Search Results (275)

Background/Objectives: People with HIV (PWH) often have a suboptimal response to vaccines, raising concerns regarding the efficacy of coronavirus disease 2019 (COVID-19) vaccines in this population. We aimed to evaluate the humoral immune response to the B.1 lineage and Omicron variant in PWH on antiretroviral therapy (ART) following COVID-19 vaccination. Methods: We conducted a prospective study of 19 PWH on ART who received a two-dose series of the COVID-19 mRNA vaccine and a booster six months later. Participants without HIV infection (n = 25) were included as a healthy control (HC) group. The humoral response to the COVID-19 vaccine (anti-SARS-CoV-2 S IgG levels and ability to block ACE2-S interaction) against both the original B.1 lineage and the Omicron variant was assessed using immunoassays. Results: The humoral response in PWH was very strong (geometric mean fold rise, GMFR > 8) after the second dose and strong (GMFR > 4) after the booster dose for both the B.1 lineage and the Omicron variant. We found comparable humoral responses to the B.1 lineage and Omicron variant between PWH and HC groups after the second and booster doses (q-value > 0.05). The COVID-19 vaccine generated a significantly weaker humoral response against the Omicron variant compared to the B.1 lineage in both groups (q-value < 0.05). However, this response improved after the booster dose, although it remained weaker in PWH. Conclusions: PWH showed a strong humoral response to the COVID-19 vaccine against B.1 and Omicron, though the Omicron response was weaker than B.1. Booster doses in PWH improved the Omicron response, but it stayed lower than B.1. Findings confirm vaccine effectiveness in PWH, stressing the critical role of boosters and potential need for updated vaccines for variants like Omicron. Full article

The emergence of HIV strains resistant to the current anti-retroviral drugs has necessitated the search for new anti-retroviral medications. Methanolic and aqueous T. ferdinandiana fruit extracts have potent inhibitory activity against several phases of the HIV-1 replicative cycle. Cell infectivity studies using a non-resistant HIV-1 pseudovirus demonstrated that the methanolic (IC₅₀ 16 µg/mL) and aqueous extracts (IC₅₀ 19 µg/mL) were potent inhibitors of viral infection in a non-replicating HIV-1 assay. Both extracts also inhibited HIV-1 reverse transcriptase (IC₅₀ values of 35 and 33 µg/mL for methanolic and aqueous extracts, respectively) and HIV-1 protease (IC₅₀ values of 19 and 27 µg/mL, respectively) in recombinant enzyme assays. Given their inhibitory activities against multiple phases of HIV-1 replication, T. ferdinandiana fruit extracts may be particularly useful as HIV-1 therapeutics. Furthermore, both extracts displayed good safety profiles and therapeutic indices, indicating their suitability for therapeutic usage. LC-MS metabolomic profiling analysis of the methanolic extract identified several interesting constituents, including a relative abundance of tannins, as well as several flavonoids and stilbenes. All of these compounds have previously been reported to have bioactivities consistent with the anti-HIV-1 activities reported herein. Based on these studies, methanolic and aqueous T. ferdinandiana fruit extracts are promising potential therapies for the prevention, treatment and management of HIV-1. Full article

Backgrounds: The rapid initiation of highly active anti-retroviral therapy (HAART) can control HIV-1 viremia and stabilize the long-term health of people living with HIV-1 (PLWH). Despite this, individuals who are diagnosed late and exhibit poor therapeutic efficacy still pose a great challenge to global HIV management. To address this, we conducted comprehensive multiparametric immune profiling and analyzed its association with disease progression and therapeutic efficacy. Methods: Multicolor flow cytometry was used to characterize the circulating immune cell composition and cellular phenotypes in 40 treatment-naive individuals (16 chronic, 24 newly diagnosed), 26 HAART-treated individuals, and 18 healthy controls. Comparative analyses of T cell subsets, immune activation markers, and viral load signatures were performed, followed by network construction. We carried out principal component analysis and displayed the data by dimensionality reduction. Results: Persistent immune activation, dysregulated regulatory immunity, and aberrant memory differentiation markers were identified in T cells of HIV-1-infected individuals and were associated with disease progression. Additionally, HAART-treated patients which did not fully restore CD4 T cells exhibited higher levels of activated markers, suggesting possible biomarkers of therapeutic efficacy. Conclusions: This study describes changes in immune cell profiles throughout HIV-1 disease progression and explores suitable laboratory predictors for future clinical and therapeutic settings by monitoring pathological immune cell events. Full article

