AIDS research and human retroviruses最新文献

Under the background of the main epidemic HIV strains (CRF01_AE and CRF07_BC) co-circulation in China, more HIV second-generation recombinant (SGR) strains with CRF01_AE and CRF07_BC as the backbone were also emerging. In this study, we characterize a novel HIV-1 second-generation circulating recombinant form (CRF117_0107) consisting of CRF01_AE and CRF07_BC fragments from three epidemiologically unrelated individuals infected with HIV-1. One near full-length genome (NFLG) sequence was amplified, sequenced, and spliced in two halves using RNA extracted from the plasma of a homosexual in Shenzhen, Guangdong Province. Two other NFLG sequences were obtained from the Los Alamos HIV Sequence Database under accession numbers KY201177 and MK397789, which were isolated from men who have sex with men (MSM) in Guangdong Province and Zhejiang Province, respectively. Phylogenetic analysis revealed that these NFLG sequences formed a monophyletic cluster with a high bootstrap value of 1.0. Recombination analysis demonstrated that the genome of CRF117_0107 was separated into three segments by two breakpoints. Further subregional phylogenetic analysis was performed that showed segment I+III (790-5990nt, 8295-9412nt) of CRF117_0107 originated from the CRF07_BC cluster, and Segment I+III (5991-8294nt) originated from the CRF01_AE cluster. The appearance of CRF117_0107 further highlights that HIV-1 SGR strains containing CRF01_AE and CRF07_BC will be generated more frequently and will most likely be more conducive to accelerating the spread of HIV in China. This study suggested it's essential to monitor HIV-1 second-generation CRFs among high-risk populations such as MSM for the epidemic and evolution dynamics of HIV-1 in China.

The objective of this study was to estimate the structure and relationships between four h ypothesized frailty dimensions (physical, emotional, cognitive, and social) and the extent to which personal and HIV-related factors and comorbidity associate with these frailty dimensions. This is a secondary analysis of an existing dataset arising from Positive Brain Health Now study (n = 856) in people aging with HIV (mean age: 52.3 ± 8.1 years). Structural equation modeling (SEM) models were applied to two cross-sections of the data: one at study entry and one at second visit, 9-month apart. Multidimensional frailty was modeled based on the combined Wilson-Cleary and International Classification of Functioning, Disability and Health framework. Four dimensions were operationalized with patient-reported and self-report measures from standardized questionnaires. The SEM model from the first visit was replicated using data from the second visit, testing measurement invariance. The proposed model showed acceptable fit at both visits (including no violation of measurement invariance). The final model for the first visit showed that sex, body mass index, HIV diagnosis pre-1997, current or nadir CD4 counts, and comorbidity did not associate with any frailty dimension; however, age (β range: 0.12-0.25), symptoms (β range: -0.35 to -0.58), and measured cognition (β range: 0.10-0.24) directly associated with all frailty dimensions. The model remained stable across the two visits. This study contributes evidence for operationalizing multidimensional frailty. Evidence-based interventions are available for many of the measures considered here, offering opportunities to improve the lives of people with frailty in the context of HIV.

As the number of older people with HIV (PWH) grows, accidental falls and their associated negative health outcomes are of increasing concern. Fall risk can be measured using novel screening tools such as evaluating postural stability using force plate technology. The aims of this study were to test this technology to assess fall risk among older PWH. In a cross-sectional, observational study of people without HIV (PWoH) with a range of fall risk, participants underwent balance assessment using the validated BTrackS balance plate. Postural stability was compared by HIV serostatus. Multivariable linear regressions were used to examine the relationship between postural stability and validated measures of fall risk balance and frailty status. Among 34 PWH and 30 PWoH, all ≥50 years, postural stability was worse among PWH (35.4 cm vs. 28.3 cm, p = .07). In multivariable models, worse postural stability was associated with reporting a fall in the past 6 months (β = 0.32, p = .004), worse fall efficacy (β = 0.45, p < .001), and being frail or prefrail (β = 0.26, p = .027). In multivariable models stratified by HIV serostatus, worse postural stability was significantly associated with worse fall efficacy (β = 0.53, p < .01) and lower balance confidence (β = -0.33, p =. 04) among PWH but not PWoH. Among older PWH and PWoH, worse postural stability was associated with validated measures of fall risk, including history of falls and poorer fall efficacy. Assessment of postural sway is a promising objective screening test for fall risk among older PWH.

