Immunological Non-responders Research Articles

Gut lactate-producing bacteria promote CD4 T cell recovery on Anti-retroviral therapy in HIV-infected patients

Anti-retroviral therapy (ART) effectively suppresses viral replication in HIV-infected patients, however CD4 + cell restoration to normal value is not achieved by 15–20% of patients who are called immune non-responders. Gut microbiota composition has been shown to influence host immunity. Herein, to identify intestinal microbial agents that may influence the CD4 recovery in HIV-infected patients, we utilized a “Quasi-paired cohort” method to analyze intestinal metagenome data from immunological responders (IRs) and immunological non-responders (INRs). This method identified significant enrichment for Streptococcus sp. and related lactate-producing bacteria (LAB) in IRs. In a validation cohort, positive correlations between the abundance of these LAB and the post-ART CD4 + recovery was observed, and a prediction model based on these LAB performed well in predicting immune recovery. Finally, experiments using a germ-free mouse model of antibody-induced CD4 + cell depletion showed that supplementation with a lactate-producing commensal Streptococcus thermophilus strongly promoted CD4 recovery. In conclusion, our study identified a group of LAB that was associated with enhanced immune recovery in post-ART HIV-infected patients and promotes CD4 + cell restoration in a mouse model. These findings favour supplementation of LAB commensal as a therapeutic strategy for CD4 + cell count improvement in HIV-infected patients.

Increased early activation of CD56dimCD16dim/- natural killer cells in immunological non-responders correlates with CD4+ T-cell recovery.

BackgroundNatural killer (NK) cells play a critical role in suppressing human immunodeficiency virus-1 (HIV-1) infection, but knowledge on whether and how NK cells affect immune reconstitution in HIV-1-infected individuals who receive antiretroviral therapy (ART) is limited.MethodsWe performed a case-control study with 35 healthy individuals and 66 HIV-1-infected patients including 32 immunological non-responders (INRs) with poor CD4+ T-cell recovery (<500 cells/μL after 4 years of ART) and 34 immunological responders (IRs) with improved CD4+ T-cell recovery (>500 cells/μL after 4 years of ART). NK cell phenotype, receptor repertoire, and early activation in INRs and IRs were investigated by flow cytometry.ResultsA significantly higher proportion of CD56dimCD16dim/- NK cells was observed in INRs than IRs before ART and after 4 years of ART. The number of CD56dimCD16dim/- NK cells was inversely correlated with CD4+ T-cell counts in INRs before ART (r = –0.344, P = 0.050). The more CD69-expressing NK cells there were, the lower the CD4+ T-cell counts and ΔCD4, and these correlations were observed in INRs after ART (r = –0.416, P = 0.019; r = –0.509, P = 0.003, respectively). Additionally, CD69-expressing CD56dimCD16dim/- NK cells were more abundant in INRs than those in IRs (P = 0.018) after ART, both of which had an inverse association trend towards significance with CD4+ T-cell counts. The expression of the activating receptors NKG2C, NKG2D, and NKp46 on CD56dimCD16dim/- NK cell subsets were higher in IRs than that in INRs after 4 years of ART (all P < 0.01). Strong inverse correlations were observed between CD69 expression and NKG2C, NKG2A-NKG2C+, NKG2D, and NKp46 expression on CD56dimCD16dim/- NK cells in INRs after ART (NKG2C: r = –0.491, P = 0.004; NKG2A-NKG2C+: r = –0.434, P = 0.013; NKG2D: r = –0.405, P = 0.021; NKp46: r = –0.457, P = 0.008, respectively).ConclusionsINRs had a larger number of CD56dimCD16dim/- NK cells characterized by higher activation levels than did IRs after ART. The increase in the CD56dimCD16dim/- NK cell subset may play an adverse role in immune reconstitution. Further functional studies of CD56dimCD16dim/- NK cells in INRs are urgently needed to inform targeted interventions to optimize immune recovery.

CD4 testing after initiation of antiretroviral therapy: Analysis of routine data from the South African HIV programme.

