Baseline characteristics of people living with HIV with different CD4(+) T cell depletion.

People living with HIV-1 (PLWH) treated with combination antiretroviral therapy (cART) have similar incidence of SARS-CoV-2 infection compared to people without HIV-1 (PWoH). Yet, roughly 25% PLWH worldwide are currently not accessing cART. The influence of CD4+ T cell depletion on human coronavirus (HCoV) (re)infection risk, including SARS-CoV-2, is largely unknown. In this research, we investigated the incidence of infection by the four endemic HCoVs (HCoV-NL63, HCoV-229E, HCoV-OC43, and HCoV-HKU1), to inform on future reinfections by SARS-CoV-2. We compared the HCoV infection incidence rate between PLWH (n = 24) and PWoH (n = 25) who were followed up in 1984–1993; i.e., before cART became generally available in high income countries. Both populations were followed up at 6-month intervals for 7 or 8 years. We also compared the HCoV infection incidence rate among PLWH with and without immune deficiency, defined as CD4+ T cell count < 350 cell/mm3 and > 350 cell/mm3 respectively. We found that the antibody levels for all HCoVs were significantly lower in PLWH than PWoH across all timepoints. However, we observed no significant difference on HCoV infection incidence rate between PLWH and PWoH. We also observed no difference in HCoV infection incidence rate among PLWH with and without immune deficiency. We conclude that PLWH not on cART may not be at increased risk of HCoV reinfections.

BackgroundImmune cells and cytokines have been linked to viremia dynamic and immune status during HIV infection. They may serve as useful biomarkers in the monitoring of people living with HIV-1 (PLHIV-1). The present work was aimed to assess whether cytokines and immune cell profiles may help in the therapeutic follow-up of PLHIV-1.MethodsForty PLHIV-1 in treatment success (PLHIV-1s) and fifty PLHIV-1 in treatment failure (PLHIV-1f) followed at the University Hospital of Abomey-Calavi/Sô-Ava in Benin were enrolled. Twenty healthy persons were also recruited as control group. Circulating cytokines and immune cells were quantified respectively by ELISA and flow cytometry.ResultsPLHIV-1 exhibited low proportions of CD4 + T cells, NK, NKT, granulocytes, classical and non-classical monocytes, and high proportions of CD8 + T cells, particularly in the PLHIV-1f group, compared to control subjects. Eosinophils, neutrophils and B cell frequencies did not change between the study groups. Circulating IFN-γ decreased whereas IL-4 significantly increased in PLHIV-1s compared to PLHIV-1f and control subjects even though the HIV infection in PLHIV-1s downregulated the high Th1 phenotype observed in control subjects. However, Th1/Th2 ratio remained biased to a Th1 phenotype in PLHIV-1f, suggesting that high viral load may have maintained a potential pro-inflammatory status in these patients. Data on inflammatory cytokines showed that IL-6 and TNF-α concentrations were significantly higher in PLHIV-1s and PLHIV-1f groups than in control subjects. Significant high levels of IL-5 and IL-7 were observed in PLHIV-1f compared to controls whereas PLHIV-1s presented only a high level of IL-5. No change was observed in IL-13 levels between the study groups.ConclusionOur study shows that, in addition to CD4/CD8 T cell ratio, NK and NKT cells along with IL-6, TNF-α, IL-5 and IL-7 cytokines could serve as valuable immunological biomarkers in the therapeutic monitoring of PLHIV-1 although a larger number of patients would be necessary to confirm these results.

Limited efficiency of endogenous interleukin-7 levels in T cell reconstitution during HIV-1 infection: will exogenous interleukin-7 therapy work?

Nicotinamide mononucleotide impacts HIV-1 infection by modulating immune activation in T lymphocytes and humanized mice

