Immune nonresponder (INR) HIV-1–infected subjects are characterized by their inability to reconstitute the CD4⁺ T cell pool after antiretroviral therapy. This is linked to poor clinical outcome. Mechanisms underlying immune reconstitution failure are poorly understood, although, counterintuitively, INRs often have increased frequencies of circulating CD4⁺ T cells in the cell cycle. While cycling CD4⁺ T cells from healthy controls and HIV⁺ patients with restored CD4⁺ T cell numbers complete cell division in vitro, cycling CD4⁺ T cells from INRs do not. Here, we show that cells with the phenotype and transcriptional profile of Tregs were enriched among cycling cells in health and in HIV infection. Yet there were diminished frequencies and numbers of Tregs among cycling CD4⁺ T cells in INRs, and cycling CD4⁺ T cells from INR subjects displayed transcriptional profiles associated with the impaired development and maintenance of functional Tregs. Flow cytometric assessment of TGF-β activity confirmed the dysfunction of Tregs in INR subjects. Transcriptional profiling and flow cytometry revealed diminished mitochondrial fitness in Tregs among INRs, and cycling Tregs from INRs had low expression of the mitochondrial biogenesis regulators peroxisome proliferator–activated receptor γ coactivator 1-α (PGC1α) and transcription factor A for mitochondria (TFAM). In vitro exposure to IL-15 allowed cells to complete division, restored the expression of PGC1α and TFAM, and regenerated mitochondrial fitness in the cycling Tregs of INRs. Our data suggest that rescuing mitochondrial function could correct the immune dysfunction characteristic of Tregs in HIV-1–infected subjects who fail to restore CD4⁺ T cells during antiretroviral therapy.

Objectives: Chronic hepatitis C virus (HCV) and HIV viral infections are characterized by systemic inflammation. Yet the relative levels, drivers and correlates of inflammation in these settings are not well defined.Methods: Seventy‐nine HIV‐infected patients who had been receiving antiretroviral therapy (ART) for more than 2 years and who had suppressed plasma HIV levels (< 50 HIV‐1 RNA copies/mL) were included in the study. Two patient groups, HCV‐positive/HIV‐positive and HCV‐negative/HIV‐positive, and a control group comprised of healthy volunteers (n = 20) were examined. Markers of systemic inflammation [interleukin (IL)‐6, interferon gamma‐induced protein (IP)‐10, soluble tumour necrosis factor receptor‐I (sTNF‐RI) and sTNF‐RII], monocyte/macrophage activation [soluble CD163 (sCD163), soluble CD14 and neopterin], intestinal epithelial barrier loss [intestinal fatty acid binding protein (I‐FABP) and lipopolysaccharide (LPS)] and coagulation (d‐dimers) were analysed. CD4 naïve T cells and CD4 recent thymic emigrants (RTEs) were enumerated.Results: Plasma levels of IP‐10, neopterin and sCD163 were higher in HCV/HIV coinfection than in HIV monoinfection and were positively correlated with indices of hepatic damage [aspartate aminotransferase (AST), alanine aminotransferase (ALT) and the AST to platelet ratio index (APRI)]. Levels of I‐FABP were comparably increased in HIV monoinfection and HIV/HCV coinfection but LPS concentrations were highest in HCV/HIV coinfection, suggesting impaired hepatic clearance of LPS. Plasma HCV levels were not related to any inflammatory indices except sCD163. In coinfected subjects, a previously recognized relationship of CD4 naïve T‐cell and RTE counts to hepatocellular injury was defined more mechanistically by an inverse relationship to sCD163.Conclusions: Hepatocellular injury in HCV/HIV coinfection is linked to elevated levels of certain inflammatory cytokines and an apparent failure to clear systemically translocated microbial products. A related decrease in CD4 naïve T cells and RTEs also merits further exploration.

