cART-treated Patients Research Articles

Abnormal spirometric patterns and respiratory symptoms in HIV patients with no recent pulmonary infection in a periurban hospital in Ghana.

Human immunodeficiency virus (HIV) infection is associated with chronic airway obstruction, even in patients who have achieved viral suppression from combination antiretroviral treatment (cART). Spirometry is a supplementary test that aids in diagnosing pulmonary dysfunction in people living with HIV. To compare the prevalence of spirometric abnormalities among cART-treated HIV patients and cART-naïve HIV patients with non-HIV controls with no recent history of pulmonary infection in a peri-urban hospital in Ghana. In a case-control design, spirometry was performed in 158 cART-treated HIV patients, 150 cART-naïve HIV patients and 156 non-HIV controls. Clinical, sociodemographic data and respiratory symptoms were collected using a structured questionnaire. Spirometric abnormalities were categorised as obstructive (OSP) or restrictive (RSP) spirometric patterns based on the Cameroonian reference equation. The prevalence of OSP was higher in the cART-treated and cART-naïve HIV patients compared to non-HIV controls (13.9% vs 10.7% vs 5.1% respectively, p = 0.026), whereas that of RSP was similar among the study groups. Respiratory symptoms were common among cART-treated and cART-naïve HIV patients compared to non-HIV controls (48.1% vs 40% vs 19.2% respectively, p < 0.001). The major factors associated with OSP were female gender [OR (95% CI) = 2.46 (1.09-5.13), p = 0.031], former cigarette smoking [1.92 (1.04-3.89), p < 0.001], exposure to medium-to-high levels of biomass [3.07 (1.16-8.73), p = 0.019], presence of a respiratory symptom [1.89 (1.11-5.08), p = 0.029] and unemployment [3.26 (1.19-8.95), p = 0.042]. The major determinants of RSP were age, female gender [1.74 (1.05-4.29), p = 0.041], former cigarette smoking [2.31 (1.27-6.77), p < 0.001] and medium-to-high biomass exposure [1.58 (1.06-5.37), p = 0.043]. In HIV patients without any recent pulmonary infection in a peri-urban area of Ghana, there was a higher prevalence of OSP among cART-treated and cART naïve HIV patients compared to the non-HIV control. However, the prevalence of RSP was similar among HIV patients and non-HIV controls.

Autophagy Deregulation in HIV-1-Infected Cells Increases Extracellular Vesicle Release and Contributes to TLR3 Activation.

Human immunodeficiency virus type 1 (HIV-1) infection can result in HIV-associated neurocognitive disorder (HAND), a spectrum of disorders characterized by neurological impairment and chronic inflammation. Combined antiretroviral therapy (cART) has elicited a marked reduction in the number of individuals diagnosed with HAND. However, there is continual, low-level viral transcription due to the lack of a transcription inhibitor in cART regimens, which results in the accumulation of viral products within infected cells. To alleviate stress, infected cells can release accumulated products, such as TAR RNA, in extracellular vesicles (EVs), which can contribute to pathogenesis in neighboring cells. Here, we demonstrate that cART can contribute to autophagy deregulation in infected cells and increased EV release. The impact of EVs released from HIV-1 infected myeloid cells was found to contribute to CNS pathogenesis, potentially through EV-mediated TLR3 (Toll-like receptor 3) activation, suggesting the need for therapeutics to target this mechanism. Three HIV-1 TAR-binding compounds, 103FA, 111FA, and Ral HCl, were identified that recognize TAR RNA and reduce TLR activation. These data indicate that packaging of viral products into EVs, potentially exacerbated by antiretroviral therapeutics, may induce chronic inflammation of the CNS observed in cART-treated patients, and novel therapeutic strategies may be exploited to mitigate morbidity.

Brief Report: In cART-Treated HIV-Infected Patients, Immunologic Failure Is Associated With a High Myeloid-Derived Suppressor Cell Frequency.

During HIV infection, effective combined antiretroviral therapy suppresses viral replication and restores the number of circulating CD4+ T cells. However, 15%-30% of treated patients show a discordant response to combined antiretroviral therapy. Myeloid-derived suppressor cells (MDSC) are expanded in HIV+ patients; to better understand the role of MDSC on CD4 T-cell recovery, we evaluated the frequency of MDSC in HIV+ patients under combined antiretroviral therapy and its association with immunologic response. We enrolled 60 HIV+ patients, including complete responders (R, n = 44), virologic nonresponders (VNR, n = 5), and immunologic nonresponders (INR, n = 11). The frequency of circulating MDSC and the percentage of activated and naïve CD4 T cells were evaluated by flow cytometry. Plasmatic cytokine levels were analyzed by automated ELISA. As previously observed, polymorphonuclear MDSC (PMN-MDSC) frequency was higher in HIV+ patients compared with healthy donors. Furthermore, PMN-MDSC percentage was higher in INR than R patients, and a significant association between MDSC frequency and immunologic failure was confirmed by a receiver operator characteristic analysis. Accordingly, an inverse correlation was found between the percentages of PMN-MDSC and naïve CD4 T cells. A positive correlation was observed between PMN-MDSC frequency and the percentage of human leucocyte antigen locus DR + CD4 T cells and the plasmatic level of IL-1β and IL-8. Our results show that a high frequency of PMN-MDSC persists in INR, possibly because of immune activation, contributing to CD4 T-cell recovery failure. These findings further highlight the detrimental role of MDSC during HIV infection, suggesting these cells as a possible new therapeutic target.

