Baseline Inflammatory Biomarkers Identify Subgroups of HIV-Infected African Children With Differing Responses to Antiretroviral Therapy.

BACKGROUND: Identifying determinants of morbidity and mortality may help target future interventions for human immunodeficiency virus (HIV)-infected children. METHODS: CD4(+) T-cell count, HIV viral load, and levels of biomarkers (C-reactive protein, tumor necrosis factor α [TNF-α], interleukin 6 [IL-6], and soluble CD14) and interleukin 7 were measured at antiretroviral therapy (ART) initiation in the ARROW trial (case-cohort design). Cases were individuals who died, had new or recurrent World Health Organization clinical stage 4 events, or had poor immunological response to ART. RESULTS: There were 115 cases (54 died, 45 had World Health Organization clinical stage 4 events, and 49 had poor immunological response) and 485 controls. Before ART initiation, the median ages of cases and controls were 8.2 years (interquartile range [IQR], 4.4-11.4 years) and 5.8 years (IQR, 2.3-9.3 years), respectively, and the median percentages of lymphocytes expressing CD4 were 4% (IQR, 1%-9%) and 13% (IQR, 8%-18%), respectively. In multivariable logistic regression, cases had lower age-associated CD4(+) T-cell count ratio (calculated as the ratio of the subject's CD4(+) T-cell count to the count expected in healthy individuals of the same age; P < .0001) and higher IL-6 level (P = .002) than controls. Clustering biomarkers and age-associated CD4(+) and CD8(+) T-cell count ratios identified 4 groups of children. Group 1 had the highest frequency of cases (41% cases; 16% died) and profound immunosuppression; group 2 had similar mortality (23% cases; 15% died), but children were younger, with less profound immunosuppression and high levels of inflammatory biomarkers and malnutrition; group 3 comprised young children with moderate immunosuppression, high TNF-α levels, and high age-associated CD8(+) T-cell count ratios but lower frequencies of events (12% cases; 7% died); and group 4 comprised older children with low inflammatory biomarker levels, lower HIV viral loads, and good clinical outcomes (11% cases; 5% died). CONCLUSIONS: While immunosuppression is the major determinant of poor outcomes during ART, baseline inflammation is an additional important factor, identifying a subgroup of young children with similar mortality. Antiinflammatory interventions may help improve outcomes.

The impact of viraemia on inflammatory biomarkers and CD4+ cell subpopulations in HIV-infected children in sub-Saharan Africa.

OBJECTIVE: To determine the impact of virological control on inflammation and cluster of differentiation 4 depletion among HIV-infected children initiating antiretroviral therapy (ART) in sub-Saharan Africa. DESIGN: Longitudinal cohort study. METHODS: In a sub-study of the ARROW trial (ISRCTN24791884), we measured longitudinal HIV viral loads, inflammatory biomarkers (C-reactive protein, tumour necrosis factor alpha, interleukin 6 (IL-6), soluble CD14) and (Uganda only) whole blood immunophenotype by flow cytometry in 311 Zimbabwean and Ugandan children followed for median 3.5 years on first-line ART. We classified each viral load measurement as consistent suppression, blip/post-blip, persistent low-level viral load or rebound. We used multi-level models to estimate rates of increase or decrease in laboratory markers, and Poisson regression to estimate the incidence of clinical events. RESULTS: Overall, 42% children experienced viral blips, but these had no significant impact on immune reconstitution or inflammation. Persistent detectable viraemia occurred in one-third of children and prevented further immune reconstitution, but had little impact on inflammatory biomarkers. Virological rebound to ≥5000 copies/ml was associated with arrested immune reconstitution, rising IL-6 and increased risk of clinical disease progression. CONCLUSIONS: As viral load testing becomes more available in sub-Saharan Africa, repeat testing algorithms will be required to identify those with virological rebound, who need switching to prevent disease progression, whilst preventing unnecessary second-line regimen initiation in the majority of children with detectable viraemia who remain at low risk of disease progression.

B-cell development and pneumococcal immunity in vertically acquired HIV infection.