The persistence of latent HIV-1 proviruses in CD4⁺ T cells is a major obstacle to curing HIV. The “shock and kill” strategy involves reversing latency with latency-reversing agents (LRAs) and selectively inducing cell death in infected cells. However, current LRAs have shown limited efficacy in eliminating the ex vivo HIV reservoir and thus failed in clinical study. In this study, we repurposed PZ703b, a pro-apoptotic protein degrader initially developed for anti-leukemia therapy, to target HIV eradication. PZ703b induced the degradation of Bcl-2 and Bcl-xL, activating the non-canonical NF-kB pathway and caspases cascade, resulting in latency reversal and the selective apoptosis of infected cells. The treatment of ex vivo CD4⁺ T cells from ART-suppressed HIV-1 patients led to approximately a 50% reduction in the replication-competent reservoir. While this result does not reach the threshold required for a complete cure, it demonstrates the potential of a dual degrader of Bcl-2/Bcl-xL in reversing HIV latency and inducing selective cell death. Our study provides a proof-of-concept for using dual degraders of Bcl-2/Bcl-xL as a novel category of LRAs in therapeutic strategies aimed at reducing HIV reservoirs. This approach may pave the way for the further exploration of targeted interventions to eliminate the HIV-inducible reservoir. Full article

Background/Objectives: Individuals with HIV on combined antiretroviral therapy (ART) with virologic suppression exhibit chronic immune activation and immune dysfunction. Numerous studies have shown that human milk oligosaccharide (HMO) controls the postnatal transmission of HIV-1, but its effect on adult HIV-1 infection is not known. The purpose of this study was to investigate the anti-HIV activity of Lacto-N-fucopentaose III (LNFPIII) in adult blood-borne macrophages. Methods: Primary human monocyte-derived macrophages from the blood of HIV-seronegative individuals were infected with HIV and treated with or without dextran-conjugated LNFPIII (P3DEX). HIV replication was measured by quantifying the accumulation of HIV Gag p24 in the culture supernatants by ELISA. The quantities of chemokines MIP-1α, MIP-1β, and CCL5 in the culture supernatant were also measured by ELISA. The expression of IL-1β, IL-18, TNFα, IL-10, BECN1, and housekeeping gene HuPO in the macrophages was determined by qRT PCR. The expression of NF-kB, LC3, p62, and β-actin was measured by immunoblotting. Results: We found that P3DEX controls HIV replication without affecting HIV binding and/or internalization by human macrophages. The treatment of HIV-infected macrophages with P3DEX increased the quantity of beta (β)-chemokines MIP-1α, CCL5, and MIP-1β, which are known to have anti-HIV activity. Furthermore, the treatment of HIV-infected macrophages with P3DEX increased autophagic flux in a TLR8-dependent manner and ameliorated the expression of proinflammatory cytokines. These results suggest that P3DEX is a prominent milk-derived sugar that simultaneously augments anti-viral mechanisms and controls immune activation. These findings prudently justify the use and clinical development of P3DEX as a host-directed therapeutic option for people living with HIV. Full article

Lentiviral vector-transduced T cells were approved by the FDA as gene therapy anti-cancer medications. Little is known about the effects of host genetic variation on the safety and efficacy of the lentiviral vector gene delivery system. To narrow this knowledge gap, we characterized hepatic gene delivery by lentiviral vectors across the Collaborative Cross (CC) mouse genetic reference population. For 24 weeks, we periodically measured hepatic luciferase expression from lentiviral vectors in 41 CC mouse strains. Hepatic and splenic vector copy numbers were determined. We report that the CC mouse strains showed highly diverse outcomes following lentiviral gene delivery. For the first time, a moderate correlation between mouse-strain-specific sleeping patterns and transduction efficiency was observed. We associated two quantitative trait loci (QTLs) with intrastrain variations in transduction phenotypes, which mechanistically relates to the phenomenon of metastable epialleles. An additional QTL was associated with the kinetics of hepatic transgene expression. Genes found in the above QTLs are potential targets for personalized gene therapy protocols. Importantly, we identified two mouse strains that open new directions for characterizing continuous viral vector silencing and HIV latency. Our findings suggest that wide-range patient-specific outcomes of viral vector-based gene therapy should be expected. Thus, novel clinical protocols should be considered for non-fatal diseases. Full article