Sepsis is the third leading cause of death in neonates after asphyxia and low birth weight babies (LBW). Abnormal blood glucose, both hypoglycemia and hyperglycemia, were common metabolic changes in neonatal sepsis. This condition can higher the risk of morbidity and mortality in neonatal sepsis. The aim of this study is to prove the difference in mortality of neonatal sepsis with abnormal blood glucose compared to normal blood glucose. This was a cohort retrospective study with subjects were neonate with 28-42 weeks of gestational age with neonatal sepsis confirmed from clinical sign or blood culture at neonatal ward Sanglah hospital in the period January-August 2020. Subjects were classified as abnormal and normal blood glucose level. <i>Chi-square</i> test was used to assess the difference of mortality in blood glucose level. Multivariate analysis was performed with logistic regression. A total of 64 subjects with abnormal blood glucose and 64 subjects with normal blood glucose were included in this study. Mortality in subject with abnormal blood glucose was 50% and 17.2% with normal blood glucose (<I>P</I><0,005). Multivariate analysis found abnormal blood glucose increases the risk of mortality 3,04 times compare with normal blood glucose (95% CI 1.09 to 8,45, <I>P</I><0.033). Mechanical ventilation and asphyxia can also increase the risk of mortality in neonatal sepsis by 12,33 times (95% CI 3,99 to 38,07, <I>P</I><0,001) and 8.17 times (95% CI 2,35 to 28,37, <I>P</I><0,001) respectively. Subanalysis found hypoglycemia increases the risk of mortality 3.75 times compare to normoglycemia (95% CI 2.06 to 6.82, <I>P</I><0.005), and hyperglycemia increases the risk of mortality 2.12 times compare to normoglycemia (95% CI 1.04 to 4.26, <I>P</I>=0.035). Conclusion there are significant difference of mortality in neonatal sepsis with abnormal blood glucose which is higher than normal blood glucose level. This research also found mechanical ventilation and asphyxia can effect the mortality in neonatal sepsis.

BackgroundOlder people living with HIV-1 (PLWH) experience a dual burden from the combined effects of aging and HIV-1 infection, resulting in significant immune dysfunction. Despite receiving HAART, immune reconstitution is not fully optimized. The objective of this study was to investigate the impact of aging and HAART on T cell subsets and function in PLWH across different age groups, thereby providing novel insights into the prognosis of older PLWH.MethodThis study was conducted at Yunnan AIDS Care Center, China, to explore the immunological responses of old PLWH to HAART and compared with the middle-age and the younger. Blood samples were collected from 146 PLWH to analyze T cell subsets and their functions, with a particular emphasis on markers related to T cell differentiation, activation, exhaustion, inflammation, and cellular function, using multicolor flow cytometry analysis.ResultsOlder age may have a greater effect on long-term CD4+T cell recovery. Compared with young and middle-aged PLWH, older PLWH presented distinct alterations in their immune profile, including a decline in the Naïve CD4+T and CD8+T cell subsets, an expansion of effector memory cells, and other potential immune risk phenotypes, such as activation, exhaustion, and up-regulation of aging markers. In addition, we observed a significant association between the CD4 + EM3 subset and the CD8 + EM2 subset with HIV-1 progression, independent of age, suggesting their potential as reliable markers for assessing immune reconstitution in all PLWH.ConclusionOur study extends previous findings showing that older participants exhibit a wide range of late differentiation, senescence, or exhaustion phenotypes in cells, including all the CD4+T and CD8+T subsets, consistent with an immunosenescent phenotype. This may accelerate poor immune recovery in older PLWH. Identifying new strategies to improve the immune risk phenotypes of older PLWH may help improve their immune reconstitution outcomes. The CD4 + EM3 subset and the CD8 + EM2 subset should be studied as additional markers of late presentation.

HIV-1 infection has been associated with increased COVID-19-related hospitalization and greater SARS-CoV-2 shedding. People living with HIV-1 (PLWH) also have higher risks to other respiratory infections and lower response rates to influenza and pneumococcal vaccines, even after antiretroviral therapy. This observational study evaluated serum antibody responses after mRNA COVID-19 vaccination in elderly male cohorts of PLWH on antiretroviral therapy and people without HIV-1 (PWOH). Specifically we measured the titers, isotypes/subtypes, and functions of antibodies after the third dose of mRNA COVID-19 vaccines. SARS-CoV-2-specific total immunoglobulin (Ig) titers were significantly higher in blood samples from PLWH vs. PWOH. Notably, PLWH had higher levels of IgG2 and IgG4, two IgG subtypes with minimal Fc activities. Correspondingly, lower Fc capacities were displayed by PLWH, and they correlated inversely with SARS-CoV-2-specific IgG4 levels. Our data point to changes in SARS-CoV-2-specific antibody distribution elicited in PLWH after mRNA COVID-19 vaccinations, resulting in the curtailments in the Fc functionalities that may contribute to suboptimal antiviral responses.