BackgroundPeople living with HIV (PLHIV) who have low CD4 counts require advanced clinical care (ACC) to minimise morbidity and mortality risk. These patients include immunological non-responders (INRs) with low CD4 counts despite a suppressed viral load.ObjectivesTo determine the proportion of patients with low CD4 counts after antiretroviral therapy (ART) initiation and to describe INRs within that group.MethodsRoutine Three Interlinked Electronic Registers.Net (TIER.Net) data from four South African districts were analysed for adult PLHIV on ART > 12 months. Immunological non-responders were defined as patients on ART > 4 years who were virally suppressed (viral load < 1000 copies/mL) with a CD4 count ≤ 350 cell/mm3.ResultsBaseline CD4 was recorded for 80.9% of the 869 571 patients newly initiating ART, with 37.2% of those starting ART since 2017 having baseline counts ≤ 200 cells/mm3. Amongst all 1 178 190 patients on ART, only 46.5% had a CD4 test after ART initiation and of these, 14.3% had CD4 ≤ 200 cells/mm3. This proportion was highest amongst patients on ART ≤ 2 years (19.7%) (p < 0.001). Amongst virally suppressed patients, 20.0% were INRs. Immunological non-response was significantly more likely amongst patients on second-line ART (adjusted odds ratio [aOR] 1.79), those aged 35-45 and ≥ 45 years (aOR 1.15 and 1.50, respectively), males (aOR 2.28) and patients with confirmed TB (aOR 2.49), and was significantly less likely in cases with higher baseline CD4 count (aOR 0.35).ConclusionCD4 testing subsequent to ART initiation is poorly implemented and there is a notable proportion of patients with low CD4 counts. Guidelines regarding CD4 testing and ACC need to be more widely implemented to identify patients with low CD4 counts and improve their outcomes.

Safety and efficacy of allogeneic natural killer cell immunotherapy on human immunodeficiency virus type 1 immunological non-responders: a brief report.

Background:Allogeneic natural killer (NK) cell immunotherapy is recognized as a promising anti-tumor strategy, but whether it plays a role in poor CD4 recovery among human immunodeficiency virus type 1 (HIV-1) infected patients is unknown. This study aimed to investigate the safety and effectiveness of allogeneic NK cells immunotherapy on HIV-1 immunological non-responders (INRs) receiving antiretroviral therapy (ART).Methods:From February to April 2018, a prospective, randomized, controlled, open-label clinical trial, which enrolled 20 HIV-1 INRs following specific inclusion criteria, was conducted at Nankai University Second People's Hospital. Participants were randomly allocated (simple randomization 1:1) to either the combined treatment (NK + ART) group (n = 10) or the control (ART) group (n = 10). The allogenic highly activated NK cells from killer cell immunoglobulin-like receptor (KIR)/human leukocyte antigen (HLA)-Cw mismatched healthy donor were prepared (108 cells in each injection) and intravenously infused to each recruited patient of NK+ART group in three courses. Key immune parameters (CD4 count, CD8 count, CD4/CD8 ratio), laboratory tests (count of blood cells, biochemistry panel) and symptoms at baseline and at month 1, 3, 6, 9, 12, and 24 were measured/collected to analyze the safety and efficacy of the therapy. Comparisons were between the seven time-points of both groups using repeated measurement analysis of variance (ANOVA) test. Generalized estimating equations (GEE) model was performed to evaluate the overall effect of the NK+ART group vs. the ART group.Results:From baseline to 24 months, we noted a mean CD4 count augmentation (139 to 243 cells/μL) in the NK + ART group and (144 to 176 cells/μL) in the ART group (difference, 67; 95% CI, 10 to 124; P = 0.024). Our estimations revealed that NK+ART group could improve CD4 level (β = 54.59, P = 0.006) and CD8 level (β = 322.47, P = 0.010) on average among the six measurements compared with the ART group. Only two (2/10, 20%) participants in the NK+ART group developed a transient mild fever after the first course.Conclusions:This preliminary study informs that HIV-1 INRs, allogenic NK cells immunotherapy is safe and could significantly improve CD4 recovery but not CD4/CD8 ratio. The practical effects, however, need long-term follow-up observations. Further study on the potential underlying mechanism is warranted.Registration info:www.chictr.org.cn/showproj.aspx?proj=34912 (No. ChiCTR1900020634).