Development and Validation of a Clinical Prediction Model for the Efficacy of CD19 CAR T-Cell Therapy in DLBCL

Currently, Autologous CD19 chimeric antigen receptor T-cell therapy (CART) has become the most important treatment modality for relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL) beyond conventional multi-line treatments. However, it is worth noting that over 60% of CD19 CAR-T recipients will eventually experience relapse. A substantial amount of clinical research has been conducted to explore the reasons for the ineffectiveness or relapse of CAR-T therapy. Based on a comprehensive analysis of clinical data, we selected various combinations of predictive factors and used the TRIPOD guidelines to construct a logistic regression model for predicting the efficacy of CD19 CAR-T therapy. This study was conducted as a retrospective cohort study, including patients with confirmed diagnosis of DLBCL who underwent CD19 CAR-T therapy and met the following criteria: (1) aged 18 years or older but not exceeding 80 years; (2) voluntarily participated in the study and signed an informed consent form. The exclusion criteria for this study were: (1) addition of other chemotherapy drugs or targeted drugs within 90 days before assessing the best response after infusion, except for those who achieved complete response (CR) or progressive disease (PD); (2) death caused by non-tumor progression factors within 90 days after infusion. After the inclusion and exclusion criteria, a total of 54 patients with DLBCL undergoing CD19 CART at Shanghai Tongji Hospital of Tongji University ultimately participated in this study from January 1, 2019, to April 31, 2023. The derivation cohort consisted of 45 patients enrolled in clinical trials (NCT02537977, NCT03154775, CTR20201986, CTR20200561). The median age of the patients in the derivation cohort was 60 years (IQR: 50-67 years). Out of the 45 participants, 25 (55.6%) were male, and 29 (64.4%) had the non-germinal center B-cell (non-GCB) subtype, 1 had grade 3-4 Cytokine Release Syndrome (CRS). The validation cohort consisted of 9 patients involved in real-world studies. The median age of the patients in the validation cohort was 55 years (IQR: 52.5-69 years). Out of the 9 participants, 5 (55.6%) were male, and 6 (66.7%) had the non-GCB subtype, 2 had grade 3-4 CRS. The demographic and clinical characteristics of the derivation cohort were similar to those of the validation cohort. Based on the best CD19 CART response at 90 days, we divided the derivation cohort into two groups, CR and non-CR. Then, we selected a series of candidate predictive factors from baseline data such as clinical features, genetic features, and laboratory features before CART (Table 1). The results of univariate and multivariate logistic regression analysis were used to select specific factors (Gender, ECOG, TP53) as model prediction indicators based on p-values (p&amp;lt;0.05). There was no significant correlation between these factors (p&amp;gt;0.1). A score nomogram (Model1) was plotted using the regression coefficients of each predictive factor as weights (Fig.1 A), C-index (Model1) =0.872 (Fig.1 C). To facilitate better clinical use, we also constructed a risk nomogram (Model2) to assess the degree of risk (Fig.1 D). Model2 considers three factors: Male, ECOG≥2, TP53 altered. If a person has not any of these risk factors, they are categorized as low risk. If there is one risk factor present, they are deemed to be at moderate risk, whereas having two or more risk factors classifies them as high risk. C-index (Model2) =0.845 (Fig.1 F). Finally, the model's clinical efficacy was validated using real-world CART-treated patients, and the C-index was calculated as Model1=0.875 (Fig.1 G), Model2=0.7 (Fig.1 H), confirming the clinical impact of the model. In conclusion, this study has successfully developed an easily implementable clinical prediction model. For the first time, we have used CART clinical studies as the derivation cohort and real-world results as the validation cohort. Our scoring system provides clinicians with accurate and objective efficacy information, helping them identify the appropriate population for CAR-T therapy in DLBCL.