Plasmacytoid dendritic cells (pDCs) rapidly produce type I interferon (IFN-I) in response to acute virus infections. During chronic HIV-1 infection, persistent activation of pDCs contributes to inflammatory diseases. Combination antiretroviral therapy (cART) effectively suppresses HIV-1 replication and prolongs the life span of people living with HIV-1 (PLWH). The persistence of viral reservoir cells under cART, however, is associated with suboptimal immune reconstitution, impaired anti-HIV immunity, and non-AIDS-defining inflammatory diseases through unclear mechanisms. We report here that pDC depletion in HIV-infected humanized mice with suppressive cART alleviated HIV-associated inflammation, reversed T cell immune exhaustion, enhanced HIV-specific CD8+ T cell responses, and reduced HIV-1 reservoirs in lymphoid and nonlymphoid tissues through CD8+ T cell-dependent mechanisms. Specifically, pDC depletion in the mice led to an increase in TCF-1+PD-1+Tim-3- stem-like memory CD8+ T cells in HIV-infected lymphoid tissues, which correlated with a reduction in the HIV-1 reservoir. We further showed that pDCs suppressed the polyfunctional activity of anti-HIV stem-like memory CD8+ T cells isolated from PLWH in vitro. As in the HIV-infected humanized mice, pDC depletion or IFN-I blockade functionally rescued the stem-like memory CD8+ T cells, enhancing their anti-HIV responses. Combination therapy with PD-1 blockade further improved stem-like memory T cell function both in vitro and in HIV-infected humanized mice. Our findings indicate that HIV-induced inflammatory pDCs impair anti-HIV stem-like memory CD8+ T cell responses and suggest that the combination of pDC depletion with PD-1 immune checkpoint blockade represents a candidate therapeutic approach to treating HIV-1 infection and its associated inflammatory diseases.

HIV-1 infection is associated with multiple procoagulant changes and increased thrombotic risk. Possible mechanisms for this risk include heigthened expression of procoagulant tissue factor (TF) on circulating monocytes, extracellular vesicles, and viral particles and/or acquired deficiency of protein S (PS), a critical cofactor for the anticoagulant protein C (PC). PS deficiency occurs in up to 76% of people living with HIV-1 (PLWH). As increased ex vivo plasma thrombin generation is a strong predictor of mortality, we investigated whether PS and plasma TF are associated with plasma thrombin generation. We analyzed plasma samples from 9 healthy controls, 17 PLWH on first diagnosis (naive), and 13 PLWH on antiretroviral therapy (ART). Plasma thrombin generation, total and free PS, PC, C4b-binding protein, and TF activity were measured. We determined that the plasma thrombin generation assay is insensitive to PS, because of a lack of PC activation, and developed a modified PS-sensitive assay. Total plasma PS was reduced in 58% of the naive and 38% of the ART-treated PLWH samples and correlated with increased thrombin generation in the modified assay. Conversely, plasma TF was not increased in our patient population, suggesting that it does not significantly contribute to ex vivo plasma thrombin generation. These data suggest that reduced total plasma PS contributes to the thrombotic risk associated with HIV-1 infection and can serve as a prothrombotic biomarker. In addition, our refined thrombin generation assay offers a more sensitive tool to assess the functional consequences of acquired PS deficiency in PLWH.