The Impact of microRNA Regulation on Immune Recovery in HIV-1-Infected Patients Treated during Acute Infection: A Pilot Study

microRNAs (miRNAs) are small noncoding RNAs involved in a large range of cellular activities and can be used as biomarkers and indicators for diagnosis. We investigated the alterations in miRNA profiles in immune reconstituted vs. nonimmune reconstituted HIV-1-infected individuals to assess the association between miRNAs and the occurrence of immunological nonresponses, with the aim of searching for miRNA-based biomarkers for these HIV-1-infected individuals. Thirteen immunological responders (IRs) and 12 immunological nonresponders (INRs) were recruited, and RNA was collected from the plasma samples of the 25 HIV-1-infected individuals at both baseline and after 24 months of maintaining virological suppression (VS). Next-generation sequencing was used to detect miRNAs and evaluate the expression differences in miRNAs between IR and INR patients and between baseline and after 24 months of maintaining VS. Samples from 13 IRs and 11 INRs were successfully sequenced. The horizontal comparison of differentially expressed miRNAs between the groups and the longitudinal comparison of differentially expressed miRNAs between baseline and after 24 months of maintaining VS showed that a large proportion of miRNAs in INRs are downregulated compared to the levels in IRs. We also found that the miRNA let-7d-5p was downregulated in 9 INRs but only in 2 IRs by more than 2-fold. The difference was significant. In summary, these results demonstrate for the first time that a large proportion of miRNAs are downregulated in INRs compared with IRs, and the miRNA let-7d-5p is a potential biomarker for INRs.

Human Immunodeficiency Virus-Infected Immunological Nonresponders Have Colon-Restricted Gut Mucosal Immune Dysfunction.

BackgroundHuman immunodeficiency virus (HIV)–infected immunological nonresponders (INRs) fail to reconstitute their CD4+ T-cell pool after initiation of antiretroviral therapy, and their prognosis is inferior to that of immunological responders (IRs). A prevailing hypothesis is that the INR phenotype is caused by a persistently disrupted mucosal barrier, but assessments of gut mucosal immunology in different anatomical compartments are scarce.MethodsWe investigated circulating markers of mucosal dysfunction, immune activation, mucosal Th17 and Th22 cells, and mucosa-adherent microbiota signatures in gut mucosal specimens from sigmoid colon and terminal ileum of 19 INRs and 20 IRs in addition to 20 HIV-negative individuals.ResultsINRs had higher blood levels of the enterocyte damage marker intestinal fatty acid–binding protein than IRs. In gut mucosal biopsies, INRs had lower fractions of CD4+ T cells, higher fractions of interleukin 22, and a tendency to higher fractions of interleukin 17–producing CD4+ T cells. These findings were all restricted to the colon and correlated to circulating markers of enterocyte damage. There were no observed differences in gut microbial composition between INRs and IRs.ConclusionsRestricted to the colon, enterocyte damage and mucosal immune dysfunction play a role for insufficient immune reconstitution in HIV infection independent of the gut microbiota.

Increased Prevalence of Liver Fibrosis and HIV Viremia among Patients with HIV, HBV, and Tuberculosis in Botswana.

People with concomitant human immunodeficiency virus (HIV) and tuberculosis (TB) have an increased risk of hepatotoxic reactions due to antiretroviral therapy (ART) and anti-TB therapy (ATT). Concomitant hepatitis B virus (HBV) in these patients may lead to poorer health outcomes. To assess liver enzyme levels and immune response in adults with HIV, HBV, and TB, data from 300 antiretroviral-naïve people living with HIV (PLWHIV) were analyzed. The prevalence of HIV/HBV (cHIV/HBV) and HIV/TB (cHIV/TB) was 28% (95% CI: 23.0–33.4) and 10% (95% CI: 6.8–14.0), respectively. HIV/HBV/TB (cHIV/HBV/TB) prevalence was 5.3% (95% CI: 3.1–8.5). There was a statistically significant difference between the groups of participants in HIV viral load (p = 0.004), hemoglobin levels (p = 0.025), and body mass index (p = 0.011). A larger proportion of cHIV/HBV/TB participants (37.5%) had an aspartate aminotransferase to platelet ratio index (APRI) score ≥0.5 (p = 0.013), a lower cutoff for significant liver fibrosis. Immunological non-responders (CD4+ T-cell count <20% gain and HIV viral load <400 copies/mL at 6 months) were observed in all groups except those with cHIV/TB. Our findings support the need to screen for infections that could cause excessive liver damage prior to ATT or ART initiation, such as HBV.

