Altered gut microbiota correlate with different immune responses to HAART in HIV-infected individuals.

BACKGROUND: Although gut microbiota dysbiosis has been reported in HIV infected individuals recently, the relationship between the gut microbiota and immune activation in patients with different immune responses to highly active antiretroviral therapy (HAART) is still not well understood. Gut microbiota and immune activation were studied in 36 non-HIV-infected subjects (healthy controls) and 58 HIV-infected individuals, including 28 immunological responders (IR) and 30 immunological non-responders (INR) (≥500 and < 200 CD4+ T-cell counts/µl after 2 years of HIV-1 viral suppression respectively) without comorbidities. RESULTS: Metagenome sequencing revealed that HIV-infected immunological responders and immunological non-responders could not recover completely from the gut microbiota dysbiosis. At a 97% similarity level, the relative abundances of Fusobacterium, Ruminococcus gnavus and Megamonas were greater, whereas Faecalibacterium, Alistipes, Bifidobacterium, Eubacterium rectale and Roseburia were more depleted in the IR and INR groups than those in the healthy controls. Ruminococcaceae and Alistipes were positively correlated with nadir and current CD4+ T-cell counts, but negatively correlated with CD8 + CD57+ T-cell counts. Inflammation markers and translocation biomarkers (LPS) levels were positively correlated with the abundances of genera Ruminococcus and Fusobacterium but were negatively correlated with the genus Faecalibacterium. The relative abundances of Escherichia-Shigella and Blautia were significantly higher in the IR than those in the INR group. Escherichia-Shigella were negatively correlated with the CD4/CD8 ratio but positively correlated with the amount of CD8 + CD57+ T-cells. Roseburia and Blautia were negatively associated with nadir CD4+ T-cell and positively associated with CD8 + CD57+ T-cell counts. CONCLUSIONS: Gut microbiota dysbiosis may be one of the factors contributing to different immune responses and treatment outcomes to HAART.

Oral microbiota signatures associated with viremia and CD4 recovery in treatment-naïve HIV-1-infected patients.

PURPOSE: Few reports focused on the role of oral microbiome diversity in HIV infection. We characterized the microbiota-immunity axis in a cohort of treatment-naïve HIV-1-infected patients undergoing antiretroviral therapy (ART) focusing on the oral microbiome (OM) and immunological responsivity. METHODS: The sequencing of 16S rRNA V3-V4 hypervariable region was performed on salivary samples of 15 healthy control (HC) and 12 HIV + patients before starting ART and after reaching virological suppression. Then, we correlated the OM composition with serum cytokines and the Short Chain Fatty acids (SCFAs). RESULTS: The comparison between HIV patients and HC oral microbiota showed differences in the bacterial α-diversity and richness. We documented a negative correlation between oral Prevotella and intestinal valeric acid at before starting ART and a positive correlation between oral Veillonella and gut acetic acid after reaching virological suppression. Finally, an increase in the phylum Proteobacteria was observed comparing saliva samples of immunological responders (IRs) patients against immunological non-responders (INRs). CONCLUSIONS: For the first time, we described an increase in the oral pro-inflammatory Proteobacteria phylum in INRs compared to IRs. We provided more evidence that saliva could be a non-invasive and less expensive approach for research involving the oral cavity microbiome in HIV patients.

Response assessment of GBM during immunotherapy by delayed contrast treatment response assessment maps.

