Cryptococcosis-Associated Immune Reconstitution Inflammatory Syndrome Is Associated With Dysregulation of IL-7/IL-7 Receptor Signaling Pathway in T Cells and Monocyte Activation.

BACKGROUND: Systemic levels of interleukin (IL)-7 at antiretroviral therapy (ART) initiation have previously been shown to be predictive of HIV-linked paradoxical cryptococcosis-associated immune reconstitution inflammatory syndrome (C-IRIS). We therefore explored IL-7/IL-7 receptor (IL-7/IL-7R) signaling pathway dysfunction, with related alterations in immune function, as a mechanism underlying C-IRIS. METHOD: HIV-infected patients with cryptococcal meningitis who experienced C-IRIS (n = 27) were compared with CD4 T-cell count-matched counterparts without C-IRIS (n = 27), after antifungal therapy and pre-ART initiation. Flow cytometry was used to assess T-cell and monocyte phenotypes and functions. RESULTS: Proportions of IL-7R+ CD4 or CD8 T cells correlated positively with CD4 T-cell counts and proportions of central memory and naive CD4 and CD8 T-cell pre-ART (all r > 0.50 and P < 0.05); however, the former negatively correlated with CD4 T-cell counts fold-increase on ART in non-C-IRIS but not C-IRIS patients. Higher frequencies of activated monocytes (CD14CD86 or CD14+HLA-DR+; P ≤ 0.038) were also observed in C-IRIS compared with non-C-IRIS patients, and those who failed to clear cryptococci from cerebrospinal fluid before ART had higher levels of activated monocytes (CD14+HLA-DR+, P = 0.017) compared with those who cleared. In multivariate regression, CD14+HLA-DR+ monocytes were independently associated with C-IRIS [hazard ratio = 1.055 (1.013-1.098); P = 0.009]. CONCLUSION: In contrast to non-C-IRIS patients, C-IRIS patients displayed a lack of association between proportions of IL-7R+ T cells and several markers of T-cell homeostasis. They also exhibited higher monocyte activation linked to cerebrospinal fluid cryptococcal culture positivity before ART. These data suggest a role for IL-7/IL-7R signaling pathway dysregulation in the pathogenesis of C-IRIS, possibly linked to monocyte activation and residual pathogen burden before ART.

Interleukin 1-Beta (IL-1ß) Production by Innate Cells Following TLR Stimulation Correlates With TB Recurrence in ART-Treated HIV-Infected Patients.

BACKGROUND: Tuberculosis (TB) remains a major cause of global morbidity and mortality, especially in the context of HIV coinfection because immunity is not completely restored following antiretroviral therapy (ART). The identification of immune correlates of risk for TB disease could help in the design of host-directed therapies and clinical management. This study aimed to identify innate immune correlates of TB recurrence in HIV+ ART-treated individuals with a history of previous successful TB treatment. METHODS: Twelve participants with a recurrent episode of TB (cases) were matched for age, sex, time on ART, pre-ART CD4 count with 12 participants who did not develop recurrent TB in 60 months of follow-up (controls). Cryopreserved peripheral blood mononuclear cells from time-points before TB recurrence were stimulated with ligands for Toll-like receptors (TLR) including TLR-2, TLR-4, and TLR-7/8. Multicolor flow cytometry and intracellular cytokine staining were used to detect IL-1ß, TNF-α, IL-12, and IP10 responses from monocytes and myeloid dendritic cells (mDCs). RESULTS: Elevated production of IL-1ß from monocytes following TLR-2, TLR-4, and TLR-7/8 stimulation was associated with reduced odds of TB recurrence. In contrast, production of IL-1ß from both monocytes and mDCs following Bacillus Calmette-Guérin (BCG) stimulation was associated with increased odds of TB recurrence (risk of recurrence increased by 30% in monocytes and 42% in mDCs, respectively). CONCLUSION: Production of IL-1ß by innate immune cells following TLR and BCG stimulations correlated with differential TB recurrence outcomes in ART-treated patients and highlights differences in host response to TB.

Association of Polymorphisms in the Regulatory Region of the Cyclophilin a Gene (PPIA) with Gene Expression and HIV/AIDS Disease Progression.

BACKGROUND: Human cyclophilin A (CypA) encoded by peptidyl prolyl isomerase A gene (PPIA), enhances HIV-1 replication by aiding capsid uncoating. The association of genetic variation in the PPIA regulatory region with susceptibility to HIV-1 infection, disease progression, and gene expression among black South Africans at risk for infection or infected with HIV-1 is unknown. METHODS: We genotyped 539 participants from 2 longitudinal study cohorts of black South Africans at high risk for infection or infected with HIV-1 for PPIA regulatory single nucleotide polymorphisms by polymerase chain reaction-restriction fragment length polymorphism. RESULTS: Minor allele (G) of SNP rs6850 (rs6850 G) significantly associated with higher viral loads (mean 4.85 versus 4.46 log copies/mL, P = 0.0006) and lower CD4 T-cell counts (mean 506 versus 557 cells/µL, P = 0.0256) during the acute phase of infection in the Centre for the AIDS Programme of Research in South Africa (CAPRISA) 002 cohort. Consistently, rs6850 G significantly associated with higher viral loads (mean 4.49 versus 4.01 log copies/mL, P < 0.0001) and lower CD4 T-cell counts (mean 442 versus 494 cells/µL, P = 0.0002) during the early chronic phase of infection in the CAPRISA 002 cohort; rs6850 G further associated significantly with rapid CD4 T-cell decline in the CAPRISA 002 cohort (P = 0.0481) and Sinikithemba chronic infection cohort (P = 0.0156). Interestingly, rs6850 G significantly associated with elevated CypA mRNA levels in HIV-1-positive individuals (P = 0.0061). CONCLUSIONS: These data suggest that rs6850 G enhances HIV-1 replication through upregulation of CypA expression following HIV-1 infection. The data support ongoing efforts to develop anti-HIV-1 drugs that block interaction of HIV-1 and cellular proteins.

Neither microbial translocation nor TLR responsiveness are likely explanations for preexisting immune activation in women who subsequently acquired HIV in CAPRISA 004.

Innate immune activation was a strong predictor of HIV acquisition in women at risk for HIV in CAPRISA 004. Identifying the cause(s) of activation could enable targeted prevention interventions. In this study, plasma concentrations of lipopolysaccharide, soluble CD14, and intestinal fatty acid-binding protein did not differ between subjects who did or did not subsequently acquire HIV nor were these levels correlated with plasma cytokines or natural killer cell activation. There was no difference between HIV acquirers and non-acquirers in the chemokine and cytokine responses of peripheral blood mononuclear cells stimulated with TLR2, 4, or 7/8 agonists. Further studies are required.