A role for CD4 helper cells in HIV control and progression

It remains unclear why HIV persists in most untreated individuals, and why a small minority of individuals can control the virus, either spontaneously or after an early treatment. The present work motivated by the striking differences in the functional avidity of CD4 T cells discovered between patient cohorts in a recent study [1] offers an experimentally–testable mathematical model that explains the diverse outcome of infection. The model predicts an arms race between viral dissemination and the proliferation of HIV-specific CD4 helper cells leading to one of two states: a low-viremia state or a high-viremia state. Helper CD4 cells with a higher avidity favor virus control. The parameter segregating spontaneous and post-treatment controllers is the infectivity asymmetry between activated and resting CD4 T cells. The predictions are found to be consistent with the data from [1] and with data on the avidity CD8 T cells [2]. I also analyze the alternative explanation of T cell exhaustion previously proposed to explain the diverse patient cohorts and demonstrate that it does not explain these and some other experimental data.

Twenty-Four–Hour Central (Aortic) Systolic Blood Pressure: Reference Values and Dipping Patterns in Untreated Individuals

Central (aortic) systolic blood pressure (cSBP) is the pressure seen by the heart, the brain, and the kidneys. If properly measured, cSBP is closer associated with hypertension-mediated organ damage and prognosis, as compared with brachial SBP (bSBP). We investigated 24-hour profiles of bSBP and cSBP, measured simultaneously using Mobilograph devices, in 2423 untreated adults (1275 women; age, 18–94 years), free from overt cardiovascular disease, aiming to develop reference values and to analyze daytime-nighttime variability. Central SBP was assessed, using brachial waveforms, calibrated with mean arterial pressure (MAP)/diastolic BP (cSBP MAP/DBPcal ), or bSBP/diastolic blood pressure (cSBP SBP/DBPcal ), and a validated transfer function, resulting in 144 509 valid brachial and 130 804 valid central measurements. Averaged 24-hour, daytime, and nighttime brachial BP across all individuals was 124/79, 126/81, and 116/72 mm Hg, respectively. Averaged 24-hour, daytime, and nighttime values for cSBP MAP/DBPcal were 128, 128, and 125 mm Hg and 115, 117, and 107 mm Hg for cSBP SBP/DBPcal , respectively. We pragmatically propose as upper normal limit for 24-hour cSBP MAP/DBPcal 135 mm Hg and for 24-hour cSBP SBP/DBPcal 120 mm Hg. bSBP dipping (nighttime-daytime/daytime SBP) was −10.6 % in young participants and decreased with increasing age. Central SBP SBP/DBPcal dipping was less pronounced (−8.7% in young participants). In contrast, cSBP MAP/DBPcal dipping was completely absent in the youngest age group and less pronounced in all other participants. These data may serve for comparison in various diseases and have potential implications for refining hypertension diagnosis and management. The different dipping behavior of bSBP versus cSBP requires further investigation.

Effect of HIV‐1 Infection on Angiopoietin 1 and 2 Levels and Measures of Microvascular and Macrovascular Endothelial Dysfunction