Background: External guide sequences (EGSs) are small RNA molecules capable of hybridizing to a target mRNA and rendering the target RNA susceptible to degradation by ribonuclease P (RNase P), a tRNA processing enzyme. Methods: In this study, natural tRNA-originated and engineered variant EGSs were constructed to target the mRNA encoding human CC-chemokine receptor 5 (CCR5), an HIV co-receptor. Results: The EGS variant was about 100-fold more efficient in inducing RNase P-mediated cleavage of the CCR5 mRNA sequence in vitro than a natural tRNA-derived EGS. Furthermore, the expressed variant and natural tRNA-originated EGSs decreased CCR5 expression by 98% and 73–77% and reduced infection by the CCR5-tropic HIV_Ba-L strain in cells by more than 900- and 50-fold, respectively. By contrast, cells expressing these EGSs exhibited no change in the expression of CXCR4, another HIV co-receptor, and showed no reduction in infection by the CXCR4-tropic HIV_IIIB strain, which uses CXCR4 instead of CCR5 as the co-receptor. Thus, the EGSs specifically targeted CCR5 but not CXCR4. Conclusions: Our results demonstrate that EGSs are effective and specific in diminishing HIV infection and represent a novel class of gene-targeting agents for anti-HIV therapy. Full article

Background: People with HIV (PWH) are at increased risk of vascular dysfunction and cardiovascular disease (CVD). SARS-CoV-2 infection has been associated with acute CVD complications. The aim of the study was to as-sess macrovascular function as an early indicator of CVD risk in PWH after mild SARS-CoV-2 infection. Methods: PWH aged 20–60 years, with undetectable viral load (RNA < 20 copies/mL), on stable anti-retroviral therapy (≥6 months) and history of mild COVID-19 (≥30 days) without any CVD manifestations prior to enrollment were recruited. Participants were excluded if they had history of diabetes mellitus, end-stage renal disease, heart or respiratory disease. Participants were matched 1:1 to pre-pandemic PWH. A health survey, surrogate measures of CVD risk, and macrovascular function (brachial artery flow-mediated vasodilation and arterial stiffness assessments via applanation tonometry) were compared between group. Results: A total of 17 PWH and history of COVID-19 (PWH/COV+) were matched with 17 PWH without COVID-19 (PWH/COV−) pre-pandemic. Mean age (45.5 years), sex (76.5% male), body mass index (27.3), and duration of HIV infection (12.2 years) were not different between groups. Both groups had comparable CVD risk factors (total cholesterol, LDL, HDL, systolic and diastolic blood pressure). There were no differences in measures of flow mediated arterial dilatation or arterial stiffness after 30 days of SARS-CoV-2 infection. Conclusions: After recent SARS-CoV-2 infection, PWH did not demonstrate evidence of macrovascular dysfunction and increased CVD risk. Results suggest that CVD risk may not be increased in people with well-controlled HIV who did not manifest CVD complications SARS-CoV-2 infection. Full article

Background: Despite tremendous advances in antiretroviral therapy (ART) against HIV-1 infections, no cure or vaccination is available. Therefore, discovering novel therapeutic strategies remains an urgent need. In that sense, miRNAs and miRNA therapeutics have moved intensively into the focus of recent HIV-1-related investigations. A strong reciprocal interdependence has been demonstrated between HIV-1 infection and changes of the intrinsic cellular miRNA milieu. This interrelationship may direct potential alterations of the host cells’ environment beneficial for the virus or its suppression of replication. Whether this tightly balanced and controlled battle can be exploited therapeutically remains to be further addressed. In this context, the fluoroquinolone antibiotic Enoxacin has been demonstrated as a potent modulator of miRNA processing. Here, we test the hypothesis that this applies also to selected HIV-1-related miRNAs. Methods: We studied the effect of Enoxacin on HIV-1 replication coupled with miRNA qRT-PCR analysis of HIV-1-related miRNAs in CEM-SS and MT-4 T-cells. The effects of miRNA mimic transfections combined with Enoxacin treatment on HIV-1 replication were assessed. Finally, we employed an in vitro DICER1 cleavage assay to study the effects of Enoxacin on a pro-HIV-1 miRNA hsa-miR-132 processing. Results: We established that Enoxacin, but not the structurally similar compound nalidixic acid, exhibits strong anti-HIV-1 effects in the T-cell line CEM-SS, but not MT-4. We provide experimental data that this effect of Enoxacin is partly attributed to the specific downregulation of mature hsa-miR-132-3p, but not other tested pro- or anti-HIV-1 miRNAs, which is likely due to affecting DICER1 processing. Conclusions: Our findings show an anti-retroviral activity of Enoxacin at least in part by downregulation of hsa-miR-132-3p, which may be relevant for future antiviral therapeutic applications by modulation of the RNA interference pathway. Full article

