Tyrosine kinase inhibitors (TKIs) have been extensively used as a treatment for chronic myeloid leukemia (CML). Dasatinib is a broad-spectrum TKI with off-target effects that give it an immunomodulatory capacity resulting in increased innate immune responses against cancerous cells and viral infected cells. Several studies reported that dasatinib expanded memory-like natural killer (NK) cells and γδ T cells that have been related with increased control of CML after treatment withdrawal. In the HIV infection setting, these innate cells are associated with virus control and protection, suggesting that dasatinib could have a potential role in improving both the CML and HIV outcomes. Moreover, dasatinib could also directly induce apoptosis of senescence cells, being a new potential senolytic drug. Here, we review in depth the current knowledge of virological and immunogenetic factors associated with the development of powerful cytotoxic responses associated with this drug. Besides, we will discuss the potential therapeutic role against CML, HIV infection and aging.

The dynamics of the HIV reservoir during antiretroviral therapy (ART) exhibit variability, with a pronounced decline during the initial years of treatment. However, the identification of biomarkers and host factors associated with the decay of the different forms of HIV proviruses remains to be fully elucidated. We conducted a longitudinal study on people with HIV provided by the Spanish National HIV cohort. We assessed the HIV-DNA levels by Intact Proviral DNA Assay, and inflammatory markers using the Proximity Extension Assay, before and after ART initiation. A multivariate linear regression model was employed to identify potential predictive markers. Our results highlight the identification of novel inflammatory markers, such as ADA, DNER, CDCP1, SCF, among others, that varied significantly over ART initiation. In addition, we observed several markers associated with intact HIV-DNA before ART initiation (CD8A, CX3CL1, and ST1A1) or during undetectable viral load post-ART (IL-10). Moreover, up to five markers were able to predict the intact HIV reservoir decay over ART. The strongest predictor was Stem Cell Factor (SCF), where higher baseline levels of this marker were associated with a greater decline in the intact HIV reservoir. In conclusion, we have identified inflammatory markers associated with the size and dynamics of the HIV-DNA reservoir. These findings provide new insights that could contribute to the development of multi-targeted intervention strategies aimed at modulating or monitoring the HIV reservoir size.

People with HIV (PWH) experience chronic inflammation and more age-related comorbidities despite antiretroviral therapy (ART). Classical senescence biomarkers (e.g., SA-βGal, p16^INK4a, γH2AX and Bcl-2) and senescence-associated secretory phenotype (SASP) factors such as IL-6 reflect cellular senescence. This study assesses those markers in a male cohort of PWH across infection stages, pre/post-ART. We analyzed blood samples from 39 PWH at primary, chronic and advanced HIV infection, before and after one year on ART, and 13 age- and sex-matched HIV-negative controls. Classical cellular senescence biomarkers in T-cells and monocytes, along with plasma SASP factors and immune checkpoints, were assessed via flow cytometry and Luminex. PWH exhibited elevated cellular senescence, SASP and immune checkpoint markers (such as SA-βGal, p16^INK4a, γH2AX, Bcl-2, CD87, IL-6, IL-10, TNF-RI/RII, CD30, IL-8, RANTES, CXCL1, PD-1, PD-L1, PD-L2, LAG-3, CTLA-4 and TIM-3) particularly in chronic and advanced stages, which generally persisted after ART, but not in PWH treated in primary HIV infection. Senescence biomarkers in T-cells and SASP components in plasma positively correlated with immunosenescence, T-cell activation, HIV p24 expression and negatively correlated with CD4 count and CD4/CD8 ratio. HIV infection promotes persistent cellular senescence despite ART in advanced and chronic infection. Thus, future senolytic or senomorphic strategies against cellular senescence may reduce chronic inflammation and aging-related complications in PWH.

Background: Fingolimod, a treatment for multiple sclerosis (MS), decreases autoreactive lymphocytes by lymph node sequestration. In vitro , fingolimod decreases HIV-1 infection and viral reservoir (VR) through SAMHD1 phosphorylation inhibition and reducing lymphocyte activation and CD4 expression. We identified an exceptional MS patient infected with HIV-1 (HIV+ MS+) while on fingolimod therapy and we have analyzed its impact on HIV-1 infection in vivo and ex vivo . Methods: The case was the HIV+ MS+ patient. Controls were 20 PWH (HIV+ MS-), five HIV-negative donors (HIV-MS) and three HIV-negative MS patients treated with fingolimod (HIV-MS+), as the case reported. VR was quantified by IPDA and HIV-1 intracellular RNAs (icRNAs) by ddPCR in peripheral blood CD4 ⁺ T-cells. CD4 ⁺ T-cells were infected in vitro with an NL4.3-Renilla strain. Immunophenotype, activation markers and phosphorylated SAMHD1 levels were determined by flow cytometry. Findings: At diagnosis, HIV+ MS+ viral load was nine-fold lower than HIV+ MS- treated at similar Fiebig stage. One year after ART, HIV+ MS+ showed lower intact and defective VR than the HIV+ MS- control group (28-and six-fold decrease respectively). After three years on ART no intact proviruses were detected in HIV+ MS+ . HIV-1 in vitro infection was decreased in HIV+ MS+ and HIV- MS + vs HIV+ MS- and HIV-MS-. CD4 ⁺ T-cells levels from fingolimod treated patients were lower and showed decreased CD4 expression, lymphocyte activation and SAMHD1 phosphorylation vs HIV- MS-. icRNAs were significantly increased after T-cell activation in the HIV+ MS-, while they were barely detected at resting and activated HIV+ MS+ CD4 ⁺ T-cells. Conclusions: We describe a strong restriction to HIV-1 infection and replication in vivo and ex vivo leading to indetectable intact VR in HIV+ MS+ after three years of ART. Potential mechanisms of restriction are CD4 downregulation, T-cell activation inhibition, and SAMHD1 activity enhancement.

People with HIV (PWH) may exhibit altered immune responses to SARS-CoV-2 vaccination due to persistent immune dysregulation despite antiretroviral therapy. We evaluated humoral immunogenicity following mRNA SARS-CoV-2 vaccination in PWH according to CD4 T-cell count and compared responses with HIV-negative controls. The study included 57 PWH stratified by CD4 count (<200 and ≥200 cells/µL), alongside 12 HIV-negative controls. Neutralizing antibody titers (NT50) against SARS-CoV-2 pseudoviruses expressing the D614G and Omicron BA.5 spike variants were measured using a luciferase-based neutralization assay one month (M1) and six months (M6) after primary vaccination with BNT162b2 or mRNA-1273. PWH with CD4 counts ≥ 200 cells/µL demonstrated higher neutralizing titers against D614G at M1 and M6, with significant differences observed between CD4 groups (M1: p = 0.03; M6: p = 0.02). Neutralization of BA.5 was lower overall; while no overall group differences were observed at M1, higher titers were detected among individuals with CD4 ≥ 200 cells/µL at six months (p = 0.04). Neutralizing titers correlated positively with CD4 counts among PWH. Responses were broadly comparable between PWH and HIV-negative controls and did not differ substantially by vaccine type. These findings indicate that immune status, reflected by CD4 T-cell count, is a key determinant of SARS-CoV-2 vaccine-induced humoral responses in PWH and support prioritizing vaccination strategies for individuals with advanced immunosuppression.