Integrase strand transfer inhibitor-based regimens (eg, containing dolutegravir [DTG]) are associated with weight/body mass index (BMI) increases among people living with HIV-1 (PLWH). Assessing antiretroviral therapy (ART)-related weight/BMI changes is challenging, as PLWH may experience return-to-health weight gain as a result of viral suppression. This retrospective, longitudinal real-world study compared weight/BMI outcomes among overweight/obese (BMI ≥25 kg/m2; thus excluding return-to-health weight/BMI changes), treatment-naïve PLWH who initiated darunavir (DRV)/cobicistat (c)/emtricitabine (FTC)/tenofovir alafenamide (TAF) or DTG + FTC/TAF. Treatment-naïve PLWH with BMI ≥25 kg/m2 who initiated DRV/c/FTC/TAF or DTG + FTC/TAF (index date) had ≥12 months of baseline observation and ≥1 weight/BMI measurement in baseline and post-index periods in the Symphony Health IDV® database (07/17/2017-12/31/2021) were included. Inverse probability of treatment weighting (IPTW) was used to balance differences in baseline characteristics between cohorts. On-treatment time-to-weight/BMI increases ≥5% were compared between cohorts using weighted adjusted Cox models. Post-IPTW, 76 overweight/obese DRV/c/FTC/TAF-treated (mean age = 51.2 years, 30.7% female, 35.6% Black, mean baseline BMI = 33.2 kg/m2) and 88 overweight/obese DTG + FTC/TAF-treated PLWH (mean age = 51.5 years, 31.4% female, 31.4% Black, mean baseline BMI = 32.7 kg/m2) were included. The median [interquartile range] time from ART initiation to weight/BMI increase ≥5% was shorter for the DTG + FTC/TAF cohort (21.8 [9.9, 32.3] months) than the DRV/c/FTC/TAF cohort (median and interquartile times not reached; Kaplan-Meier rate at 21.8 months = 20.8%). Over the entire follow-up, overweight/obese PLWH initiating DTG + FTC/TAF had a more than twofold greater risk of experiencing weight/BMI increase ≥5% compared to those initiating DRV/c/FTC/TAF (hazard ratio [95% confidence interval]=2.43 [1.02; 7.04]; p = 0.036). Overweight/obese PLWH who initiated DTG + FTC/TAF had significantly greater risk of weight/BMI increase ≥5% compared to similar PLWH who initiated DRV/c/FTC/TAF and had shorter time-to-weight/BMI increase ≥5%, suggesting a need for additional monitoring to assess the risk of weight gain-related cardiometabolic disease.

Extinguish the Fire: Anti-inflammatory Strategies for Over Immune Activation in Chronic HIV-1 Infection

Clinical Safety and Efficacy Of Nilotinib Or Dasatinib In Patients (Pts) With Newly Diagnosed Chronic-Phase Chronic Myelogenous Leukemia (CML-CP) With Pre-Existing Liver and/Or Renal Dysfunction

IntroductionAntiretroviral therapy (ART) has been associated with weight gain in people living with HIV-1 (PLWH); however, limited research has assessed whether early weight gain post-ART initiation is associated with metabolic or cardiovascular outcomes among PLWH at high risk of weight gain (i.e., female, Black or Hispanic). This study aimed to evaluate the incidence of metabolic and cardiovascular outcomes between PLWH at high risk of weight gain following an observed ≥ 5% or < 5% weight/body mass index (BMI) gain within 6 months following ART initiation.MethodsA retrospective longitudinal study using Symphony Health, an ICON plc Company, IDV® electronic medical records (October 1, 2014–March 31, 2021) identified adult female, Black, or Hispanic treatment-naïve PLWH who initiated ART and who had ≥ 1 weight or BMI measurement pre- and within 6 months post-treatment (landmark period). Inverse probability of treatment weighting was used to account for differences between PLWH who experienced ≥ 5% and < 5% weight/BMI gain. The time to each outcome was compared between cohorts using weighted hazard ratios (HRs) after the landmark period.ResultsWeighted ≥ 5% and < 5% cohorts included 620 and 632 patients, respectively; baseline characteristics were similar between the two cohorts (mean age: ~ 48 years, ~ 59% female, ~ 49% Black, ~ 17% Hispanic). During a mean 2-year follow-up, PLWH with ≥ 5% weight/BMI gain were significantly more likely to be diagnosed with type 2 diabetes mellitus (T2DM; HR = 2.19; p = 0.044). There were no significant differences in the incidence of any other outcomes between the study cohorts.ConclusionDespite a short 2-year follow-up, female, Black or Hispanic PLWH experiencing ≥ 5% weight/BMI increase within 6 months following ART initiation had an increased risk of T2DM, but not other metabolic or cardiovascular outcomes, likely due to the short follow-up period. Further research with longer follow-up and specific ART regimens is warranted to examine the impact of ART-related weight gain on long-term clinical outcomes.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40121-022-00673-1.

