, T cells, and microglia. Immunologically, we observe CBD slowed CD4+ T cell decline and polarization, decreased CD14+CD16+ monocyte expansion, and reduced interferon-inducible cytokine release in rhesus macaques. We identify comparable effects on cytokine production with in vitro CBD treatment of human macrophages, T cells, and microglia. Importantly, we find CBD inhibits cytokines only when an immune response is elicited by HIV, suggesting it is not broadly immunosuppressive. Finally, we determine CBD regulates endocannabinoid receptors, modulators, and transporters and inhibits NF-{kappa}b and STAT1 activation when mediating its antiviral and anti-inflammatory effects. These findings show beneficial effects of CBD in laboratory models of untreated HIV, thus placebo-controlled clinical trials to evaluate the safety and effectiveness of adjunctive CBD use with ART is warranted.

microbiology↗

bioRxiv2025

Cocaine Acts Through Sigma-1 to Enhance HIV Infection of Microglia

Cocaine use disorder is highly comorbid in people with HIV and can accelerate infection, alter neuropathology, and exacerbate cognitive decline despite antiretroviral therapy (ART). Many of these effects are due to infection and dysregulation of CNS myeloid cells, especially microglia, which comprise a significant reservoir in this compartment. However, the precise mechanism(s) by which cocaine (Coc) enhances HIV infection in microglia are unclear, partly due to the lack of translationally relevant human microglial models suitable for mechanistic evaluation of Coc-mediated changes in viral dynamics. Canonically, Coc acts by blocking dopamine transporter activity, however, Coc has additional mechanisms beyond dopaminergic tone, involving the endoplasmic reticulum (ER) protein sigma-1, which has diverse cellular functions, including modulation of stress pathways such as the unfolded protein response (UPR). Viruses, including HIV, can exploit the UPR to amplify stress-induced protein production in host cells, enhancing viral replication. Therefore, we hypothesized that Coc-mediated activation of sigma-1 increases HIV infection of microglia via activation of the UPR. Using human-induced pluripotent stem cell microglia (iPSC-Mg), we evaluated changes in the percentage of infected iMg as well as p24Gag secretion using high-content imaging and AlphaLISA. Coc increased both p24 secretion and the number of infected iMg. The enhanced p24 secretion persisted despite ART, without the corresponding increase in percent p24, suggesting Coc augments the post-entry steps of viral replication. Inhibition of dopamine receptors did not diminish the impact of Coc, but pharmacological inhibition and CRISPR KO of sigma-1 blocked the effect. Independently, sigma-1 agonists increased p24 secretion, suggesting that Coc acts through sigma-1 rather than dopaminergic pathways. Single-cell RNA sequencing revealed distinct transcriptomic alterations in HIV+Coc-treated iPSC-Mg. Further genetic and proteomic validation confirmed activation of the IRE1-XBP1 branch of the UPR in the HIV+Coc condition, with increased XBP1 signaling and downstream cytokine (IL-4 and IL-7) secretion. The HIV+Coc condition also showed reduced expression of antiviral response genes and enhanced HIV transcriptional regulation genes. Immunofluorescence staining showed increased sigma-1 in p24-cells and reduced sigma-1 in p24+ cells in HIV+Coc cultures and revealed that HIV+Coc promotes sigma-1 movement to the ER. These findings suggest that Coc exploits sigma-1 signaling to modulate the UPR, enhancing viral replication and immune evasion. Sigma-1 emerges as a critical link between HIV-induced cellular stress and cocaine exposure, highlighting a shared molecular pathway that can be leveraged for the treatment of comorbid HIV neuropathogenesis, substance use disorder, and related neuropsychiatric disorders.

immunology↗

bioRxiv2024

Dopamine-driven Increase in IL-1β in Myeloid Cells is Mediated by Differential Dopamine Receptor Expression and Exacerbated by HIV

The catecholamine neurotransmitter dopamine is classically known for regulation of central nervous system (CNS) functions such as reward, movement, and cognition. Increasing evidence also indicates that dopamine regulates critical functions in peripheral organs and is an important immunoregulatory factor. We have previously shown that dopamine increases NF-{kappa}B activity, inflammasome activation, and the production of inflammatory cytokines such as IL-1{beta} in human macrophages. As myeloid lineage cells are central to the initiation and resolution of acute inflammatory responses, dopamine-mediated dysregulation of these functions could both impair the innate immune response and exacerbate chronic inflammation. However, the exact pathways by which dopamine drives myeloid inflammation are not well defined, and studies in both rodent and human systems indicate that dopamine can impact the production of inflammatory mediators through both D1-like dopamine receptors (DRD1, DRD5) and D2-like dopamine receptors (DRD2, DRD3, and DRD4). Therefore, we hypothesized that dopamine-mediated production of IL-1{beta} in myeloid cells is regulated by the ratio of different dopamine receptors that are activated. Our data in primary human monocyte-derived macrophages (hMDM) indicate that DRD1 expression is necessary for dopamine-mediated increases in IL-1{beta}, and that changes in the expression of DRD2 and other dopamine receptors can alter the magnitude of the dopamine-mediated increase in IL-1{beta}. Mature hMDM have a high D1-like to D2-like receptor ratio, which is different relative to monocytes and peripheral blood mononuclear cells (PBMCs). We further confirm in human microglia cell lines that a high ratio of D1-like to D2-like receptors promotes dopamine-induced increases in IL-1{beta} gene and protein expression using pharmacological inhibition or overexpression of dopamine receptors. RNA-sequencing of dopamine-treated microglia shows that genes encoding functions in IL-1{beta} signaling pathways, microglia activation, and neurotransmission increased with dopamine treatment. Finally, using HIV as an example of a chronic inflammatory disease that is substantively worsened by comorbid substance use disorders (SUDs) that impact dopaminergic signaling, we show increased effects of dopamine on inflammasome activation and IL-1{beta} in the presence of HIV in both human macrophages and microglia. These data suggest that use of addictive substances and dopamine-modulating therapeutics could dysregulate the innate inflammatory response and exacerbate chronic neuroimmunological conditions like HIV. Thus, a detailed understanding of dopamine-mediated changes in inflammation, in particular pathways regulating IL-1{beta}, will be critical to effectively tailor medication regimens.

neuroscience↗

bioRxiv2022

Enriching Representation Learning Using 53 Million Patient Notes through Human Phenotype Ontology Embedding

The Human Phenotype Ontology (HPO) is a dictionary of more than 15,000 clinical phenotypic terms with defined semantic relationships, developed to standardize their representation for phenotypic analysis. Over the last decade, the HPO has been used to accelerate the implementation of precision medicine into clinical practice. In addition, recent research in representation learning, specifically in graph embedding, has led to notable progress in automated prediction via learned features. Here, we present a novel approach to phenotype representation by incorporating phenotypic frequencies based on 53 million full-text health care notes from more than 1.5 million individuals. We demonstrate the efficacy of our proposed phenotype embedding technique by comparing our work to existing phenotypic similarity-measuring methods. Using phenotype frequencies in our embedding technique, we are able to identify phenotypic similarities that surpass the current computational models. In addition, we show that our embedding technique aligns with domain experts judgment at a level that exceeds their agreement. We show that our proposed technique efficiently represents complex and multidimensional phenotypes in HPO format, which can then be used as input for various downstream tasks that require deep phenotyping, including patient similarity analyses and disease trajectory prediction.

bioinformatics↗