Background: The increasing prevalence of drug-resistant tuberculosis (TB) underscores the urgent need for novel antimicrobial agents. Methods: This study integrates cultivation optimization, nuclear magnetic resonance (NMR) fingerprinting, and principal component analysis (PCA) to explore microbial secondary metabolites as potential anti-TB agents. Results: Using the combined approach, 11 bioactive compounds were isolated and identified, all exhibiting anti-Mycobacterium bovis BCG activity. Notable findings include borrelidin, a potent threonyl-tRNA synthetase inhibitor with broad biological activities, and L-O-Lac-L-Val-D-O-Hiv-D-Val, a peptide isolated for the first time from a plant endophyte, demonstrating broad-spectrum antimicrobial activity. Additionally, elaiophylin and polycyclic tetramate macrolactams (PTMs) displayed significant bactericidal effects, with elaiophylin achieving complete BCG inhibition at 72 h and PTMs marking their first reported anti-TB activity. The study also identified bafilomycins as potent scaffolds for anti-TB drug development, showcasing rapid bactericidal activity at low MIC values. Conclusions: These findings emphasize the value of microbial metabolites as a reservoir of bioactive compounds and provide new avenues for developing next-generation anti-TB therapies. Full article

Cytomegalovirus infections and reactivations are more frequent in people living with HIV (PLWH) and have been associated with increased risk of HIV progression and immunosenescence. We explored the impact of combination antiretroviral therapy (cART) on latent CMV infection in 225 young adults parenterally infected with HIV during childhood. Anti-CMV IgG antibodies were present in 93.7% of participants, with lower levels correlating with longer cART exposure and better immunologic parameters. Patients with immunological treatment success (CD4 > 350 cells/mL) had significantly lower CMV IgG titers compared to those with suboptimal immune response to cART. In total, 78% of the tested patients had robust CMV-specific T-cell responses, measured by an IFN-γ release assay. A good immune response to treatment was significantly associated with CMV-specific cellular immunity: IFN-γ level was positively correlated with CD4 and CD8-T cell counts. No differences were observed between patients with suppressed/non-suppressed HIV viremia in terms of CMV humoral and cellular immune response. CMV DNA was detected in only 17% of participants, with lower levels among those with cART-induced immune recovery. The successful antiretroviral treatment with subsequent immunologic reconstitution may lead to restoration of CMV-specific immune responses and effective control of latent infection, limiting episodes of CMV reactivation in HIV-positive individuals. Full article

Human Immunodeficiency Virus (HIV) proviral reservoirs are cells that harbor integrated HIV proviral DNA within their nuclear genomes. These cells form a heterogeneous group, represented by peripheral blood mononuclear cells (PBMCs), tissue-resident lymphoid and monocytic cells, and glial cells of the central nervous system. The importance of studying the properties of proviral reservoirs is connected with the inaccessibility of integrated HIV proviral DNA for modern anti-retroviral therapies (ARTs) that block virus reproduction. If treatment is not effective enough or is interrupted, the proviral reservoir can reactivate. Early initiation of ART improves the prognosis of the course of HIV infection, which is explained by the reduction in the proviral reservoir pool observed in the early stages of the disease. Different HIV subtypes present differences in the number of latent reservoirs, as determined by structural and functional differences. Unique signatures of patients with HIV, such as elite controllers, have control over viral replication and can be said to have achieved a functional cure for HIV infection. Uncovering the causes of this phenomenon will bring humanity closer to curing HIV infection, potential approaches to which include stem cell transplantation, clustered regularly interspaced short palindromic repeats (CRISPR)/cas9, “Shock and kill”, “Block and lock”, and the application of broad-spectrum neutralizing antibodies (bNAbs). Full article