Background Individuals infected with HIV have an increased risk of developing cardiovascular disease; yet, the underlying mechanisms remain unknown. Recent evidence has implicated the Tie‐2 tyrosine kinase receptor system and its associated ligands ANG1 (angiopoietin 1) and ANG2 (angiopoietin 2) in maintaining vascular homeostasis. In the general population, lower ANG1 levels and higher ANG2 levels are strongly correlated with the development of cardiovascular disease. In this study, we aim to investigate the associations of HIV infection with angiopoietin levels and endothelial dysfunction. Methods and Results In this cross‐sectional study, we compared measures of ANG1, ANG2, and endothelial dysfunction using flow‐mediated vasodilation of the brachial artery in 39 untreated subjects infected with HIV, 47 treated subjects infected with HIV, and 46 uninfected subjects from the SCOPE (Observational Study of the Consequences of the Protease Inhibitor Era) cohort. Compared with uninfected controls, treated individuals infected with HIV had 53.1% lower mean ANG1 levels ( P <0.01) and similar ANG2 levels. On the other hand, untreated individuals infected with HIV had similar ANG1 levels, and 29.2% had higher ANG2 levels ( P <0.01) compared with uninfected controls. When compared with individuals with untreated HIV infection, those with treated HIV infection had 56% lower ANG1 levels ( P <0.01) and 22% lower ANG2 levels ( P <0.01).Both treated and untreated HIV infection were associated with significant impairment in hyperemic velocity, a key measure of microvascular dysfunction (median 61 versus 72 cm/s, P <0.01), compared with uninfected controls (median 73 cm/s). This difference persisted after adjustment for ANG1 and ANG2 levels. Interestingly, when compared with untreated individuals infected with HIV, treated individuals infected with HIV had worse hyperemic velocity (−12.35 cm/s, P =0.05). In contrast, HIV status, ANG1 levels, and ANG2 levels were not associated with macrovascular dysfunction as measured by flow‐mediated dilatation and brachial artery diameter, 2 other measures of vascular homeostasis. Conclusions HIV infection affects the balance between levels of ANG1 and ANG2 and may disturb endothelial homeostasis through disruption of vascular homeostasis. Individuals with treated HIV had decreased ANG1 levels and similar ANG2 levels, whereas individuals with untreated HIV had similar ANG1 levels and increased ANG2 levels, suggesting that treatment status may alter the balance between ANG1 and ANG2. HIV also promotes endothelial dysfunction via impairment of microvascular dysfunction, independent of the Tie‐2 receptor system; the finding of worse microvascular dysfunction in the setting of treated HIV infection may reflect the impact of viral persistence on the microvasculature or toxicities of specific antiretroviral regimens. Further research to clarify the mechanism of HIV‐mediated endothelial dysfunction is necessary to advance treatment of cardiovascular complications of HIV infection.

The Triangulation WIthin a STudy (TWIST) framework for causal inference within pharmacogenetic research

In this paper we review the methodological underpinnings of the general pharmacogenetic approach for uncovering genetically-driven treatment effect heterogeneity. This typically utilises only individuals who are treated and relies on fairly strong baseline assumptions to estimate what we term the ‘genetically moderated treatment effect’ (GMTE). When these assumptions are seriously violated, we show that a robust but less efficient estimate of the GMTE that incorporates information on the population of untreated individuals can instead be used. In cases of partial violation, we clarify when Mendelian randomization and a modified confounder adjustment method can also yield consistent estimates for the GMTE. A decision framework is then described to decide when a particular estimation strategy is most appropriate and how specific estimators can be combined to further improve efficiency. Triangulation of evidence from different data sources, each with their inherent biases and limitations, is becoming a well established principle for strengthening causal analysis. We call our framework ‘Triangulation WIthin a STudy’ (TWIST)’ in order to emphasise that an analysis in this spirit is also possible within a single data set, using causal estimates that are approximately uncorrelated, but reliant on different sets of assumptions. We illustrate these approaches by re-analysing primary-care-linked UK Biobank data relating to CYP2C19 genetic variants, Clopidogrel use and stroke risk, and data relating to APOE genetic variants, statin use and Coronary Artery Disease.

Changes in the Prevalence of Metabolic Syndrome, Its Components, and Relevant Preventive Medication between 2011 and 2018 in the Northeast Hungarian Roma Population

Metabolic syndrome (MetS) is a cluster of clinical conditions that poses a major health burden worldwide. In the present study, we investigate the changes in the prevalence of MetS and its components among the Roma in two disadvantaged counties in Northeastern Hungary focusing on a seven-year-long period. The database of the present study is based on cross-sectional surveys of the Hungarian Roma population (aged 20–64 years) conducted in 2011 (n = 458) and 2018 (n = 374). The increase in the prevalence of MetS itself in the whole Roma population was not found to be significant in the period examined (although it increased from 40.0% up to 46.0%, p = 0.080); however, regarding its components, there was a significant increase in the prevalence of central obesity (from 62.7% to 73.3%, p = 0.001) and raised blood pressure (BP) or treated hypertension (from 45.2% to 54.5%, p = 0.007). These changes were mainly observed in the younger age groups, so the risk for MetS increased significantly in the 20–34 (OR = 1.10, p = 0.038) and 35–49 (OR = 1.07, p = 0.048) year age groups in the 2018 study population compared the 2011 one. The increasing prevalence of hidden hypertension and, consequently, untreated individuals with raised BP (from 29.6% to 43.5%, p = 0.014) among females is quite alarming; therefore, a targeted public health strategy and targeted interventions are desperately needed to prevent further worsening of the current situation.