CD4 T cells are the primary targets for HIV-1 infection and their loss is a hallmark of HIV-1 disease. However, T follicular helper (Tfh) cells, a distinct subset of CD4 T cells that are specialized in helping B cells form germinal centers (GCs) for the generation of high-affinity class-switched antibodies, undergo expansion in people living with HIV-1 (PLHIV). Indeed, Tfh cells with latent HIV-1 are enriched in PLHIV, whether the PLHIV are on antiretroviral therapy (ART) or not. This shows that Tfh cells are preferentially infected by HIV-1 and are able to survive infection. Through total RNAseq of tonsillar subsets of T cells, including Tfh cells, our lab was able to find a sharp upregulation of an inhibitor of apoptosis family member gene (BIRC5) and a distinct metabolic gene profile in Tfhs compared to the other subsets. We further were able to find and confirm that (1) BIRC5 was highly expressed in human tonsil Tfh cells and the expression was upregulated upon HIV-1 infection, (2) human tonsil Tfh cells had high levels of Fatty Acid Oxidation related genes, but low levels of glycolytic genes, when compared with non-Tfh CD4 T cells, and (3) inhibition of FaO and BIRC5 led to changes in the survival of Tfh cells following HIV-1 infection. Our results show that Tfh survival of HIV-1 is associated with both the metabolic profile and expression of BIRC5 due to their ability to inhibit virus-induced direct and bystander apoptosis. Supported by grants from the NIH T32: Immunology and Infectious Disease Training Program

Objective: To investigate the impact of abnormal patterns of 75 g oral glucose tolerance test (OGTT) in the second trimester on the risk of large for gestational age (LGA) newborn deliveries. Methods: General clinical data and OGTT results of 66 290 pregnant women who received regular prenatal care and delivered in Guangdong Maternal and Child Health Hospital from December 24, 2016 to July 26, 2022 were collected. According to the results of OGTT, the pregnant women were divided into 8 groups: normal blood glucose group (normal fasting blood glucose, 1-hour and 2-hour after oral glucose, 54 518 cases), gestational diabetes mellitus (GDM) 0 group (only abnormal fasting blood glucose, 1 430 cases), GDM 1 group (only abnormal blood glucose at 1-hour after oral glucose, 2 150 cases), GDM 2 group (only abnormal blood glucose at 2-hour after oral glucose, 3 736 cases), GDM 0+1 group (both fasting blood glucose and 1-hour after oral glucose were abnormal, 371 cases), GDM 0+2 group (both fasting blood glucose and 2-hour after oral glucose were abnormal, 280 cases), GDM 1+2 group (abnormal blood glucose at 1-hour and 2-hour after oral glucose, 2 981 cases) and GDM 0+1+2 group (abnormal fasting blood glucose, 1-hour and 2-hour after oral glucose, 824 cases). Multivariate logistic regression was used to analyze the effects of different abnormal OGTT patterns on LGA. In addition, the blood glucose measurements at the three time points of OGTT were combined and used as continuous variables in the receiver operating characteristic (ROC) curve to evaluate the predictive value of each blood glucose measurement mode for LGA and the area under the curve (AUC) was compared. Results: (1) Multivariate logistic regression analysis showed that the risks of LGA were significantly increased in GDM 0 group (OR=1.76, 95%CI: 1.50-2.08; P<0.001), GDM 0+1 group (OR=2.29, 95%CI: 1.72-3.04; P<0.001), and GDM 0+1+2 group (OR=1.98, 95%CI: 1.61-2.43; P<0.001). (2) ROC curve analysis showed that fasting blood glucose, 1-hour after oral glucose, 2-hour after oral glucose, fasting+1-hour after oral glucose, fasting+2-hour after oral glucose, 1-hour+2-hour after oral glucose, and fasting+1-hour+2-hour after oral glucose had certain predictive value for LGA (all P<0.001). The AUC of fasting blood glucose measurement was higher than that of 2-hour blood glucose measurement in predicting LGA, and the difference was statistically significant (P<0.05). There was no significant difference in the AUC between fasting blood glucose and other blood glucose measurement modes for predicting LGA (all P>0.05). Conclusions: In the abnormal OGTT patterns, pregnant women with abnormal fasting blood glucose, abnormal fasting+1-hour after oral glucose, and abnormal fasting+1-hour+2-hour after oral glucose have an increased risk of LGA. Fasting blood glucose measurement is of great significance for the prediction of LGA, and could be used as an optimal indicator to evaluate the risk of LGA in clinical practice.