Proportions of circulating T cells with a regulatory cell phenotype increase with HIV-associated immune activation and remain high after 1 year on ART.

CD8(+) T-cell and myeloid cell trafficking to the central nervous system may predispose patients to C-IRIS.

A proportion of HIV patients beginning antiretroviral therapy (ART) develop immune restoration disease (IRD). Immunological characteristics of IRD were investigated in a cohort of HIV patients beginning therapy in Kuala Lumpur, Malaysia. MethodsPeripheral blood mononuclear cells were collected at weeks 0, 6, 12, 24 and 48 of ART from five patients experiencing IRD [two with cryptococcal and three with Mycobacterium tuberculosis (Mtb) disease], eight non-IRD controls who had begun ART with CD4 T-cell counts of o100 cells/mL and 17 healthy controls. Leukocytes producing interferon-gamma (IFNg) were quantified by enzymelinked immunospot assay after stimulation with purified protein derivative (PPD), early secretory antigenic target-6 (ESAT-6), Cryptococcus neoformans or Cytomegalovirus antigens. Plasma immunoglobulin (IgG) antibodies reactive with these antigens were assessed by enzyme-linked immunosorbent assay. Proportions of activated (HLA-DR hi ) and regulatory (CD25 CD127 lo and CTLA-4 1 ) CD4 T-cells were quantified by flow cytometry. ResultsPlasma HIV RNA declined and CD4 T-cell counts rose within 8-27 weeks on ART. Mtb IRD patients displayed elevated IFNg responses and/or plasma IgG to PPD, but none responded to ESAT-6. Cryptococcal IRD occurred in patients with low baseline CD4 T-cell counts and involved clear IFNg and antibody responses to cryptococcal antigen. Proportions of activated and regulatory CD4 T-cells declined on ART, but remained higher in patients than in healthy controls. At the time of IRD, proportions of activated CD4 T-cells and regulatory CD4 T-cells were generally elevated relative to other patients. ConclusionsCryptococcal and Mtb IRD generally coincide with peaks in the proportion of activated T-cells, pathogen-specific IFNg responses and reactive plasma IgG. IRD does not reflect a paucity of regulatory CD4 T-cells.

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Background The role of T-cell responses against Mycobacterium tuberculosis antigens in tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is unclear. Methods Peripheral blood mononuclear cells from 45 HIV patients with treated TB, of whom 12 developed TB-IRIS, were collected at weeks 0, 2, and 6 of antiretroviral therapy (ART). Production of interferon-γ (IFN-[γ]) and interleukin-2 by T cells after stimulation with purified protein derivative (PPD) or early secretory antigenic target-6 (ESAT-6) and T-cell expressions of CCR5 and CXCR3 were assessed by flow cytometry. IFN-γ and CXCL10 were assayed by enzyme-linked immunosorbent assay. Results TB-IRIS patients had higher proportions of PPD- and ESAT-6–reactive IFN-γ+CD4+ and CD3+CD4- T cells at weeks 0, 2, and 6. IFN-γ levels were also higher in peripheral blood mononuclear cell culture supernatants at all times with PPD but only at weeks 2 and 6 with ESAT-6. There were few differences for interleukin-2. CXCL10 levels in supernatants after PPD and ESAT-6 stimulation were only higher at week 6. CXCR3+/CCR5+CD4+ T cells were higher at week 2, and CCR5+CD4+ T cells were higher at week 6. Conclusions TB-IRIS is associated with Th1 responses against M. tuberculosis antigens by CD4+ and CD3+CD4- T cells that are present before ART and amplified afterward. It is unclear if these cause immunopathology or reflect a high pathogen load.