Current HIV Research最新文献

Background: The research and development of HIV drugs is very important, but at the same time it is a long cycle and expensive system project. High-throughput drug screening systems and molecular libraries of potential hit compounds remain the main ways for the discovery of hit compounds with anti-HIV activity.

Objective: The aim of this study was to screen out the hit compounds against HIV-1 in the natural product molecule library and the antiviral molecule library, and elucidate the molecular mechanism of their inhibition of HIV-1, so as to provide a new choice for AIDS drug research.

Methods: In this study, a drug screening system using HIV Rev-dependent indicator cell line (Rev-A3R5-GFP reporter cells) with pseudoviruses (pNL4-3) was used. The natural drug molecule library and antiviral molecule library were screened, and preliminary drug mechanism studies were performed.

Results: Ten promising hit compounds were screened. These ten molecules and their drug inhibitory IC50 were as follows: Cephaeline (0.50 μM), Yadanziolide A (8.82 μM), Bruceine D (2.48 μM), Astragaloside IV (4.30 μM), RX-3117 (1.32 μM), Harringtonine (0.63 μM), Tubercidin (0.41 μM), Theaflavine-3, 3'-digallate (0.41 μM), Ginkgetin (10.76 μM), ZK756326 (5.97 μM). The results of the Time of additions showed that except for Astragaloside IV and Theaflavine-3, 3'-digallate had a weak entry inhibition effect, and it was speculated that all ten compounds had an intracellular inhibition effect. Cephaeline, Harringtonine, Astragaloside IV, Bruceine D, and Tubercidin may have pre-reverse transcriptional inhibition. Yadanziolide A, Theaflavine-3, 3'-digallate, Ginkgetin and RX-3117 may be in the post-reverse transcriptional inhibition. The inhibitory effect of ZK 75632 may be in the reverse transcriptional process.

Conclusion: A drug screening system using Rev-A3R5-GFP reporter cells with pseudoviruses (pNL4-3) is highly efficient. This study provided potential hit compounds for new HIV drug research.

HIV/ AIDS is a global pandemic, one of the most challenging; with no cure for the disease, various therapies available in the form of regimens as Highly Active Anti-Retroviral Therapy (HAART) or simply Anti-Retroviral Therapy (ART) are the only way to manage the disease. The Fixed Dose Combinations (FDCs) concept has been a well-recognised improvement in pharmacotherapy for the treatment of a variety of chronic maladies like hypertension, diabetes, HIV/AIDS, and several FDC products consisting of HIV drugs are approved. These single-tablet regimens have been essential in streamlining ART, lowering pill burden and increasing adherence. Adherence to HAART is the most vital factor to ensure medication success and virologic suppression. However, adherence is faced with several barriers including adverse effects of drugs, the complexity of ART, social-cultural factors, and pill burden among others. This writing reviews the concept of adherence to ART, and its barriers while stressing pill burden as a significant one which we suggest would be solved by using Fixed Dose Combinations (FDCs).

Introduction: The C-C chemokine receptor type 5 (CCR5) is a major co-receptor for human immunodeficiency virus (HIV). Some individuals carry the CCR5 delta-32 genetic polymorphism. People with homozygous CCR5 delta-32 gene are nearly completely resistant to HIV-1 infection. High-resolution melting curve (HRM) analysis is a post-PCR technique utilized for identifying genetic variations in a quick, affordable, and closed-tube assay. The objective of this study was to develop an HRM assay for easy detection of delta-32 mutations.

Materials and methods: DNA was extracted from peripheral blood mononuclear cells. HRM was performed to detect delta-32 mutation. The study investigated the impact of various factors, including annealing temperature, template concentration, touchdown PCR, additives, amplicon size, and program settings, on HRM Tm differentiation.

Results: It was expected that there would be a 4°C Tm difference between amplicons with and without delta-32 mutation, but the test showed a difference of only 2.3°C. In attempts to identify heterozygote delta-32 variants, a Tm difference of only 0.4°C could be achieved. Various modifications were applied, such as adjusting the template concentration, using touchdown PCR, and adding DMSO and glycerol. However, none of these changes helped to differentiate the Tm effectively, especially in delta-32 heterozygote samples.