OBJECTIVES: Many children with HIV infection now survive into adulthood. This study explored the impact of vertically acquired HIV in the era of antiretroviral therapy on the development of humoral immunity. DESIGN: Natural and vaccine-related immunity to pneumococcus and B-cell phenotype was characterized and compared in three groups of young adults: those with vertically-acquired infection, those with horizontally acquired infection and healthy controls. METHODS: Serotype-specific pneumococcal (Pnc) immunoglobulin M and G concentrations before and up to 1 year post-Pnc polysaccharide (Pneumovax) immunization were determined, and opsonophagocytic activity was analysed. B-cell subpopulations and dynamic markers of B-cell signalling, turnover and susceptibility to apoptosis were evaluated by flow cytometry. RESULTS: HIV-infected patients showed impaired natural Pnc immunity and reduced humoral responses to immunization with Pneumovax; this was greatest in those viraemic at time of the study. Early-life viral control before the age of 10 years diminished these changes. Expanded populations of abnormally activated and immature B-cells were seen in both HIV-infected cohorts. Vertically infected patients were particularly vulnerable to reductions in marginal zone and switched memory populations. These aberrations were reduced in patients with early-life viral control. CONCLUSION: In children with HIV, damage to B-cell memory populations and impaired natural and vaccine immunity to pneumococcus is evident in early adult life. Sustained viral control from early childhood may help to limit this effect and optimize humoral immunity in adult life.

Rapid viral rebound after 4 years of suppressive therapy in a seronegative HIV-1 infected infant treated from birth.

Attention has focused on the possibility of cure for HIV infected infants if treated promptly after delivery. The "Mississippi baby," who had very prolonged remission after antiretroviral discontinuation, may represent a unique situation. We report an infant treated from birth, who seroreverted, remained virologically suppressed, and had undetectable HIV-1 RNA and DNA at 4 years of age, yet experienced virologic rebound within days of discontinuation of antiretroviral therapy.

Bovine γδ T cells: cells with multiple functions and important roles in immunity.

The γδ T-cell receptor (TCR)-positive lymphocytes are a major circulating lymphocyte population in cattle, especially in young calves. In contrast, human and mice have low levels of circulating γδ TCR(+) T cells (γδ T cells). The majority of the circulating γδ T cells in ruminants express the workshop cluster 1 (WC1) molecule and are of the phenotype WC1(+) CD2(-) CD4(-) CD8(-). WC1 is a 220000 molecular weight glycoprotein with homology to the scavenger receptor cysteine-rich (SRCR) family, closely related to CD163. The existence of 13 members in the bovine WC1 gene family has recently been demonstrated and although murine and human orthologues to WC1 genes exist, functional gene products have not been identified in species other than ruminants and pigs. Highly diverse TCRδ usage has been reported, with expanded variable genes in cattle compared to humans and mice. Differential γ chain usage is evident between populations of bovine γδ T cells, this may have implications for functionality. There is a growing body of evidence that WC1(+) γδ T cells are important in immune responses to mycobacteria and may have important roles in T cell regulation and antigen presentation. In this review, we will summarize recent observations in γδ T cell biology and the importance of γδ T cells in immune responses to mycobacterial infections in cattle.

Antibodies to citrullinated vimentin are a specific and sensitive marker for the diagnosis of rheumatoid arthritis.

BACKGROUND: The last 5 years have seen the emergence and establishment of antibodies to citrullinated antigens as the diagnostic marker for rheumatoid arthritis (RA). Initially, these were detected using a synthetic peptide, which has undergone a number of modifications to give a diagnostic test with a sensitivity of 65-80% and a specificity of >95%. Antibodies to citrullinated vimentin were first described in 1994 as a highly specific marker for RA (anti-Sa). However, no easily performed assay for these antibodies has been available. METHODS: We have examined the use of a ELISA-based assay with a mutated citrullinated vimentin (MCV) antigen (Orgentec, Mainz, Germany) to assess the diagnostic and prognostic utility of this antibody in RA. RESULTS: Antibodies to MCV were detected in the sera of 74% RA patients (specificity 96%), 2% systemic lupus erythematosus, 14% Sjögren's syndrome, and 2% scleroderma. Anti-MCV was not detected in sera from healthy blood donors. There was no difference in the frequency of antibodies detected in RA patients with early (<2 years) or chronic (>2 years) disease. There was no significant variation in anti-MCV antibody concentrations in early RA patients over a 52-week period. No significant change was observed with time between the two treatment groups of methotrexate alone or methotrexate plus infliximab. CONCLUSIONS: Antibodies to MCV are a specific and sensitive marker for the diagnosis of RA.