Asymptomatic peripheral arterial disease in HIV patients in Ghana: A case-control study

BackgroundPeripheral arterial disease (PAD) is common in HIV patients and can be diagnosed noninvasively using the ankle-brachial index (ABI). The burden of PAD has not been investigated in Ghanaian HIV patients. We investigated the prevalence and risk factors associated with PAD in HIV patients at a periurban hospital in Ghana. MethodsIn a case-control design, ABI was measured in 158 cART-treated HIV patients, 150 cART-naïve HIV patients and 156 non-HIV controls with no clinical symptoms of CVDs. PAD was defined as ABI ≤ 0.9. A structured questionnaire was used to collect socio-demographic and clinical data. Fasting venous blood samples were collected to measure plasma levels of glucose, lipid profile, and CD4+ lymphocytes. ResultsThe prevalence of PAD was 13.9% among cART-treated HIV patients, 21.3% among cART-naïve HIV patients, and 15.4% among non-HIV controls. Patients with PAD had increased odds of having low CD4+ cell counts [OR (95% CI) = 3.68 (1.41–12.85)]. In cART-treated HIV patients, those on TDF-based [5.76 (1.1–30.01), p = 0.038] and EFV-based [9.28 (1.51–57.12), p = 0.016] regimens had increased odds of having PAD. ConclusionIn our study population, there was no difference in the prevalence of PAD between cART-treated HIV patients compared to cART-naïve HIV patients or non-HIV controls. Having a low CD4 cell count and being on TDF- or EFV-based regimens were associated with an increased likelihood of having PAD.

Association between cardio-ankle vascular index and cardiometabolic risk factors in HIV patients in Ghana

ABSTRACT Human immunodeficiency virus (HIV) infection is associated with increased cardiovascular diseases (CVDs) even in patients with viral suppression by combination antiretroviral therapy (cART). Arterial stiffness is an independent predictor of CVDs in diseased individuals and the general population. Cardio-ankle vascular index (CAVI) is an index of arterial stiffness that has been shown to predict target organ damage. CAVI is less studied in HIV patients. We compared the levels of arterial stiffness using CAVI and associated factors among cART-treated and cART-naïve HIV patients to those of non-HIV controls. In a case-control design, 158 cART-treated HIV patients, 150 cART-naïve HIV patients and 156 non-HIV controls were recruited from a periurban hospital. We collected data on CVD risk factors, anthropometric characteristics, CAVI, and fasting blood samples to measure plasma glucose, lipid profile, and CD4+ cell counts. Metabolic abnormalities were defined using the JIS criteria. CAVI increased in cART-treated HIV patients compared to cART-naïve HIV patients and non-HIV controls (7.8 ± 1.4 vs 6.6 ± 1.1 vs 6.7 ± 1.4 respectively, p < 0.001). CAVI was associated with metabolic syndrome in non-HIV controls [OR (95% CI) = 2.14 (1.04–4.4), p = 0.039] and cART-naïve HIV patients [1.47 (1.21–2.38), p = 0.015], but not in cART-treated HIV patients [0.81 (0.52–1.26), p = 0.353]. In cART-treated HIV patients, a tenofovir (TDF)-based regimen (β = −0.46, p = 0.023) was associated with decreased CAVI and decreased CD4+ cell count (β = −0.23, p = 0.047) was associated with increased CAVI. In a periurban hospital in Ghana, compared to non-HIV controls or cART-naïve HIV patients, cART-treated HIV patients had increased arterial stiffness measured as CAVI. CAVI is associated with metabolic abnormalities in non-HIV controls and cART-naïve HIV patients, but not in cART-treated HIV patients. Patients on TDF-based regimens had decreased CAVI.

Transforming Growth Factor β Signaling Promotes HIV-1 Infection in Activated and Resting Memory CD4+ T Cells.