Introduction: Assessing the treatment response of glioblastoma multiforme during immunotherapy (IT) is an open issue. Treatment response assessment maps (TRAMs) might help distinguish true tumor progression (TTP) and pseudoprogression (PsP) in this setting. Methods: We recruited 16 naïve glioblastoma patients enrolled in a phase II trial consisting of the Stupp protocol (a standardized treatment for glioblastoma involving combined radiotherapy and chemotherapy with temozolomide, followed by adjuvant temozolomide) plus IT with dendritic cells. Patients were followed up till progression or death; seven underwent a second surgery for suspected progression. Clinical, immunological, and MRI data were collected from all patients and histology in case of second surgery. Patients were classified as responders (progression-free survival, PFS > 12 months), and non-responders (PFS ≤ 12), HIGH-NK (natural killer cells, i.e., immunological responders), and LOW-NK (immunological non-responders) based on immune cell counts in peripheral blood. TRAMs differentiate contrast-enhancing lesions with different washout dynamics into hypothesized tumoral (conventionally blue-colored) vs. treatment-related (red-colored). Results: Using receiver operating characteristic (ROC) curves, a threshold of -0.066 in VBlue/VCE (volume of the blue portion of tumoral area/volume of contrast enhancement) variation between values obtained in the MRI performed before PsP/TTP and at TTP/PSP allowed to discriminate TTP from PsP with a sensitivity of 71.4% and a specificity of 100%. Among HIGH-NK patients, at month 6 there was a significant reduction compared to baseline and month 2 in median "blue" volumes. Discussion: In conclusion, in our pilot study TRAMs support the discrimination between tumoral and treatment-related enhancing features in immunological responders vs. non-responders, the distinction between PsP and TTP, and might provide surrogate markers of immunological response.

Severe intestinal barrier damage in HIV-infected immunological non-responders.

The intestinal epithelial barrier plays an important role during human immunodeficiency virus (HIV) disease progression. However, the extent to which the intestinal epithelial barrier is damaged in immunological non-responders (INRs) and immunological responders (IRs) is largely unknown. In this study, we investigated and compared the levels of intestinal gland damage and related molecules, including the tight junction protein claudin-1, apoptosis marker caspase-3, HIV DNA, CD4+ T cell count, and inflammation marker tumor necrosis factor-α (TNF-α) among the IRs (n = 10), INRs (n = 8), and healthy controls (HCs, n = 7). Intestinal damage was not completely restored in both INRs and IRs and was more serious in INRs than that in IRs. Moreover, intestinal damage was positively correlated with HIV DNA levels and negatively correlated with CD4+ T cell counts. These results provide insight into understanding the characteristics of intestinal epithelial barrier damage between IRs and INRs.

Prevalence of and prognosis for poor immunological recovery by virally suppressed and aged HIV-infected patients.

Background: Antiretroviral therapy (ART) prolongs lifespan and decreases mortality of HIV infected patients. However, many patients do not achieve optimal immune reconstitution. The influence of non-optimal immune recovery on non-AIDS related diseases is not well defined in aged HIV-infected patients receiving ART. Methods: A retrospective study was conducted at Tianjin Second People's Hospital, China to evaluate the association of an inadequate immunological response and non-AIDS diseases in HIV infected patients ≥60 years of age and virally suppressed for at least 2 years by ART. Results: The study included patients (n = 666) who initiated ART between August 2009 and December 2020. The prevalence of patients with an inadequate immunological response was 29.6%. The percentage of non-AIDS diseases such as hypertension, cardiovascular disease (CVD), diabetes, tumor, and chronic kidney disease (CKD) was 32.9, 9.9, 31, 4.1, and 13%, respectively. In addition to baseline CD4+ T cell counts, CVD and tumor were associated with poor immune reconstitution in aged Chinese HIV-1 infected patients. The adjusted odds ratios (95% confidence interval) were AOR 2.45 (95% CI: 1.22-4.93) and 3.06 (95% CI: 1.09-8.56, p = 0.03). Inadequate immunological response was associated with greater mortality (AOR: 2.83, 95% CI: 1.42-5.67, p = 0.003) in this cohort. Conclusion: These results tend to demonstrate appropriate drug selection at ART initiation and prevention of non-AIDS complications during ART decreased mortality of and an inadequate immunological response in aged HIV infected patients.

Effects of viremia and CD4 recovery on gut "microbiome-immunity" axis in treatment-naïve HIV-1-infected patients undergoing antiretroviral therapy.