Association of intestinal and systemic inflammatory biomarkers with immune reconstitution in HIV+ patients on ART

BackgroundHIV infection is characterized by CD4+ T-cells depletion related to gut damage, microbial translocation, immune activation and intestinal and systemic low-grade inflammation. With the use of antiretroviral treatment, these alterations in HIV+ patients reach similar levels to HIV- controls. However, almost 20% patients have deficient immune reconstitution of CD4+ T-cells, which make them more susceptible to develop non-AIDS and AIDS comorbidities.MethodsHIV+ patients on ART, with sustained virologic control were grouped according to their immune reconstitution as: immunological responders (n = 18) and immunological non-responders (n = 18); also, HIV- controls were enrolled (n = 14). CD4+ and CD8+ T-cell activation (HLA-DR+ and CD38+ single and co-expression) were measured by flow cytometry. Serum levels of sCD14, sCD163, lipopolysaccharide, I-FABP, sST2, as well as fecal levels of calprotectin, lactoferrin and secretory IgA were evaluated by ELISA. Levels of C-reactive protein were determined by a high sensibility singleplex bead-based immunoassay. Serum and fecal concentrations of proinflammatory cytokines were quantified by multiplex bead-based immunoassay.ResultsHLA-DR+ and CD38+ co-expression, as well as median fluorescence intensity in CD4+ and CD8+ T-cells subpopulations was greater in immunological non-responders group, after normalization and fold change calculation. Similarly, this group presented higher levels of sCD14, C-reactive protein, as well as fecal calprotectin and lactoferrin. Furthermore, both HIV+ groups showed elevated levels of proinflammatory cytokines in stool.ConclusionsOur data suggests that despite the virologic control, HIV+ patients under treatment with deficient immune reconstitution showed elevation of both innate and T-cells immune activation, as well as intestinal and systemic inflammation. However, some patients with CD4+ T-cells count above 350 cells/μL also presented these alterations. Future studies are necessary to evaluate the dynamics of multiple systemic and intestinal biomarkers in diverse types of HIV+ patients, as such as their clinical impact.

Chronic immune activation reduces CD4+T cell susceptibility to IL-7 in HIV-infected patients that poorly respond to antiretroviral therapy

Approximately 30 % of HIV-infected patients with viral load being suppressed during the course of antiretroviral therapy do not recover their peripheral CD4+T-lymphocyte counts. The reason for this phenomenon, named immunological non-response to treatment, remains unknown. In HIV-positive subjects receiving treatment, interleukin 7 plays a key role in increasing the number and supporting the viability of CD4+T-lymphocytes. We hypothesized that chronic immune activation, which develops in response to immunological failure during the therapy course, may reduce the susceptibility of CD4+T-cells to interleukin 7 in HIV-positive subjects. We examined 38 HIV-infected immunological non-responders to therapy; 42 HIVpositive patients with a standard response to treatment; 19 uninfected volunteers. The content of CD4+, CD4+CD127+ and activated HLA-DR+CD38+T-lymphocytes was determined in the peripheral blood of the examined individuals; the concentration of interleukin 7 was established. As a result, it was shown that interleukin 7 concentrations in the blood plasma of HIV positive immunological non-responders to treatment does not differ from the corresponding values of patients who gave a standard response to antiretroviral therapy. At the same time, immunological non-responders to treatment compared with subjects of both control groups were characterized by a deficiency of absolute and relative CD4+CD127+T-cell counts capable of responding to interleukin 7. Moreover, the interleukin 7 receptor expression level was reduced on CD4+T-lymphocytes of immunological non-responders. The higher was the frequency of activated CD4+T-lymphocytes; the lower was the CD127+ expression density. It should be noted that after excluding the data obtained from patients coinfected with HIV and hepatitis C virus, which are known to have significantly higher levels of chronic immune activation and systemic inflammation, we found no differences in CD127 expression between HIVpositive patients with distinct effectiveness of the immunological response to treatment. Thus, in the present study, we showed that in HIV-infection, poor immunologic response to antiretroviral therapy is associated with a decrease in the CD4+CD127+T-cell counts. Moreover, an increase in the level of chronic immune activation is associated with a decrease in CD127 expression density on CD4+T-lymphocytes.