Despite advancements in antiretroviral therapy (ART) that reduces the viral load to undetectable levels and improve CD4 T cell counts, viral eradication has not been achieved due to HIV-1 persistence in resting CD4⁺ T-cells. We, therefore, characterized the tat gene, which is essential for HIV-1 replication and pathogenesis, from 20 virologically controlled aging individuals with HIV (HIV⁺) on long-term ART and improved CD4⁺ T-cell counts, with a particular focus on older individuals. Peripheral blood mononuclear cell genomic DNA from HIV⁺ were used to amplify tat gene by polymerase chain reaction followed by nucleotide sequencing and analysis. Phylogenetic analysis showed that each HIV⁺ tat sequences were confined to their own subtrees and well discriminated from other HIV⁺ sequences. Moreover, there was a low degree of viral heterogeneity and lower estimates of genetic diversity within these individuals' tat sequences, which decreased with increasing CD4 T counts in these HIV⁺. Most HIV⁺ Tat deduced amino acid sequences showed intact open reading frames and maintained the important functional domains for Tat functions, including transactivation, TAR binding, and nuclear localization. Furthermore, Tat-deduced amino acid sequences showed variation in previously characterized cytotoxic T lymphocytes (CTL) epitopes, suggesting escape mutants. In conclusion, a low degree of genetic variability and conservation of functional domains and variations in CTL epitopes were the features of tat sequences that may be contributing to viral persistence in these 20 aging individuals with HIV on long-term ART.

Human T cell lymphotropic virus type 1 (HTLV-1) is associated with adult T cell leukemia/lymphoma (ATLL), a fetal malignant infection. Recently, HTLV-1 new asymptomatic carriers (ACs) have frequently been reported among blood donors. Reaching the profound concept of HTLV-1-associated molecular pathogenesis could result in finding novel therapeutic strategies. The current study aimed to determine leukemia-related signaling regulation in ATLL. Thirty participants were evaluated in 3 groups, including 10 ATLL patients, 10 ACs, and 10 normal controls. Blood samples were isolated without any chemotherapy history from ATLL patients. Also, blood samples were recovered from ACs and normal individuals. White blood cells isolation was done on the collected blood samples. After this, RNA was extracted from the prepared samples and used for the cDNA synthesis. TAX and HTLV-1 basic leucine zipper factor as viral genes and cellular genes, including MKP-1, EVI-1, JNK-1, FOXO-1, AKT-1, DEPTOR, MTOR, and JUN, were investigated using real-time PCR. The mean age of ATLL patients was 53.2 ± 7.32 years, and 9 (90%) were male. The EVI-1 and FOXO-1 expression levels were significantly associated with ATLL patients compared with the internal control. However, the significant differences in expression of other genes in the remaining groups were not seen. Discovering viral and cellular signaling pathways that regulate HTLV-1 transformation is essential. A novel therapeutic strategy for ATLL-regulating cellular signaling pathways in vivo could be considered. Therefore, clinical trials using activators and inhibitors of related cellular signaling pathways for cell therapy of ATLL are recommended. It is recommended that more investigation be conducted on FOXO-1 and EVI-1 to target these genes and reveal the molecular pathogenesis of ATLL.

During male-to-female transmission, HIV-1 must cross the mucosal epithelium of the female reproductive tract to gain access to underlying target cells. Previously, we demonstrated that HIV-1 can penetrate intact columnar and squamous genital epithelia in both ex vivo and in vivo systems. We found that the virus enters the squamous epithelium via a diffusion-based mechanism, but the mechanism of entry in columnar epithelium remained elusive. Using a similar set of approaches, we now demonstrate that HIV enters the endocervical simple columnar epithelium via endocytosis. By exposing human endocervical explant tissue to small molecule endocytosis inhibitors prior to virus exposure, we show that virus penetration into the simple columnar barrier is impeded. These data suggest a transcytosis-based mechanism for HIV-1 penetration into the endocervical columnar barrier.

This study aims to compare intestinal mucosal damage and the expression levels of occludin, zonula occludens-1 (ZO-1), vascular endothelial (VE)-cadherin, β-catenin, and plasmalemma vesicle-associated protein (PLVAP) in the gut vascular barrier (GVB) among people living with HIV (PLWH), asymptomatic PLWH, and healthy volunteers (non-PLWH). Three groups were selected for the study: PLWH, asymptomatic PLWH, and healthy volunteers. Colonic mucosal tissue samples were collected via colonoscopy from all participants. Histological examination of the colonic mucosa was conducted using hematoxylin and eosin staining. The expression levels of occludin, ZO-1, VE-cadherin, β-catenin, and PLVAP were assessed using RT-qPCR, immunohistochemistry, and western blot analyses. Pathological scores of colonic mucosa in PLWH and asymptomatic PLWH were significantly higher than those in non-PLWH (p < .001 and p = .0056, respectively). CD4⁺ T cell counts in asymptomatic PLWH and non-PLWH were significantly higher than in PLWH (p < 0.05). The CD4⁺/CD8+ T cell ratio in non-PLWH significantly exceeded those in PLWH and asymptomatic PLWH (p < .05). Analysis of protein and mRNA expression revealed: (1) no statistically significant differences in PLVAP-mRNA expression across all groups (p > .05); (2) higher PLVAP protein levels in PLWH compared with asymptomatic PLWH and non-PLWH (p < .05), with no significant differences between asymptomatic PLWH and non-PLWH (p = .632); (3) significantly higher PLVAP expression in the colonic mucosa of PLWH and asymptomatic PLWH compared with non-PLWH (p = .034 and p = .011, respectively), with no significant differences between PLWH and asymptomatic PLWH (p > .999). ZO-1 expression was significantly lower in PLWH than in non-PLWH (p = .012), with no notable differences between asymptomatic PLWH and other groups. PLWH, compared with healthy controls, exhibit significant inflammatory changes in the intestinal mucosa. PLVAP expression serves as a potential indicator to assess the extent of GVB damage and disease progression in PLWH.