Conclusion: The HRM test identified four samples with heterozygote mutations in each HIV-infected (8.89%) and control (5.72%) groups. More importantly, this study showed that identifying the delta-32 mutation of the CCR5 gene using HRM assay is not as straightforward as previously suggested in some literature, and it requires special setup conditions.

Background: Human immunodeficiency virus-1 infection still remains a global health threat. While antiretroviral therapy is the primary treatment option, concerns about the emergence of drug-resistance mutations and treatment failure in HIV-infected patients persist.

Objective: In this study, we investigated the development of drug resistance in HIV-1-infected individuals receiving antiretroviral therapy for 6-10 years.

Methods: In this cross-sectional study, we evaluated 144 people living with HIV-1 who had received antiretroviral therapy for at least 6 years. Plasma specimens were collected, and the HIV-1 viral load and drug-resistance mutations were assessed using molecular techniques.

Results: The demographic and epidemiological characteristics of the participants were also analyzed: Twelve [8.3%) of the studied patients showed a viral load over 1000 copies per/mL, which indicates the suboptimal response to antiretroviral therapy. Significant correlations were found between viral load and CD4 count, as well as epidemiological factors, such as vertical transmission, history of imprisonment, and needle stick injuries. Drug resistance mutations were detected in 10 (83.3%) of patients who failed on antiretroviral therapy, with the most common mutations observed against nucleoside reverse transcriptase inhibitors (5 (41.7%)) and non-nucleoside reverse transcriptase inhibitors (9 (75%)). Phylogenetic analysis revealed that 12 patients who failed treatment were infected with CRF35_AD.

Conclusion: Our study provides important insights into the characteristics and development of drug resistance in HIV-1-infected individuals receiving long-term antiretroviral therapy in Iran. The findings underline the need for regular viral load monitoring, individualized treatment selection, and targeted interventions to optimize treatment outcomes and prevent the further spread of drug-resistant strains.

Background: The interaction of human immunodeficiency virus (HIV), host and antiretroviral therapy (ART) causes a range of metabolic disorders that can be characterized as a metabolic syndrome (MetS) that increases the cardiovascular risk. MetS involves central obesity, which can be detected using different anthropometric parameters.

Objective: To assess the abilities of different anthropometric parameters in the prediction of MetS in HIV-infected men on ART.

Method: The study involved 92 male participants (mean age 44.46±10.38 years), divided into two groups: with and without MetS. All subjects underwent biochemical evaluation (triglycerides, HDL-cholesterol, fasting glucose), blood pressure measurement and anthropometric assessment: body mass, body height, body mass index (BMI), body fat mass, body circumferences (chest, upper arm, forearm, waist, hip, proximal and middle thigh and calf), sagittal abdominal diameter (SAD), skinfold thicknesses (subscapular, anterior and posterior upper arm, anterior and lateral forearm, abdominal, supraspinal, thigh and calf), waist-to-hip ratio (WHR), waist-to-height ratio (WHtR), waist-to-thigh ratio (WTR), sagittal abdominal diameter-to-body height ratio (SADH), body adiposity index (BAI) and conicity index. MetS was specified according to IDF criteria.

Results: Subjects with MetS had statistically significant higher values of all anthropometric parameters except middle thigh circumference, calf skinfold and body height. According to ROC analysis and Binary Logistic Regression, SAD has been shown as the best predictor of MetS with a predictive value of 21.40 cm (AUC:0.91), followed by WHR with a predictive value of 0.93.

Conclusion: Sagittal abdominal diameter is the strongest anthropometric indicator of MetS in HIV-infected patients on ART.

Introduction: Abacavir is among the first-line initial antiretroviral regimens for most patients living with HIV/AIDS (PLWHA). Although well tolerated, it is associated with hypersensitivity reaction (HSR), which is treatment-limiting and potentially life-threatening. HSR was shown to be associated with the class I MHC allele, HLA-B*57:01. In this study, we aimed to evaluate the prevalence of HLA-B*57:01 in PLWHA in Istanbul, Türkiye.