Understanding the facilitator of HIV-1 infection and subsequent latency establishment may aid the discovery of potential therapeutic targets. Here, we report the elevation of plasma transforming growth factor β (TGF-β) during acute HIV-1 infection among men who have sex with men (MSM). Using a serum-free in vitro system, we further delineated the role of TGF-β signaling in mediating HIV-1 infection of activated and resting memory CD4+ T cells. TGF-β could upregulate both the frequency and expression of the HIV-1 coreceptor CCR5, thereby augmenting CCR5-tropic viral infection of resting and activated memory CD4+ T cells via Smad3 activation. The production of live HIV-1JR-FL upon infection and reactivation was increased in TGF-β-treated resting memory CD4+ T cells without increasing CD4 expression or inducing T cell activation. The expression of CCR7, a central memory T cell marker that serves as a chemokine receptor to facilitate T cell trafficking into lymphoid organs, was also elevated on TGF-β-treated resting and activated memory CD4+ T cells. Moreover, the expression of CXCR3, a chemokine receptor recently reported to facilitate CCR5-tropic HIV-1 infection, was increased on resting and activated memory CD4+ T cells upon TGF-β treatment. These findings were coherent with the observation that ex vivo CCR5 and CXCR3 expression on total resting and resting memory CD4+ T cells in combination antiretroviral therapy (cART)-naive and cART-treated patients were higher than in healthy individuals. Overall, the study demonstrated that TGF-β upregulation induced by acute HIV-1 infection might promote latency reservoir establishment by increasing infected resting memory CD4+ T cells and lymphoid organ homing of infected central memory CD4+ T cells. Therefore, TGF-β blockade may serve as a potential supplementary regimen for HIV-1 functional cure by reducing viral latency. IMPORTANCE Incomplete eradication of HIV-1 latency reservoirs remains the major hurdle in achieving a complete HIV/AIDS cure. Dissecting the facilitator of latency reservoir establishment may aid the discovery of druggable targets for HIV-1 cure. This study showed that the T cell immunomodulatory cytokine TGF-β was upregulated during the acute phase of infection. Using an in vitro serum-free system, we specifically delineated that TGF-β promoted HIV-1 infection of both resting and activated memory CD4+ T cells via the induction of host CCR5 coreceptor. Moreover, TGF-β-upregulated CCR7 or CXCR3 might promote HIV-1 latent infection by facilitating lymphoid homing or IP-10-mediated viral entry and DNA integration, respectively. Infected resting and central memory CD4+ T cells are important latency reservoirs. Increased infection of these cells mediated by TGF-β will promote latency reservoir establishment during early infection. This study, therefore, highlighted the potential use of TGF-β blockade as a supplementary regimen with cART in acute patients to reduce viral latency.

Metabolic Syndrome and Combination Antiretroviral Therapy in HIV Patients in Periurban Hospital in Ghana: A Case-Control Study.

There is an increasing prevalence of cardiovascular diseases (CVDs) and risk factors in HIV patients as the levels of AIDS-related mortality and morbidity decrease. Metabolic syndrome (MetS) is the accumulation of various CVD risk factors that predict the occurrence of CVDs. We investigated the prevalence of MetS and associated risk factors in HIV patients treated with combination antiretroviral therapy (cART), cART-naïve HIV patients, and non-HIV controls. In a case-control design, 158 cART-treated HIV patients, 150 cART-naïve HIV patients, and 156 non-HIV controls were recruited from a periurban hospital in Ghana. A structured questionnaire was used to collect data on demography, lifestyle, and medication. Anthropometric indices and blood pressure were measured. Fasting blood samples were collected to measure the plasma levels of glucose, lipid profile, and CD4+ cells. The presence of MetS was defined using the joint scientific statement criteria. The prevalence of MetS was higher in cART-treated HIV patients compared with cART-naïve HIV patients and non-HIV controls (57.3% vs. 23.6% vs. 19.2% and p < 0.001, respectively). MetS was associated with cART-treated HIV patients (odds ratio (95% CI) = 7.24 (3.41-15.39) and p < 0.001), cART-naïve HIV patients (2.04 (1.01-4.15), p=0.048), and female gender (2.42 (1.39-4.23) and p=0.002). In cART-treated HIV patients, those on zidovudine (AZT)-based regimens were associated with increased likelihood (3.95 (1.49-10.43) and p < 0.006), while those on tenofovir (TDF)-based had decreased likelihood (0.32 (0.13-0.8) and p=0.015) of having MetS. In our study population, there was a high prevalence of MetS in cART-treated HIV patients compared to cART-naïve HIV patients and non-HIV controls. HIV patients on AZT-based regimens had an increased likelihood of having MetS, while those on TDF-based regimens had a reduced likelihood of having MetS.

Physiological Corticosterone Attenuates gp120-Mediated Microglial Activation and Is Associated with Reduced Anxiety-Like Behavior in gp120-Expressing Mice.

Despite the benefits of combinatorial antiretroviral therapies (cART), virotoxic HIV proteins are still detectable within the central nervous system. Approximately half of all cART-treated patients contend with neurological impairments. The mechanisms underlying these effects likely involve virotoxic HIV proteins, including glycoprotein 120 (gp120). Glycoprotein-120 is neurotoxic due to its capacity to activate microglia. Corticosterone has been found to attenuate neuronal death caused by gp120-induced microglial cytokine production in vitro. However, the concentration-dependent effects of corticosterone on microglial activation states and the associated behavioral outcomes are unclear. Herein, we conducted parallel in vitro and in vivo studies to assess gp120-mediated effects on microglial activation, motor function, anxiety- and depression-like behavior, and corticosterone's capacity to attenuate these effects. We found that gp120 activated microglia in vitro, and corticosterone attenuated this effect at an optimal concentration of 100 nM. Transgenic mice expressing gp120 demonstrated greater anxiety-like behavior on an elevated plus maze, and a greater duration of gp120 exposure was associated with motor deficits and anxiety-like behavior. Circulating corticosterone was lower in gp120-expressing males and diestrous females. Greater circulating corticosterone was associated with reduced anxiety-like behavior. These findings may demonstrate a capacity for glucocorticoids to attenuate gp120-mediated neuroinflammation and anxiety-like behavior.