Evaluation of splenic accumulation and colocalization of immature reticulocytes and Plasmodium vivax in asymptomatic malaria: A prospective human splenectomy study

Background A very large biomass of intact asexual-stage malaria parasites accumulates in the spleen of asymptomatic human individuals infected with Plasmodium vivax. The mechanisms underlying this intense tropism are not clear. We hypothesised that immature reticulocytes, in which P. vivax develops, may display high densities in the spleen, thereby providing a niche for parasite survival. Methods and findings We examined spleen tissue in 22 mostly untreated individuals naturally exposed to P. vivax and Plasmodium falciparum undergoing splenectomy for any clinical indication in malaria-endemic Papua, Indonesia (2015 to 2017). Infection, parasite and immature reticulocyte density, and splenic distribution were analysed by optical microscopy, flow cytometry, and molecular assays. Nine non-endemic control spleens from individuals undergoing spleno-pancreatectomy in France (2017 to 2020) were also examined for reticulocyte densities. There were no exclusion criteria or sample size considerations in both patient cohorts for this demanding approach. In Indonesia, 95.5% (21/22) of splenectomy patients had asymptomatic splenic Plasmodium infection (7 P. vivax, 13 P. falciparum, and 1 mixed infection). Significant splenic accumulation of immature CD71 intermediate- and high-expressing reticulocytes was seen, with concentrations 11 times greater than in peripheral blood. Accordingly, in France, reticulocyte concentrations in the splenic effluent were higher than in peripheral blood. Greater rigidity of reticulocytes in splenic than in peripheral blood, and their higher densities in splenic cords both suggest a mechanical retention process. Asexual-stage P. vivax-infected erythrocytes of all developmental stages accumulated in the spleen, with non-phagocytosed parasite densities 3,590 times (IQR: 2,600 to 4,130) higher than in circulating blood, and median total splenic parasite loads 81 (IQR: 14 to 205) times greater, accounting for 98.7% (IQR: 95.1% to 98.9%) of the estimated total-body P. vivax biomass. More reticulocytes were in contact with sinus lumen endothelial cells in P. vivax- than in P. falciparum-infected spleens. Histological analyses revealed 96% of P. vivax rings/trophozoites and 46% of schizonts colocalised with 92% of immature reticulocytes in the cords and sinus lumens of the red pulp. Larger splenic cohort studies and similar investigations in untreated symptomatic malaria are warranted. Conclusions Immature CD71+ reticulocytes and splenic P. vivax-infected erythrocytes of all asexual stages accumulate in the same splenic compartments, suggesting the existence of a cryptic endosplenic lifecycle in chronic P. vivax infection. Findings provide insight into P. vivax-specific adaptions that have evolved to maximise survival and replication in the spleen.

The Triangulation WIthin A STudy (TWIST) framework for causal inference within Pharmacogenetic research

In this paper we review the methodological underpinnings of the general pharmacogenetic approach for uncovering genetically-driven treatment effect heterogeneity. This typically utilises only individuals who are treated and relies on fairly strong baseline assumptions to estimate what we term the `genetically mediated treatment effect' (GMTE). When these assumptions are seriously violated, we show that a robust but less efficient estimate of the GMTE that incorporates information on the population of untreated individuals can instead be used. In cases of partial violation, we clarify when Mendelian randomization and a modified confounder adjustment method can also yield consistent estimates for the GMTE. A decision framework is then described to decide when a particular estimation strategy is most appropriate and how specific estimators can be combined to further improve efficiency. Triangulation of evidence from different data sources, each with their inherent biases and limitations, is becoming a well established principle for strengthening causal analysis. We call our framework `Triangulation WIthin a STudy' (TWIST)' in order to emphasise that an analysis in this spirit is also possible within a single data set, using causal estimators that are approximately statistically uncorrelated, but reliant on different sets of assumptions. We illustrate these approaches by re-analysing primary-care-linked UK Biobank data relating to CYP2C19 genetic variants, Clopidogrel use and stroke risk, and data relating to APOE genetic variants, statin use and Coronary Artery Disease.