Material and methods: Five HIV treatment centers in Istanbul included all sequential treatmentnaïve, ≥ 18 years adult PLWHA, between December 2017- December 2021. Demographic, clinical, and laboratory data were collected at baseline and during treatment. HLA-B* 57:01 genotyping was determined with PCR-SSP.

Results: Eight hundred sixty-seven PLWHA were included (male:91%, mean age 39.6±11.1 years). 1.6% of patients were found to be HLA-B*57:01 positive. Among HLA-B*57:01 positive patients, 4 were initially given abacavir-containing treatment; they were switched to non-abacavir treatment upon the allele found to be positive.

Conclusion: Although previous studies reported the HLA-B*57:01 prevalence of PLWHA in Türkiye as 3-3.6%, we have found the prevalence to be 1.6%. The current study includes higher numbers of patients than the previous studies. Furthermore, patients from all over the country apply to the centers in Istanbul; compared to the other studies, which involve patients limited to the relevant regions. It can be assumed that the number in our cohort is more representative of the country. In conclusion, the prevalence of the HLA-B*57:01 allele in PLWHA in this study is relatively low. With evident benefit in preventing abacavir HSR, HLA-B*57:01 should be screened in planning antiretroviral therapy.

Background: Dolutegravir (DTG) is a novel yet preferential first- and -second-line treatment for persons living with HIV (PLH). Owing to its recent introduction, DTG-based regimens have not undergone a comprehensive, systematic evaluation regarding their real-world utilization and safety profile among a sizeable Indian population.

Objective: This study aimed to assess the 24 week immunovirological outcomes, anthropometric and metabolic changes, tolerability, and adverse events (AEs) of DTG-based antiretroviral (ART) regimens.

Methods: A single-centre phase-IV non-interventional observational study involving 322 ART naïve and treatment-experienced PLH initiating DTG-based-regimens until October 2022 were followed up for outcomes at 24 weeks.

Results: At 24 weeks, all PLH (n = 113) in the naïve group, all PLH (n = 67) in the first-line substitution group, 93.9% PLH (n = 46) in the first-line failure group, and 95.7% PLH (n = 89) in the second-line substitution group were virologically suppressed to plasma HIV-RNA <1000 copies/mL. Virological suppression rates to plasma HIV-RNA <200 copies/mL and <50 copies/mL were consistent among PLH who received DTG as first- or second-line ART. The mean-unadjusted weight gain observed was 3.5 kg (SE: 0.330), and it was significantly higher in PLH with poorer health at baseline (either HIV-RNA ≥ 1000 copies/ml or CD4 cell count <350 cells/μL). Overall, 27.3% PLH (n = 88) gained ≥10% of their baseline body weight, corresponding to 3.7% incidence (n = 12) of treatment-emergent clinical obesity. DTG had an overall lipid-neutral effect, with an advantageous effect being observed in PLH switching from non-nucleoside analogue reverse-transcriptase inhibitors (NNRTI) or ritonavir-boosted protease inhibitors (b/PI), especially in dyslipidemic pre-treated PLH (median change in total cholesterol: 28.5 mg/dL and triglycerides: 51 mg/dL), possibly emanating from the withdrawal of the offending ART. The incidence of DTG-specific AEs, including CNS AEs, was low. Two PLH developed proximal myopathy and one developed transaminitis, warranting DTG discontinuation. Asymptomatic serum-CPK elevation and drug-induced transaminitis were seen in 25.2% (n = 27) and 3.2% (n = 10) PLH, respectively. No apparent negative effects on renal function were detected.

Conclusion: Our results from a large Indian cohort indicate a favourable virological and metabolic response, with good tolerance of DTG-based ART at 24 weeks.

Objective: The aim of the study was to assess the clinical features of women infected with the human immunodeficiency virus (HIV) using Holter monitoring.