Inflammation and intracellular exposure of dolutegravir, darunavir, tenofovir and emtricitabine in people living with HIV.

Antiretroviral (ARV) therapy reduces inflammation and immune activation in people with HIV, but not down to the levels observed in people without HIV. Limited drug penetration within tissues has been argued as a potential mechanism of persistent inflammation. Data on the inflammation role on ARV plasma/intracellular (IC) pharmacokinetics (PK) through to expression of cytochrome P450 3A/membrane transporters are limited. The aim of this study was to investigate the correlation between inflammation markers (IM) and plasma/IC PK of ARV regimen in HIV-positive patients. We included ART-experienced patients switching to three different ARV regimens. Plasma and IC ARV drug concentration means at the end of dosing interval (T0 ), IM on samples concomitantly with ARV PK determination: sCD14, CRP, IL-6 and LPS were analysed. Plasma and IC drug concentrations were measured in 60 samples. No significative differences between CRP, sCD14, IL-6 and LPS values in the three arms were observed. A significant inverse correlation between tenofovir plasma concentration and sCD14 (rho = -0.79, P < .001), and between DRV IC/plasma ratio and Log10 IL-6 concentrations (rho = -0.36, P = .040), and a borderline statistically significant positive trend between DRV plasma concentration and sCD14 (rho = 0.31, P = .070) were suggested. Furthermore, a borderline statistically significant inverse trend between DTG IC concentrations and sCD14 (rho = -0.34, P = .090) was observed in 24 patients on DTG-based triple therapy. Our preliminary data support the hypothesis of lower DRV and DTG IC concentrations and lower TFV plasma exposure in patients with higher plasma IM suggesting an interplay between HIV drug penetration and persistent inflammation in cART-treated HIV-positive patients.

CD56dim NK Cell is an Important Factor in T Cell Depletion of cART-Treated AIDS Patients.

PurposeTo investigate factors involved in T-cell depletion in combination antiretroviral therapy (cART)-treated human immunodeficiency virus 1 (HIV-1)-positive patients.Patients and Methods29 HIV-1-positive patients were enrolled. The CD4+, CD8+ T cell subsets and CD56dim NK cells were detected by flow cytometry. The concentrations of cytokines were measured by enzyme-linked immunosorbent assay. Extraction, amplification, and viral load quantification of specimens were performed using the Roche Cobas Ampliprep/Cobas TaqMan HIV-1 test.ResultsCompared with IR group, the total number of red blood cells (RBCs) and lymphocytes (LCs) in INR group was significantly reduced, and there was a significant positive correlation between the number of RBCs and that of LCs. The overall production rates of T cells-related cytokines were lower in INR group. However, the cell-surface expression of programmed death-1 (PD-1) on CD4+ T and CD8+ T cells were markedly elevated in INR group. Moreover, it was found that the proportion and the killing ability of CD56dim NK cells significantly increased in INR patients, and significantly correlated with apoptosis of T lymphocytes.ConclusionA poor immune reconstitution in HIV-positive patients might result from multiple factors, including bone marrow suppression, high PD-1 expression on the surface of CD4+ T cells, and over-activation of T and NK cells. Besides, the activity of NK cells and RBCs count might be important auxiliary indicators for immune reconstitution and provided a reliable guidance for developing strategies to improve immune reconstitution.

Factors Influencing Immune Restoration in People Living with HIV/AIDS.

Introduction: Immune restoration is a key clinical aspect that is pursued in the care of human immunodeficiency virus (HIV)-infected patients. Despite effective antiretroviral treatment and undetectable viremia, immune recovery is often incomplete. Materials and methods: Data from 311 Caucasian patients were collected. SNP in CCR2(rs1799864), CX3CR1(rs3732378), HLAC-35(rs9264942), and CCR5(promoter, rs1799988); a 32bp deletion(Δ32) in CCR5; and HLA-B*5701 genotypes were correlated with clinical data and selected endpoints. Kaplan–Meier and Cox proportional hazards models were used to analyze the effects of genetic factors over time. Results: For HLA-B*5701, the effect on the CD4+/CD8+ >0.8 cell ratio was lost within 48 months (HR = 2.04, 95% CI: 1.04–4.03), and the effect on the CD4+ cell count >500 cells/µL was lost within 12 months (HR = 2.12, CI: 1.11–4.04). The effect of CCR2 GG on the CD4+/CD8+ >0.8 cell ratio was lost within 36 months (HR = 1.7, CI: 1.05–2.75). For CCR5 wt/Δ32, the effect on the CD4+/CD8+ >1.0 cell ratio was lost within 24 months (HR = 2.0, CI: 1.08–3.69), and the effect on the CD4+ >800 cells/µL cell count was lost within 18 months (HR = 1.98, CI: 1.14–4.73). Conclusions: Selected genetic polymorphisms, namely CCR2 GG and CCR5 Δ32, and the presence of the HLA-B*5701 allele positively influenced immune restoration in cART-treated patients with HIV/AIDS.