Objective: The effects of hepatitis C virus (HCV) coinfection on immune homeostasis and immune restoration in treated HIV infection are not well understood. Methods: We studied 79 HIV-infected patients who had been receiving HAART for more than 2 years and who had HIV viral load below 50 copies/ml. Four patient groups were studied: HIV⁺/HCV⁺, CD4⁺ cells above 350/μl; HIV⁺/HCV⁺, CD4⁺ cells below 350/μl; HIV⁺/HCV^–, CD4⁺ cells above 350/μl; HIV⁺/HCV^–, CD4⁺ cells below 350/μl. Controls comprised 20 healthy volunteers. Naive, central memory, effector memory, and terminal effector CD4⁺ T cells were enumerated. Naive CD4⁺CD31⁺ T cells were counted as recent thymic emigrants (RTEs). Activation state and ex-vivo apoptosis of CD4⁺ T cells, levels of liver enzymes, and aspartate aminotransferase-to-platelet ratio index were evaluated. Results: CD4⁺ T-cell counts and the numbers of all circulating CD4⁺ T-cell maturation subsets were diminished in HIV infection; CD4⁺ T-cell activation and apoptosis were increased in HIV infection, but none of these indices was affected by HCV coinfection. RTE numbers were diminished in HIV infection, were inversely related to age, and were increased in women and lower in HIV⁺/HCV⁺ patients than in singly HIV-infected patients. In coinfected patients, RTE numbers were inversely related to levels of liver enzymes, but not to HCV viral load. Conclusion: Whereas we could find no relationship between HCV infection and most indices of CD4⁺ T-cell homeostasis or activation, CD4⁺ RTEs are diminished in the circulation of HCV coinfected persons and appear to be related to indices of ongoing hepatic damage or inflammation.

People living with HIV (PLWH) who are immune nonresponders (INRs) are at greater risk of comorbidity and mortality than are immune responders (IRs) who restore their CD4⁺ T cell count after antiretroviral therapy (ART). INRs have low CD4⁺ T cell counts (<350 c/μL), heightened systemic inflammation, and increased CD4⁺ T cell cycling (Ki67⁺). Here, we report the findings that memory CD4⁺ T cells and plasma samples of INRs from several cohorts are enriched in gut-derived bacterial solutes p-cresol sulfate (PCS) and indoxyl sulfate (IS) that both negatively correlated with CD4⁺ T cell counts. In vitro PCS or IS blocked CD4⁺ T cell proliferation, induced apoptosis, and diminished the expression of mitochondrial proteins. Electron microscopy imaging revealed perturbations of mitochondrial networks similar to those found in INRs following incubation of healthy memory CD4⁺ T cells with PCS. Using bacterial 16S rDNA, INR stool samples were found enriched in proteolytic bacterial genera that metabolize tyrosine and phenylalanine to produce PCS. We propose that toxic solutes from the gut bacterial flora may impair CD4⁺ T cell recovery during ART and may contribute to CD4⁺ T cell lymphopenia characteristic of INRs.

Background & objectives: Under the lymphopenic condition, T-cells divide to maintain their peripheral pool size. Profound chronic lymphopenia in some treated HIV-infected patients, characterized by poor T-cell recovery, might result in intensive homeostatic proliferation and can cause T-cell exhaustion and/or senescence. The present study was undertaken to evaluate the homeostatic proliferation of CD4⁺ T-cells in treated HIV-infected individuals, and to determine the amount of phenotypically exhausted and senescent CD4 T-lymphocytes. Methods: Thirty seven treated HIV-infected patients with suppressed HIV viral load (<50 copies/ml) were studied. Patients were divided into two groups: immunological non-responders (INRs) with CD4⁺ T-cells 350/μl (n=21). T-cell subsets [naïve, central memory (CM), and effector memory (EM)] and proportions of cycling (Ki-67⁺), senescent (CD57⁺) and exhausted (PD-1⁺) T-lymphocytes were assessed using flow cytometry. Results: CD4⁺ T-cell cycling rate was higher in INRs than in IRs due to more extensive proliferation of CM, 4.7 vs 2.7 per cent (P <0.01) and EM, 4.8 vs 3.2 per cent (P <0.05). The percentages of CD4⁺ Ki-67⁺ CM and EM T-lymphocytes were inversely related to the CD4⁺ T-cell counts in the appropriate subset, r=–0.584 (P <0.001) and r=–0.556, (P <0.001), respectively. Exhaustion [24.2 vs 16.7% (P 0.05)] was more pronounced in the INR group than in the IR group. The frequency of CD4⁺ Ki-67⁺ CM T-cells was related to the proportion of CD4⁺ PD-1⁺ cells of the same subset, r=0.789 (P <0.001). The numbers of CD4⁺ Ki-67⁺ PD-1⁺ CM and EM T-cells were substantially higher in INRs than in IRs. Interpretation & conclusions: The present data indicated that intensive homeostatic proliferation contributed to the T-cell exhaustion in HIV-infection.

The binding of antigens with antibodies forms immune complexes in the body. Usually these complexes are eliminated by the system of mononuclear phagocytes without development of pathological changes....