Diagnostic Accuracy with Total Adenosine Deaminase as a Biomarker for Discriminating Pleural Transudates and Exudates in a Population-Based Cohort Study

Background. An initial step in the evaluation of patients with pleural effusion syndrome (PES) is to determine whether the pleural fluid is a transudate or an exudate. Objectives. To investigate total adenosine deaminase (ADA) as a biomarker to classify pleural transudates and exudates. Methods. An assay of total ADA in pleural fluids (P-ADA) was observed using a commercial kit in a population-based cohort study. Results. 157 pleural fluid samples were collected from untreated individuals with PES due to several causes. The cause most prevalent in transudate samples (21%, n = 33 / 157 ) was congestive heart failure (79%, 26/33) and that among exudate samples (71%, n = 124 / 157 ) was tuberculosis (28.0%, 44/124). There was no significant difference in the proportion of either sex between the transudate and exudate groups. The median values of P-ADA were significantly different ( P < 0.0001 ) between both total exudates (18.4 U/L; IQR, 9.85-41.4) and exudates without pleural tuberculosis (11.0 U/L; IQR, 7.25-19.75) and transudates (6.85; IQR, 2.67-11.26). For exudates, the AUC was 0.820 (95% CI, 0.751-0.877; P < 0.001 ), with excellent discrimination. The optimum cut-off point in the ROC curve was determined as the level that provided the maximum positive likelihood ratio (PLR; 14.64; 95% CI, 2.11-101.9) and was22.0 U/L. For transudates, the AUC was 0.8245 (95% CI, 0.7470-0.9020; P < 0.0001 ). Internal validation of the AUC after 1000 resamples was evaluated with a tolerance minor than 2%. The clinical utility was equal to 92% (95% CI, 0.84 to 0.96, P < 0.05 ).Conclusions. P-ADA is a useful biomarker for distinguishing pleural exudates from transudates.

HIV-1 Accessory Proteins: Which one is Potentially Effective in Diagnosis and Vaccine Development?

Background:: The combination antiretroviral therapy (cART) could increase the number of circulating naive CD4 T lymphocytes, but was not able to eradicate human immunodeficiency virus-1 (HIV-1) infection. Objective:: Thus, induction of strong immune responses is important for control of HIV-1 infection. Furthermore, a simple and perfect serological method is required to detect virus in untreated-, treated- and drug resistant- HIV-1 infected individuals. Methods:: This study was conducted to assess and compare immunogenic properties of Nef, Vif, Vpr and Vpu accessory proteins as an antigen candidate in mice and their diagnostic importance in human as a biomarker. Results:: Our data showed that in mice, all heterologous prime/ boost regimens were more potent than homologous prime/ boost regimens in eliciting Th1 response and Granzyme B secretion as CTL activity. Moreover, the Nef, Vpu and Vif proteins could significantly increase Th1 immune response. In contrast, the Vpr protein could considerably induce Th2 immune response. On the other hand, among four accessory proteins, HIV-1 Vpu could significantly detect treated group from untreated group as a possible biomarker in human. Conclusion:: Generally, among accessory proteins, Nef, Vpu and Vif antigens were potentially more suitable vaccine antigen candidates than Vpr antigen. Human antibodies against all these proteins were higher in HIV-1 different groups than healthy group. Among them, Vpu was known as a potent antigen in diagnosis of treated from untreated individuals. The potency of accessory proteins as an antigen candidate in an animal model and a human cohort study are underway.