Altered Glymphatic System in Middle-Aged cART-Treated Patients With HIV: A Diffusion Tensor Imaging Study.

Objective:The brain relies on the glymphatic system to clear metabolic wastes and maintain brain homeostasis to fulfill its functions better. Yet, the complexity of the glymphatic flow and clearance and its changes in HIV infection and its role in neurocognitive dysfunction remain poorly understood. This study aims to explore the impact of HIV and combination antiretroviral therapy (cART) on the glymphatic system and establish a potential biomarker of HIV-associated neurocognitive disorders (HAND).MethodsHere, we examined the glymphatic profiles of middle-aged virosuppressed patients with HIV (n = 27) receiving cART over 1–6 years and healthy controls (n = 28) along the perivascular space (PVS) using diffusion tensor image analysis along the perivascular space (ALPS) with guided and unguided approaches. We later combined data from these analyses to investigate MRI glymphatic correlates of cognitive impairment and other clinical tests of HIV (CD4+ T-cell counts and CD4+/CD8+ ratio).ResultsWe found that glymphatic function as measured by the ALPS index increased significantly in the right and left PVSs of patients with HIV having cART. On antiretroviral therapy, a changing pattern in glymphatic clearance function in patients with HIV having cART correlated with attention and working memory. Duration on cART was also associated with cognitive performances of abstract and executive function and learning and memory.ConclusionThese findings provide MRI evidence of the presence of HIV-induced changes in the glymphatic flow and clearance, which might underlie cognitive impairment among patients with HIV having cART. An increase in the glymphatic activity might reflect a compensatory mechanism to regulate microenvironment homeostasis compromised by HIV. This compensation might be necessary to maintain the proper functioning of the brain while coping with HIV pathology. These findings also shed light on the clinical importance of evaluating glymphatic function based on the ALPS index and suggest that improving the glymphatic system may serve as an alternative therapeutic strategy for HAND.

Hepatitis C Virus Influences HIV-1 Viral Splicing in Coinfected Patients.

Coinfection with hepatitis C virus (HCV) influences HIV reservoir size. However, it is unknown whether this coinfection also induces a higher provirus transcription. Viral transcription is promoted by synergy between cellular factors such as NF-κB and the viral regulator Tat. The impact of HCV coinfection on HIV provirus transcription was analyzed in resting (r)CD4 T+ cells (CD3+CD4+CD25-CD69-HLADR-) and rCD4 T cells-depleted PBMCs (rCD4 T- PBMCs) from a multicenter cross-sectional study of 115 cART-treated HIV patients: 42 HIV+/HCV+ coinfected individuals (HIV+/HCV+), 34 HIV+ patients with HCV spontaneous clearance (HIV+/HCV−) and 39 HIV patients (HIV+). Viral transcription was assessed in total RNA through the quantification of unspliced, single spliced, and multiple spliced viral mRNAs by qPCR. Linear correlations between viral reservoir size and viral splicing were determined. A 3-fold increase of multiple spliced transcripts in rCD4 T+ cells of HIV+/HCV+ patients was found compared to HIV+ individuals (p < 0.05). As Tat is synthesized by multiple splicing, the levels of Tat were also quantified in these patients. Significant differences in single and multiple spliced transcripts were also observed in rCD4 T- PBMCs. Levels of multiple spliced mRNAs were increased in rCD4 T+ cells isolated from HIV+/HCV+ subjects, which could indicate a higher Tat activity in these cells despite their resting state.

Transcriptional signature of resting-memory CD4 T cells differentiates spontaneous from treatment-induced HIV control.