Signature genes associated with immunological non-responsiveness to anti-retroviral therapy in HIV-1 subtype-c infection.

ObjectiveHIV-infected individuals undergoing therapy may show an immunological-discordant response to therapy, with poor CD4+ T cells recovery, despite viral suppression below the detection limit. The present study was carried out to delineate the underlying molecular mechanisms of immunological non-responsiveness to HIV therapy.DesignWe conducted microarray-based whole gene expression profiles of 30 subjects infected with HIV-1 subtype C, in peripheral blood to discern the signature genes associated with immunological non-responsiveness. After a thorough analysis and comparison of gene-expression profiles, microarray data was validated via qRT-PCR approach.ResultsOverall, we found 10 genes significantly up-regulated and 60 genes down-regulated (≥2-fold change) in immunological non-responders as compared to responders. Based on these results and pathway analysis of the protein-protein interaction, 20 genes were shortlisted for validation in human infected cases. We found statistically significant differences in expression levels of twelve genes IL-1α, IL-1β, IL-7R, TNF-α, FoxP3, PDCD5, COX7B, SOCS1, SOCS3, RPL9, RPL23, and LRRN3 respectively among immunological non-responders compared to therapy responders, confirming their an intimate relationship with immunological responsiveness to therapy.ConclusionsAltogether, microarray and qRT-PCR validation results indicated that the aberrant expression of key genes involved in the regulation of T cell homeostasis, immune activation, inflammatory cytokine production, apoptosis, and immune-regulatory processes are possibly associated with immunological non-responsiveness in HIV-1 C infected individuals on ART.

CCR5 genotype and pre-treatment CD4+ T-cell count influence immunological recovery of HIV-positive patients during antiretroviral therapy.

This study was performed to assess the association of CCR5Δ32 and SDF1-3'A polymorphisms with immunological recovery failure and to investigate the influence of sociodemographic and clinical data on immune reconstitution in human immunodeficiency virus (HIV)-positive patients during antiretroviral therapy (ART). Two hundred and forty-eight HIV-positive patients under ART with undetectable plasma viral load (<40copies/mL) were enrolled in this study and classified into two groups according to their CD4+ T-cell count changes: immunological responders (CD4+ T-cell count gain≥200/µL or≥30% compared with baseline) and immunological non-responders (CD4+ T-cell count gain<200/µL or<30% compared with baseline). DNA extraction was performed followed by CCR5Δ32 and SDF1-3'A genotyping. Sociodemographic and clinical data were evaluated from medical records. The logistic regression model showed that heterozygosity for CCR5Δ32 allele and lower pre-treatment CD4+ T-cell count (<500cells/µL) were statistically associated with immunological recovery failure (OR=5.873, 95%CI=1.204-28.633, P=0.028 and OR=10.00, 95%CI=3.224-31.016, P=0.028, respectively). No association of SDF1-3'A polymorphism with immune reconstitution failure was found. Additionally, we observed that there was a statistically significant difference between lower CD4+ T-cell count and INR status than the IR group (Z=4.687, P<0.001). Our results demonstrated, through a logistic regression model, that CCR5Δ32 polymorphism and pre-treatment CD4+ T-cell count have significant influence on immune reconstitution of HIV-positive patients during ART. These findings highlight some immunological factors associated with poor CD4+ T-lymphocytes recovery, which affect immune response level of ART-treated HIV-positive patients.

Incomplete immune reconstitution in HIV/AIDS patients on antiretroviral therapy: Challenges of immunological non-responders.