Cytokines are key mediators of immune regulation, orchestrate communication between immune cells, and play a pivotal role in shaping the immune landscape during chronic infection and cancer. The therapeutic potential of IL-15/IL-15Rα and IL-12 has been explored individually in various immunotherapeutic strategies, though not as a combination. Therefore, we investigated whether the combination of IL-15/IL-15Rα and IL-12 treatment would enhance the potency and quality of either NK cells, SIV-specific CD8 T cells, or both, compared with single cytokine treatment. Our findings reveal that in vitro IL-15/IL-15Rα and IL-15/IL-15Rα plus IL-12 treatment results in an expansion of functional CD8 T cells and NK cells from uninfected and chronically infected macaques with simian/human immunodeficiency virus. Additionally, the cytokine combination significantly reduced CCR5 expression on total CD4 T cells, limiting the number of viral targets. This study supports the potential utilization of combined IL-15/IL-15Rα plus IL-12 treatment for chronic viral infections and cancer.

Daily oral medication is currently the most common antiretroviral therapy (ART) for people living with human immunodeficiency virus (PLWH). As the first complete long-acting (LA) ART regimen, cabotegravir (CAB) and rilpivirine (RPV), offer a novel treatment approach with less frequent administration, via bimonthly infusion. Due to the upcoming availability of this regimen in China, the study aimed to analyze the willingness and reasons of PLWH to switch to CAB+RPV therapy. A questionnaire survey among PLWH receiving oral ART was carried out between March 25 and April 8, 2023, in the Second Hospital of Nanjing, China. Participants were asked about their willingness to switch to the CAB+RPV LA regimen and provided reasons for their decision. We analyzed the reasons for switching, and the factors affecting their willingness were analyzed by multinomial logistic regression. Among 693 participants, 56.7% expressed willingness to switch to the CAB+RPV regimen, 32.6% were uncertain, and 10.7% were unwilling. The primary reason for switching to CAB+RPV therapy was not being concerned about daily adherence to ART (22.6%). Uncertainty about switching was mainly associated with participants' concerns in terms of price (31.6%) and safety (31.1%) of the novel drugs. Unwillingness was mainly due to participants' satisfaction with their current treatment regimen (20.3%). In multivariate analysis, higher education (odds ratio [OR]: 2.990; 95% confidence interval [CI]: 1.171-7.636) was positively associated with willingness to switch, whereas the age of ≥60 (OR: 0.142; 95% CI: 0.036-0.554) was negatively associated. Our survey demonstrated that the majority of PLWH were willing to switch to CAB+RPV therapy, mainly due to its improved convenience and reduced risk of disease exposure. However, their concerns regarding price, efficacy, and safety could be the key challenges for the clinical implementation of the CAB+RPV LA regimen in the future.

The human immunodeficiency virus (HIV), a retrovirus targeting the immune system and the primary agent causing acquired immunodeficiency syndrome (AIDS), can have fatal consequences. Although antiretroviral treatment has significantly reduced mortality and comorbidity in people living with HIV (PLHIV), its impact on metabolic syndrome (MetS) remains notable. Several genome-wide association studies have identified a link between the glucokinase gene (GCK) and MetS, particularly in type 2 diabetes. However, no studies have investigated the association between this gene and HIV status. Our study aims to evaluate the association of the rs1799884 polymorphism in the GCK gene with HIV status in a group of Moroccan patients. This case-control study includes 207 PLHIV and 181 HIV-uninfected controls. Genotyping of the rs1799884 polymorphism in the GCK gene was performed using a predesigned TaqMan single-nucleotide polymorphism genotyping assay. The genotypic distribution between PLHIV and HIV-uninfected controls revealed a significant difference. Patients with the CT genotype had a 4.47-fold increased risk of infection [odds ratio (OR) = 4.47; 95% confidence interval (CI) = 2.75-7.29; p = .001]. However, the TT genotype conferred protection against HIV in a recessive model (OR = 0.50; 95% CI = 0.28-0.91; p = .021). Interestingly, the risk associated with the CT genotype was even higher in AIDS-related cases (OR = 9.37; 95% CI = 4.32-20.36; p = .0001). Additionally, under the dominant model, individuals with CT and TT genotypes had a 7.67-fold increased risk of infection (OR = 7.67; 95% CI = 3.60-16.36; p < .0001). However, the TT genotype under the recessive model was not significantly associated with disease progression. No significant association was observed between these genotypes and CD4 count; however, there was a significant variation in viral load after treatment. Our findings suggest that the rs1799884-C/T variant of the GCK gene may influence susceptibility to HIV status, progression to AIDS, and response to treatment.