The HIV reservoir is the main barrier to eradicating HIV infection, and resting memory CD4 T (Trm) cells are one of the most relevant cellular component harboring latent proviruses. This is the first study analyzing the transcriptional profile of Trm cells, in two well-characterized groups of HIV patients with distinct mechanisms of viral replication control (spontaneous versus treatment-induced). We use a systems biology approach to unravel subtle but important differences in the molecular mechanisms operating at the cellular level that could be associated with the host's ability to control virus replication and persistence. Despite the absence of significant differences in the transcriptome of Trm cells between Elite Controllers (ECs) and cART-treated (TX) patients at the single gene level, we found 353 gene ontology (GO) categories upregulated in EC compared with TX. Our results suggest the existence of mechanisms at two different levels: first boosting both adaptive and innate immune responses, and second promoting active viral replication and halting HIV latency in the Trm cell compartment of ECs as compared with TX patients. These differences in the transcriptional profile of Trm cells could be involved in the lower HIV reservoir observed in ECs compared with TX individuals, although mechanistic studies are needed to confirm this hypothesis. Combining transcriptome analysis and systems biology methods is likely to provide important findings to help us in the design of therapeutic strategies aimed at purging the HIV reservoir. KEY MESSAGES: HIV-elite controllers have the lowest HIV-DNA content in resting memory CD4 T cells. HIV-ECs show a particular transcriptional profile in resting memory CD4 T cells. Molecular mechanisms of enhanced adaptative and innate immune response in HIV-ECs. High viral replication and low viral latency establishment associate to the EC status.

Underestimated effect of intragenic HIV-1 DNA methylation on viral transcription in infected individuals

BackgroundThe HIV-1 proviral genome harbors multiple CpG islands (CpGIs), both in the promoter and intragenic regions. DNA methylation in the promoter region has been shown to be heavily involved in HIV-1 latency regulation in cultured cells. However, its exact role in proviral transcriptional regulation in infected individuals is poorly understood or characterized. Moreover, methylation at intragenic CpGIs has never been studied in depth.ResultsA large, well-characterized HIV-1 patient cohort (n = 72), consisting of 17 long-term non-progressors and 8 recent seroconverters (SRCV) without combination antiretroviral therapy (cART), 15 early cART-treated, and 32 late cART-treated patients, was analyzed using a next-generation bisulfite sequencing DNA methylation method. In general, we observed low level of promoter methylation and higher levels of intragenic methylation. Additionally, SRCV showed increased promoter methylation and decreased intragenic methylation compared with the other patient groups. This data indicates that increased intragenic methylation could be involved in proviral transcriptional regulation.ConclusionsContrasting in vitro studies, our results indicate that intragenic hypermethylation of HIV-1 proviral DNA is an underestimated factor in viral control in HIV-1-infected individuals, showing the importance of analyzing the complete proviral genome in future DNA methylation studies.

Management of HIV-infected patients in the intensive care unit.

The widespread use of combination antiretroviral therapies (cART) has converted the prognosis of HIV infection from a rapidly progressive and ultimately fatal disease to a chronic condition with limited impact on life expectancy. Yet, HIV-infected patients remain at high risk for critical illness due to the occurrence of severe opportunistic infections in those with advanced immunosuppression (i.e., inaugural admissions or limited access to cART), a pronounced susceptibility to bacterial sepsis and tuberculosis at every stage of HIV infection, and a rising prevalence of underlying comorbidities such as chronic obstructive pulmonary diseases, atherosclerosis or non-AIDS-defining neoplasms in cART-treated patients aging with controlled viral replication. Several patterns of intensive care have markedly evolved in this patient population over the late cART era, including a steady decline in AIDS-related admissions, an opposite trend in admissions for exacerbated comorbidities, the emergence of additional drivers of immunosuppression (e.g., anti-neoplastic chemotherapy or solid organ transplantation), the management of cART in the acute phase of critical illness, and a dramatic progress in short-term survival that mainly results from general advances in intensive care practices. Besides, there is a lack of data regarding other features of ICU and post-ICU care in these patients, especially on the impact of sociological factors on clinical presentation and prognosis, the optimal timing of cART introduction in AIDS-related admissions, determinants of end-of-life decisions, long-term survival, and functional outcomes. In this narrative review, we sought to depict the current evidence regarding the management of HIV-infected patients admitted to the intensive care unit.

Cardiovascular Toxicity and Clinical Outcomes Following Chimeric Antigen Receptor T-Cell Infusion (CART) for Lymphoid Malignancies