BACKGROUND: Human immunodeficiency virus type 1 (HIV-1) infection is characterized by persistent systemic inflammation and immune activation, even in patients receiving effective antiretroviral therapy (ART). Converging data from many cross-sectional studies suggest that gut microbiota (GM) changes can occur throughout including human immunodeficiency virus (HIV) infection, treated by ART; however, the results are contrasting. For the first time, we compared the fecal microbial composition, serum and fecal microbial metabolites, and serum cytokine profile of treatment-naïve patients before starting ART and after reaching virological suppression, after 24 wk of ART therapy. In addition, we compared the microbiota composition, microbial metabolites, and cytokine profile of patients with CD4/CD8 ratio < 1 (immunological non-responders [INRs]) and CD4/CD8 > 1 (immunological responders [IRs]), after 24 wk of ART therapy. AIM: To compare for the first time the fecal microbial composition, serum and fecal microbial metabolites, and serum cytokine profile of treatment-naïve patients before starting ART and after reaching virological suppression (HIV RNA < 50 copies/mL) after 24 wk of ART. METHODS: We enrolled 12 treatment-naïve HIV-infected patients receiving ART (mainly based on integrase inhibitors). Fecal microbiota composition was assessed through next generation sequencing. In addition, a comprehensive analysis of a blood broad-spectrum cytokine panel was performed through a multiplex approach. At the same time, serum free fatty acid (FFA) and fecal short chain fatty acid levels were obtained through gas chromatography-mass spectrometry. RESULTS: We first compared microbiota signatures, FFA levels, and cytokine profile before starting ART and after reaching virological suppression. Modest alterations were observed in microbiota composition, in particular in the viral suppression condition, we detected an increase of Ruminococcus and Succinivibrio and a decrease of Intestinibacter. Moreover, in the same condition, we also observed augmented levels of serum propionic and butyric acids. Contemporarily, a reduction of serum IP-10 and an increase of IL-8 levels were detected in the viral suppression condition. In addition, the same components were compared between IRs and INRs. Concerning the microflora population, we detected a reduction of Faecalibacterium and an increase of Alistipes in INRs. Simultaneously, fecal isobutyric, isovaleric, and 2-methylbutyric acids were also increased in INRs. CONCLUSION: Our results provided an additional perspective about the impact of HIV infection, ART, and immune recovery on the "microbiome-immunity axis" at the metabolism level. These factors can act as indicators of the active processes occurring in the gastrointestinal tract. Individuals with HIV-1 infection, before ART and after reaching virological suppression with 24 wk of ART, displayed a microbiota with unchanged overall bacterial diversity; moreover, their systemic inflammatory status seems not to be completely restored. In addition, we confirmed the role of the GM metabolites in immune reconstitution.

Oral Microbiota Is Associated With Immune Recovery in Human Immunodeficiency Virus-Infected Individuals.

The role of the oral microbiota in HIV-infected individuals deserves attention as either HIV infection or antiretroviral therapy (ART) may have effect on the diversity and the composition of the oral microbiome. However, few studies have addressed the oral microbiota and its interplay with different immune responses to ART in HIV-infected individuals. Salivary microbiota and immune activation were studied in 30 HIV-infected immunological responders (IR) and 34 immunological non-responders (INR) (≥500 and < 200 CD4 + T-cell counts/µl after 2 years of HIV-1 viral suppression, respectively) with no comorbidities. Metagenome sequencing revealed that the IR and the INR group presented similar salivary bacterial richness and diversity. The INR group presented a significantly higher abundance of genus Selenomonas_4, while the IR group manifested higher abundances of Candidatus_Saccharimonas and norank_p_Saccharimonas. Candidatus_Saccharimonas and norank_p_Saccharimonas were positively correlated with the current CD4 + T-cells. Candidatus_Saccharimonas was positively correlated with the markers of adaptive immunity CD4 + CD57 + T-cells, while negative correlation was found between norank _p_Saccharimonas and the CD8 + CD38 + T-cells as well as the CD4/CD8 + HLADR + CD38 + T-cells. The conclusions are that the overall salivary microbiota structure was similar in the immunological responders and immunological non-responders, while there were some taxonomic differences in the salivary bacterial composition. Selenomona_4, Candidatus_Saccharimonas, and norank _p_Saccharimonas might act as important factors of the immune recovery in the immunodeficiency patients, and Candidatus_Saccharimonas could be considered in the future as screening biomarkers for the immune responses in the HIV-infected individuals.