The morbidity and mortality of HIV type‐1 (HIV‐1)‐related diseases were dramatically diminished by the grounds of the introduction of potent antiretroviral therapy, which induces persistent suppression of HIV‐1 replication and gradual recovery of CD4+ T‐cell counts. However, ∼10–40% of HIV‐1‐infected individuals fail to achieve normalization of CD4+ T‐cell counts despite persistent virological suppression. These patients are referred to as “inadequate immunological responders,” “immunodiscordant responders,” or “immunological non‐responders (INRs)” who show severe immunological dysfunction. Indeed, INRs are at an increased risk of clinical progression to AIDS and non‐AIDS events and present higher rates of mortality than HIV‐1‐infected individuals with adequate immune reconstitution. To date, the underlying mechanism of incomplete immune reconstitution in HIV‐1‐infected patients has not been fully elucidated. In light of this limitation, it is of substantial practical significance to deeply understand the mechanism of immune reconstitution and design effective individualized treatment strategies. Therefore, in this review, we aim to highlight the mechanism and risk factors of incomplete immune reconstitution and strategies to intervene.

Determinants of discordant immune response in a cohort of human immunodeficiency virus-infected patients initiating antiretroviral therapy

Background: The introduction and wide use of highly active antiretroviral therapy (HAART) have significantly resulted in decline in morbidity and mortality from human immunodeficiency virus (HIV) infection and its related complications. These drugs can effectively induce virological suppression of the HIV-RNA replication to below the level of quantification, with eventual rise in the CD4+ cells counts. This is the therapeutic goal of using HAART in HIV-infected patients. However, some HIV-infected patients commencing HAART might have adequate virological suppression without a corresponding rise in CD4+ cells count-a phenomenon referred to as discordant immune response (DIR) or immunological nonresponse. Objective: The objective is to determine the factors associated with DIR among HIV-infected patients with adequate virological suppression, after initiating HAART. Materials and Methods: This study was a descriptive, retrospective, cross-sectional study that analyzed data from 200 HIV-infected adults that have been on HAART for 12 months descriptive statistics were used to describe the demographic profile of the participants, and binary logistic regression was used to assess the factors predicting DIR among the studied population. Results: One hundred and thirty-six (68%) were female with a mean age of 40.5 ± 10.9 years. The mean baseline CD4+ cells count was 162 ± 95.9 cells/mm3. Twelve months after HAART initiation, 64 (32%) of patients were immunological nonresponders. On multivariate analysis (logistics regression), patients initiating treatment at a higher CD4+ cells count >200 cells/mm3 (adjusted odds ratio [AOR] 3.89; confidence interval [CI]: 1.64–9.22; P = 0.002), the presence of anemia (hemoglobin

Definition of Immunological Nonresponse to Antiretroviral Therapy: A Systematic Review.

Terms and criteria to classify people living with HIV on antiretroviral therapy who fail to achieve satisfactory CD4 T-cell counts are heterogeneous, and need revision and summarization. We performed a systematic review of PubMed original research articles containing a set of predefined terms, published in English between January 2009 and September 2018. The search retrieved initially 1360 studies, of which 103 were eligible. The representative terminology and criteria were extracted and analyzed. Twenty-two terms and 73 criteria to define the condition were identified. The most frequent term was "immunological nonresponders" and the most frequent criterion was "CD4 T-cell count <350 cells/µL after ≥24 months of virologic suppression." Most criteria use CD4+ T-cell counts as a surrogate, either as an absolute value or as a change after a defined period of time [corrected]. Distinct values and time points were used. Only 9 of the 73 criteria were used by more than one independent research team. Herein we propose 2 criteria that could help to reach a consensus. The high disparity in terms and criteria here reported precludes data aggregation and progression of the knowledge on this condition, because it renders impossible to compare data from different studies. This review will foster the discussion of terms and criteria to achieve a consensual definition.

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.