<h3>Introduction</h3> CART-cell therapy is associated with dramatic efficacy in patients with relapsed/refractory diffuse large B-cell lymphoma and B-acute lymphoblastic leukemia. However, the efficacy of CART therapy is limited by potentially fatal toxicities including cytokine release syndrome (CRS) and neurotoxicity. Increasingly, emerging reports have suggested the potential for significant hemodynamic collapse following CART therapy. Yet, whether the occurrence of these hemodynamic shifts or any other cardiovascular disease (CVD) events have bearing on clinical outcomes after CART initiation is unknown. <h3>Methods</h3> We evaluated all patients treated with CART therapy for lymphoid malignancies at The Ohio State University James Comprehensive Cancer Center between 2016-2019 and assessed the incidence of CVD events and severe hemodynamic collapse [systolic blood pressure (SBP) cutoff of less than 80 mmHg]. We also evaluated the relationship of CVD events, hemodynamic collapse, and the presence of preceding CVD on overall survival (OS) and progression-free-survival (PFS) following infusion of CART cells utilizing univariate log-rank comparison. <h3>Results</h3> We evaluated 66 patients with 62% male and 38% female with an average age of 60 years (range 23-80). 49 (74%) patients received Yescarta and 17 (26%) patients received Kymriah. With a median follow-up time of 21 months, OS and PFS at 1 year were 72% and 43%, respectively, in concordance with previously reported ZUMA1 and JULIET survival rates. Overall, from 66 CART-treated patients, 14 (21.2%) developed incident CVD events, including 11 patients with arrhythmias and 2 with CHF. The median decrease in peak systolic blood pressure after infusion was 32 mmHg (IQR 22-47 mmHg), noted at a median of 4 days post-CART. Furthermore, after infusion, 17 (25.8%) saw falls in systolic pressure to < 80 mmHg, with 10 (15.2%) developing hypotension requiring vasopressor support. Three of these patients did not have any recovery of their hypotension and died. For patients who developed a SBP < 80 mmHg, there was a significantly impaired PFS at 30 days, 90 days, and 1 year (85%, 54%, and 0%, respectively) versus those who did not develop SBP < 80 mmHg PFS (100%, 83%, and 49%, respectively), p = 0.014 (figure). OS demonstrated similar results at 30 days, 90 days, and 1 year (85%, 54%, and 14%, respectively), compared to 100%, 83%, and 49.1%, respectively, p = 0.03. There was no difference in PFS or OS, based on the presence of neurotoxicity, steroid use, vasopressor use, preceding cardiovascular risk factors, or the development of other non-hypotension CVD events. <h3>Conclusion</h3> The development of significant early hypotension is associated with a marked decrease in survival among patients receiving CART therapy. Further understanding of this finding, and its relation to CRS is urgently needed in order to maximize the effectiveness of this novel anticancer therapy.

The Increase of HIV-1 Infection, Neurocognitive Impairment, and Type 2 Diabetes in The Rio Grande Valley.

The Human Immunodeficiency Virus (HIV-1) infection remains a persistent predicament for the State of Texas, ranking seventh among the most documented HIV cases in the United States. In this regard, the Rio Grande Valley (RGV) in South Texas is considered as one of the least investigated areas of the state with respect to HIV infection and HIV associated comorbidities. Considering the 115% increase in average HIV incidence rates per 100,000 within the RGV from 2007-2015, it is worth characterizing this population with respect to their HIV-1 infection, HIV-1 Associated Neurocognitive Disorders (HAND), and the association of treatment with combined antiretroviral therapy (cART). Moreover, the increased rate of Type-2 Diabetes (T2D) in the RGV population is intertwined with that of HIV-1 infection facing challenges due to the lack of knowledge about prevention to inadequate access to healthcare. Hence, the role of T2D in the development of HAND among the people living with HIV (PLWH) in the RGV will be reviewed to establish a closer link between T2D and HAND in cART-treated patients of the RGV.

Immunological recovery failure in cART-treated HIV-positive patients is associated with reduced thymic output and RTE CD4+ Tcell death by pyroptosis.

Despite more than three decades of studies and advances in combination antiretroviral therapy (cART) against human immunodeficiency virus (HIV), the mechanisms that precisely determine immune reconstitution failure have not been completely elucidated yet. Thus, this study aimed to investigate the thymic function, immune activation, and cell death by pyroptosis and apoptosis in virologically suppressed HIV-positive patients receiving cART. Immunophenotyping analyses were performed in 57 cART-treated HIV-infected patients with undetectable plasma viral load, who were classified as immunological nonresponders (INR=29) and immunologic responders (IR=28). Sociodemographic and clinical data were also assessed from medical records. Twelve healthy volunteers were also included in this study. The INR showed lower pretreatment CD4+ Tcell count that remained low even after 1 yr of treatment, lower CD4/CD8 ratio, lower percentage of recent thymic emigrant (RTE) CD4+ Tcell (CD45RA+CD31+) and naïve CD4+ Tcell (CD45RA+CD62L+), higher levels of effector memory CD4+ Tcells (CD45RA-CD62L-), and higher pyroptosis levels of RTE CD4+ Tcells (CD31+FLICA-Caspase1+) when compared with IR. Our findings indicate that reduced thymic function and RTE CD4+ Tcell death by pyroptosis are the major mechanisms of immunological recovery failure in HIV-infected patients receiving cART.