Methods: Thirty-five female patients infected with HIV using a Holter monitor at the Ditan Hospital were retrospectively analyzed.

Results: In terms of basic rhythms, there were 30 cases of sinus rhythm, 27 cases of ventricular premature beat, 26 cases of supraventricular premature beat, 12 cases of mild reduction of HRV, 9 cases of normal heart rate variability (HRV), 8 cases of supraventricular tachycardia, 5 cases of abnormal ST-segment changes and 2 cases of sinus bradycardia 2 cases of paroxysmal atrial fibrillation 2 cases of junctional escape rhythm. There was only one case in each of the following ECG changes: persistent atrial fibrillation, sinus tachycardia, couplet supraventricular premature beats, accelerated idioventricular rhythm, sinoatrial block, second-degree Mobitz type I atrioventricular block, second-degree Mobitz type II atrioventricular block, complete right bundle branch block, T-wave abnormality, and significant reduction of HRV.

Conclusion: The Holter monitor can show more changes in the electrocardiogram (ECG) of HIV-- positive patients, particularly significant ECG abnormalities, such as paroxysmal atrial fibrillation, and can direct early clinical treatment to serious adverse results.

People Living with HIV (PLHIV) experience accelerated aging, yet strategies for healthy aging in this group are not well studied. Although survival rates have improved, non-infectious comorbidities, like cardiovascular diseases, diabetes, and cancers, are increasing and tend to appear earlier and more severely in PLHIV frailty, defined as increased vulnerability to stressors, which is a growing concern among aging PLHIV, driven by factors, like chronic inflammation, antiretroviral therapy toxicity, and traditional risk factors. Key areas of focus include inactivity, sarcopenia, vitamin D deficiency, and polypharmacy. Addressing these factors is crucial to preventing functional decline and improving the quality of life of PLHIV, though more research is necessary. The aim of this article was to identify and conduct a narrative review of these factors in a pragmatic way in order to facilitate the clinicians.

Background: Heterologous combinations in vaccine design are an effective approach to promote T cell activity and antiviral effects. The goal of this study was to compare the homologous and heterologous regimens targeting the Nef-Tat fusion antigen to develop a human immunodeficiency virus-1 (HIV-1) therapeutic vaccine candidate.

Methods: At first, the DNA and protein constructs harboring HIV-1 Nef and the first exon of Tat as linked form (pcDNA-nef-tat and Nef-Tat protein) were prepared in large scale and high purity. The generation of the Nef-Tat protein was performed in the E. coli expression system using an IPTG inducer. Then, we evaluated and compared immune responses of homologous DNA prime/ DNA boost, homologous protein prime/ protein boost, and heterologous DNA prime/protein boost regimens in BALB/c mice. Finally, the ability of mice splenocytes to secret cytokines after exposure to single-cycle replicable (SCR) HIV-1 was compared between immunized and control groups in vitro.

Results: The nef-tat gene was successfully subcloned in eukaryotic pcDNA3.1 (-) and prokaryotic pET-24a (+) expression vectors. The recombinant Nef-Tat protein was generated in the E. coli Rosetta strain under optimized conditions as a clear band of ~ 35 kDa detected on SDS-PAGE. Moreover, transfection of pcDNA-nef-tat into HEK-293T cells was successfully performed using Lipofectamine 2000, as confirmed by western blotting. The immunization studies showed that heterologous DNA prime/protein boost regimen could significantly elicit the highest levels of Ig- G2a, IFN-γ, and Granzyme B in mice as compared to homologous DNA/DNA and protein/protein regimens. Moreover, the secretion of IFN-γ was higher in DNA/protein regimens than in DNA/DNA and protein/protein regimens after exposure of mice splenocytes to SCR HIV-1 in vitro.

Conclusion: The chimeric HIV-1 Nef-Tat antigen was highly immunogenic, especially when applied in a heterologous prime/ boost regimen. This regimen could direct immune response toward cellular immunity (Th1 and CTL activity) and increase IFN-γ secretion after virus exposure.