Highly active antiretroviral therapy has led to a significant increase in the life expectancy of people living with HIV. The trade-off is that HIV-infected patients often suffer from comorbidities that require additional treatment, increasing the risk of Drug-Drug Interactions (DDIs), the clinical relevance of which has often not been determined during registration trials of the drugs involved. Therefore, it is important to identify potential clinically relevant DDIs in order to establish the most appropriate therapeutic approaches. This review aims to summarize and analyze data from studies published over the last two decades on DDI-related adverse clinical outcomes involving anti-HIV drugs and those used to treat comorbidities. Several studies have examined the pharmacokinetics and tolerability of different drug combinations. Protease inhibitors, followed by nonnucleoside reverse transcriptase inhibitors and integrase inhibitors have been recognized as the main players in DDIs with antivirals used to control co-infection, such as Hepatitis C virus, or with drugs commonly used to treat HIV comorbidities, such as lipid-lowering agents, proton pump inhibitors and anticancer drugs. However, the studies do not seem to be consistent with regard to sample size and follow-up, the drugs involved, or the results obtained. It should be noted that most of the available studies were conducted in healthy volunteers without being replicated in patients. This hampered the assessment of the clinical burden of DDIs and, consequently, the optimal pharmacological management of people living with HIV. Full article

HIV causes intense polyclonal activation of B cells, resulting in increased numbers of spontaneously antibody-secreting cells in the circulation and hypergammaglobulinemia. It is accompanied by significant perturbations in various B cell subsets, such as increased frequencies of immature/transitional B cells, activated memory B cells, atypical memory B cells, short-lived plasmablasts and regulatory B cells, as well as by decreased frequencies of resting memory and resting naïve B cells. Furthermore, both memory and antigen-inexperienced naïve B cells show exhausted and immune-senescent phenotypes. HIV also drives the expansion and functional impairment of CD4⁺ T follicular helper cells, which provide help to B cells, crucial for the generation of germinal center reactions and production of long-lived plasma and memory B cells. By suppressing viral replication, anti-retroviral therapy reverses the virus-induced perturbations and functional defects, albeit inadequately. Due to HIV’s lingering impact on B cells, immune senescence and residual chronic inflammation, people with HIV (PWH), especially immune non-responders, are immunocompromised and mount suboptimal antibody responses to vaccination for SARS-CoV-2. Here, we review how functionally and phenotypically distinct B cell subsets are induced in response to a vaccine and an infection and how HIV infection and anti-retroviral therapy (ART) impact them. We also review the role played by HIV-induced defects and perturbations in B cells in the induction of humoral immune responses to currently used anti-SARS-CoV-2 vaccines in PWH on ART. We also outline different strategies that could potentially enhance the vaccine-induced antibody responses in PWH. The review will provide guidance and impetus for further research to improve the immunogenicity of these vaccines in this human population. Full article

Background/Objectives: Despite advancements in antiretroviral therapy (ART), HIV-positive individuals face heightened risks of cardiovascular and gastrointestinal (GI) complications, often linked to persistent systemic inflammation. Left ventricular diastolic dysfunction (LVDD), prevalent in HIV patients, exacerbates this inflammatory state and may contribute to worsened GI symptoms. This study aims to explore the association between LVDD, systemic inflammation, and gastrointestinal symptoms in HIV-positive patients undergoing ART. The primary objective is to analyze how LVDD contributes to the inflammatory burden and its impact on gastrointestinal health in this population. Methods: This cross-sectional study included 320 participants divided into three groups: HIV-positive with LVDD (n = 80), HIV-positive without LVDD (n = 120), and HIV-negative controls (n = 120). Levels of inflammatory biomarkers—CRP, IL-6, TNF-α, fibrinogen, IL-1β, IFN-γ, and D-dimer—were measured, and GI symptoms were assessed. Echocardiographic evaluations were performed to determine LVDD presence and severity, while multivariate logistic regression identified predictors of GI complications. Results: Patients in the HIV + LVDD group exhibited significantly elevated levels of TNF-α, CRP, and D-dimer compared to other groups, correlating with higher incidences of nausea, diarrhea, and abdominal pain. TNF-α emerged as the strongest predictor of GI symptoms, underscoring its role in the pathophysiology linking cardiovascular and GI distress in this population. Persistent inflammation and coagulation abnormalities in the ART + LVDD group suggest that ART alone may not fully mitigate these complications. Conclusions: Our findings emphasize the compounded inflammatory burden in HIV patients with LVDD, highlighting the need for integrated approaches that address both cardiovascular and GI symptoms. Anti-inflammatory therapies targeting specific biomarkers like TNF-α could improve clinical outcomes, supporting a more comprehensive strategy to managing HIV-related comorbidities beyond viral suppression. Full article