Glycoprotein Profile Assessed by 1H-NMR as a Global Inflammation Marker in Patients with HIV Infection. A Prospective Study.

Plasma glycoproteins are a composite biomarker of inflammation and can be detected by 1H-NMR. The aim of this study was to prospectively appraise the clinical value of plasma glycoproteins assessed by 1H-NMR in people living with HIV (PLWH). A total of 221 patients with HIV infection were recruited and studied at baseline and at 48 and 144 weeks. Patients were distributed into two groups according to baseline CD4+ T-cell number below or above 200 cells/µL. Patients with fewer than 200 cells/µL were distributed into the responders and nonresponders according to antiretroviral therapy (ART) response at 144 weeks. Glycoprotein concentrations were determined by 1H-NMR arising from the protein bond N-acetylglucosamine and N-acetylgalactosamine signals (GlycA); and N-acetylneuraminic acid signal (GlycB) associated with the sugar-protein bond concentration and aggregation state (shapes (height/width)). Basal glycoprotein concentrations were higher in patients with < 200 CD4+ T-cell/µL (Glyc A: 1040(917.9-1199.1) vs. 950.4(845.5-1050.9), p < 0.001, and Glyc B: 521(440.3-610.3) vs. 468.6(417.9-507.0) µ mol/L, p < 0.001) being reduced by ART. The height/width (H/W) ratio was the parameter showing a better association with this clinical status. Baseline glycoproteins predict the condition of responder/nonresponder. In this study, 1H-NMR glycoproteins provide novel insights to assess inflammation status and have prognostic value in PLWH.

Two types of poor immunological responder showing distinct responses to long-term HAART.

OBJECTIVES: Most previous studies on poor immunological responders (PIRs) have been performed on one cohort at one time-point following highly active antiretroviral therapy (HAART). The aim of this study was to investigate whether there are different subtypes of PIR and whether a certain population might achieve better immune reconstitution following longer HAART. METHODS: This study was designed as an ambispective cohort study, including a 4-5-year retrospective study and a 2-year prospective follow-up investigation. Thymic output, activated T cell and regulatory T cell (Treg) subset frequencies, expression levels of interferon-stimulated genes, and plasma concentrations of neopterin were determined at 4-5 years and 6-7 years following HAART initiation. RESULTS: PIRs were subdivided into two populations after 4-5 years of HAART, according to the kinetics of T cell recovery. Type II PIRs exhibited a significantly lower percentage of naïve CD4+ T cells and CD31+ naïve CD4+ T cells compared with type I PIRs. After an additional 2 years of HAART treatment, type I PIRs showed a better outcome than type II PIRs. Furthermore, it was found that 2 years of additional HAART could persistently improve thymic output. CONCLUSIONS: The two PIR subgroups are different in terms of immune characteristics and the response to prolonged HAART.

Thymic Function as a Predictor of Immune Recovery in Chronically HIV-Infected Patients Initiating Antiretroviral Therapy.

Poor immunological responders (PIR) are HIV-infected patients with virologic suppression upon antiretroviral therapy (ART) but persistently low CD4+ T cell counts. Early identification of PIR is important given their higher morbimortality compared to adequate immune responders (AIR). In this study, 33 patients severely lymphopenic at ART onset, were followed for at least 36 months, and classified as PIR or AIR using cluster analysis grounded on their CD4+ T cell count trajectories. Based on a variety of immunological parameters, we built predictive models of PIR/AIR outcome using logistic regression. All PIR had CD4+ T cell counts consistently below 500 cells/µL, while all AIR reached this threshold. AIR showed a higher percentage of recent thymic emigrants among CD4+ T cells; higher numbers of sj-TRECs and greater sj/ß TREC ratios; and significant increases in thymic volume from baseline to 12 months of ART. We identified mathematical models that correctly predicted PIR/AIR outcome after 36 months of therapy in 77-87% of the cases, based on observations made until 2-6 months after ART onset. This study highlights the importance of thymic activity in the immune recovery of severely lymphopenic patients, and may help to select the patients that will benefit from closer follow-up or novel therapeutic approaches.