The predictive role of CD4+ cell count and CD4/CD8 ratio in immune reconstitution outcome among HIV/AIDS patients receiving antiretroviral therapy: an eight-year observation in China

BackgroundThe immune reconstitution after initiation of highly active antiretroviral therapy (HAART) among HIV-infected individuals substantially affects patients’ prognosis. However, the dynamic characteristics and predictors of reconstitution outcome remain unclear.MethodsIn this study, the HIV/AIDS patients with sustained virological suppression (viral load < 50 copies/ml) after HAART were enrolled. The patients were subgrouped into immunological non-responders (INRs) (< 200 cells/μl), immunological inadequate responders (IIRs) (200 ~ 500 cells/μl) and immunological responders (IRs) (> 500 cells/μl) according to the CD4 cell count after two-year HAART. The immune reconstitution data based on the CD4+ and CD8+ cell counts with 8-year follow-up were collected for analysis.ResultsThe CD4+ cell counts in the immunological responders (IRs) were significantly higher than in the immunological non-responders (INRs) and immunological inadequate responders (IIRs) (P < 0.001). The overall CD4+ cell count and CD4/CD8 ratio in the IRs increased faster than the IIRs and INRs. The CD4+ cell count growth at 0.5 year and 1 year after HAART in the IRs was significantly higher than the IIRs and INRs. The ROC curve demonstrated that 1 year CD4+ cell count had the highest predictive value, with the best cut-off value of 188 cells/μl, the predictive sensitivity was 81.0%, the predictive specificity was 85.2%, false positive rate was 14.8%, false negative rate was 19.0%, positive predictive value (IR) was 63.0%, negative predictive value (INR) was 93.5%.ConclusionsTaken together, our findings suggest that early initiation of HAART can reduce the immune reconstitution failure. The combination of baseline CD4+ cell count and baseline CD4/CD8 ratio may serve as a valid predictor of immune reconstitution prognosis after HAART.

IL18 gene polymorphism and its influence on CD4+ T-cell recovery in HIV-positive patients receiving antiretroviral therapy

BackgroundPyroptosis has been reported to be critical in human immunodeficiency virus type 1 (HIV-1) pathogenesis and acquired immunodeficiency syndrome (AIDS) progression. Even after achieving viral suppression to undetectable levels during antiretroviral therapy (ART), exacerbated CD4+ T-cell death by pyroptosis has been suggested as one of the main causes of immunological non-response. Thus, variants in genes of pyroptosis pathway were studied in individuals with poor CD4+ T-cell reconstitution under antiretroviral therapy against HIV-1. Methods248 virologically suppressed ART-treated patients, 126 immunological non-responders (INR) and 122 immunological responders (IR) were recruited. Genotyping was performed using TaqMan probe-based realtime PCR platform. Genotype-guided flow cytometry analysis with general and recent thymic emigrant (RTE) CD4+ T-cells in pyroptosis was performed based on associated polymorphisms. ResultsBoth IL18 rs187238 G allele and GG genotype were associated as protection factors against poor CD4+ T-cell recovery (OR = 0.22; 95%CI = 0.50–0.77; P = .010 and OR = 0.58; 95%CI = 0.36–0.93; P = .022, respectively). It was demonstrated a statistical association between IL18 rs187238 genotypes of ART-treated patients and death by Caspase-1 levels (P = .020). The GG genotype showed lower pyroptotic RTE CD4+ T-lymphocytes levels in the ART-treated groups comparing with CC (P = .029) and CG (P = .018) genotypes, suggesting that the G allele presence may be related to a lower IL-18 production and thus reduced dead CD4+ T-cells levels by Caspase-1. ConclusionWe observed that IL18 G variant allele and genotype were associated with a better immunological response, which may influence on immunological recovery of HIV-positive patients receiving antiretroviral therapy, and low Caspase-1 activity levels was observed on GG genotype when compared CC genotypes.

CD4 recovery is associated with genetic variation in IFNγ and IL19 genes

Not all HIV-infected patients receiving cART are able to recover optimal CD4-T cell levels despite achieving undetectable viremia. We evaluated the potential association between polymorphisms (SNPs) in cytokines involved in immune response (IL15, IFNγ and IL19) and the failure to achieve optimal CD4 T-cells restoration after cART. For this, we carried out a retrospective study in 412 HIV-infected patients starting cART with CD4<200 cells/μL. These patients were classified as immunological non-responders (INR) if having a CD4 increase (ΔCD4) below 200 cells/μL after two years on successful cART. IL15, IFNγ and IL19 polymorphisms were genotyped using Sequenom's MassARRAY platform. We found 134 INR patients with a median [IQR] ΔCD4 = 133[73–174] cells/μL. In the multivariate analysis adjusted for age, sex, infection route, ethnic origin, hepatitis co-infection and HIV infection length, the AA genotype of the SNP rs2430561 in IFNγ (OR:2.01[1.13–3.56], p = 0.017) and the TT genotype of polymorphism rs2243191 in IL19 (OR:2.58 [1.17–5.68], p = 0.019) showed significant association with the INR status. Our results show that polymorphisms in IFNγ and IL19 genes significantly impacts in the probability of not achieving an optimal immune recovery in HIV-patients starting cART with CD4 T-cells <200 cells/μL. Thus, these SNPs could represent potential predictive markers of the immunodiscordant response.

Identification of rare HIV-1-infected patients with extreme CD4+ T cell decline despite ART-mediated viral suppression.

The goal of antiretroviral therapy (ART) is to suppress HIV-1 replication and reconstitute CD4+ T cells. Here, we report on HIV-infected individuals who had a paradoxical decline in CD4+ T cells despite ART-mediated suppression of plasma HIV-1 load (pVL). We defined such an immunological outcome as extreme immune decline (EXID). EXID's clinical and immunological characteristics were compared to immunological responders (IRs), immunological nonresponders (INRs), healthy controls (HCs), and idiopathic CD4+ lymphopenia (ICL) patients. T cell immunophenotyping and assembly/activation of inflammasomes were evaluated by flow cytometry. PBMC transcriptome analysis and genetic screening for pathogenic variants were performed. Levels of cytokines/chemokines were measured by electrochemiluminescence. Luciferase immunoprecipitation system and NK-mediated antibody-dependent cellular cytotoxicity (ADCC) assays were used to identify anti-lymphocyte autoantibodies. EXIDs were infected with non-B HIV-1 subtypes and after 192 weeks of consistent ART-mediated pVL suppression had a median CD4+ decrease of 157 cells/μl, compared with CD4+ increases of 193 cells/μl and 427 cells/μl in INR and IR, respectively. EXID had reduced naive CD4+ T cells, but similar proportions of cycling CD4+ T cells and HLA-DR+CD38+CD8+ T cells compared with IR and INR. Levels of inflammatory cytokines were also similar in EXID and INR, but the IL-7 axis was profoundly perturbed compared with HC, IR, INR, and ICL. Genes involved in T cell and monocyte/macrophage function, autophagy, and cell migration were differentially expressed in EXID. Two of the 5 EXIDs had autoantibodies causing ADCC, while 2 different EXIDs had an increased inflammasome/caspase-1 activation despite consistently ART-suppressed pVL. EXID is a distinct immunological outcome compared with previously described INR. Anti-CD4+ T cell autoantibodies and aberrant inflammasome/caspase-1 activation despite suppressed HIV-1 viremia are among the mechanisms responsible for EXID.

DISCORDANT RESPONSE OF CD4+ T LYMPHOCYTES TO ANTIRETROVIRAL THERAPY

Antiretroviral therapy (ART) in HIV infected patients generally results in the suppression of viral replication and reconstitution of CD4+ T lymphocytes cell counts. In some patients (about 20%), however, a disturbance in regeneration of immune competent cells with a background of low viral load occurs. The term «immunological nonresponders» has been used to describe this phenomenon. Discordant immune response to antiviral therapy may be caused by increasing of depletion and reducing of production of CD4+ T cells. However, mechanisms for low immune reconstitution are not currently well understood. «Immunological nonresponders» exhibit booster lymphocyte proliferation, increased immune activation and reducing of CD4+ T lymphocytes survival time in comparison with patients with concordant response to the therapy. Their immune system is characterized by more pronounced aging and exhaustion. This leads to early and frequent manifestation of AIDSrelated diseases. Besides, immunological nonresponders have an increased risk of non-AIDS-related diseases due to pronounced systemic inflammation. The objective of the present review was to highlight the important problem that is rather common on аntiretroviral therapy and to enlist the specialists to the solving of this issue.