Country of residence is associated with distinct inflammatory biomarker signatures in HIV-infected patients.

Background: Inflammation and coagulation biomarkers are independent predictors of morbidity and mortality in HIV-infected patients. The impact of country of residence on these biomarkers is unknown and was investigated in persons at similar stages of HIV infection.

Methods: Cryopreserved plasma specimens were analysed from 267 ART-naive patients with CD4 cell counts <100 cells/μl from Mexico (=124) and South Africa (=143).

Administration of interleukin-7 increases CD4 T cells in idiopathic CD4 lymphocytopenia.

Idiopathic CD4 lymphopenia (ICL) is a rare syndrome defined by low CD4 T-cell counts (<300/µL) without evidence of HIV infection or other known cause of immunodeficiency. ICL confers an increased risk of opportunistic infections and has no established treatment. Interleukin-7 (IL-7) is fundamental for thymopoiesis, T-cell homeostasis, and survival of mature T cells, which provides a rationale for its potential use as an immunotherapeutic agent for ICL.

Meta-analysis in clinical trials revisited.

In this paper, we revisit a 1986 article we published in this Journal, Meta-Analysis in Clinical Trials, where we introduced a random-effects model to summarize the evidence about treatment efficacy from a number of related clinical trials. Because of its simplicity and ease of implementation, our approach has been widely used (with more than 12,000 citations to date) and the "DerSimonian and Laird method" is now often referred to as the 'standard approach' or a 'popular' method for meta-analysis in medical and clinical research. The method is especially useful for providing an overall effect estimate and for characterizing the heterogeneity of effects across a series of studies.

Clinically Indicated Corticosteroids Do Not Affect Bone Turnover During Immune Restoration of Severely Lymphopenic HIV-Infected Patients.

Unlabelled: Lymphopenia, corticosteroids, antiretroviral therapy (ART), and inflammation negatively impact bone turnover and decrease bone mineral density, but their combined effect has not been evaluated. We examined the association between corticosteroids on bone turnover markers in severely lymphopenic HIV-infected patients initiating ART. Levels of osteocalcin (bone formation marker) and C-terminal telopeptide (CTX; bone resorption marker) were measured at baseline, weeks 4, 12, and 48 of ART in individuals with severe lymphopenia and opportunistic infection (OI) who received (n=28) or did not receive corticosteroids (n=30) during the first year of ART, and in a control group with CD4 >200 (n=15).

Graves' disease as immune reconstitution disease in HIV-positive patients is associated with naive and primary thymic emigrant CD4(+) T-cell recovery.

Objective: Immune restoration disease (IRD) can develop in HIV-infected patients following antiretroviral therapy (ART) initiation as unmasking or paradoxical worsening of opportunistic infections and, rarely, autoimmune phenomena. Although IRD usually occurs in the first months of ART during memory CD4 T-cell recovery, Graves' disease occurs as a distinctive late-onset IRD and its pathogenesis is unclear.

Design: Seven patients who developed Graves' disease following ART initiation from the primary HIV care clinic at the National Institutes of Health were retrospectively identified and each was matched with two HIV-infected controls based on age, sex, and baseline CD4 T-cell count.

The development of CD4 binding site antibodies during HIV-1 infection.

Broadly neutralizing antibodies to the CD4 binding site (CD4bs) of gp120 are generated by some HIV-1-infected individuals, but little is known about the prevalence and evolution of this antibody response during the course of HIV-1 infection. We analyzed the sera of 113 HIV-1 seroconverters from three cohorts for binding to a panel of gp120 core proteins and their corresponding CD4bs knockout mutants. Among sera collected between 99 and 258 weeks post-HIV-1 infection, 88% contained antibodies to the CD4bs and 47% contained antibodies to resurfaced stabilized core (RSC) probes that react preferentially with broadly neutralizing CD4bs antibodies (BNCD4), such as monoclonal antibodies (MAbs) VRC01 and VRC-CH31.

Decreased interleukin 7 responsiveness of T lymphocytes in patients with idiopathic CD4 lymphopenia.

Background: Elevated serum interleukin 7 (IL-7) levels are observed in lymphopenic conditions, including idiopathic CD4 lymphopenia (ICL), which is characterized by CD4 lymphopenia in the absence of human immunodeficiency virus infection or other known immunodeficiency.

Methods: To test whether defective IL-7 signaling could be an etiologic or contributing factor in ICL, peripheral blood mononuclear cells from patients with ICL (median CD4 T-cell count, 160 cells/μL) and healthy controls (median CD4 T-cell count, 582 cells/μL) were evaluated for expression of IL-7Rα chain (CD127) and intracellular phosphorylated STAT-5 (a marker of γc cytokine signaling) after cytokine stimulation. Gene expression was analyzed by real-time polymerase chain reaction following IL-7 stimulation.

Selective expansion of polyfunctional pathogen-specific CD4(+) T cells in HIV-1-infected patients with immune reconstitution inflammatory syndrome.

Since the introduction of highly active antiretroviral therapies (ART), the prognosis for HIV-1 patients has improved immensely. However, approximately 25% of patients can experience a variety of inflammatory symptoms that are collectively known as immune reconstitution inflammatory syndrome (IRIS). Studying the etiology and immunopathology of IRIS has been hampered by the fact that the symptoms and associated opportunistic infections are highly varied.

The effect of leflunomide on cycling and activation of T-cells in HIV-1-infected participants.

Background: The pathogenesis of immunodeficiency due to human immunodeficiency virus (HIV)-1 is incompletely understood, but immune activation is believed to play a central role. Immunomodulatory agents that decrease immune activation may be useful in the treatment of HIV-1 infection.

Methodology: A randomized, double blind, placebo-controlled pilot study of leflunomide for 28 days was performed in participants with HIV-1 infection who were not receiving antiretroviral therapy.

Elevated frequencies of highly activated CD4+ T cells in HIV+ patients developing immune reconstitution inflammatory syndrome.

Immune reconstitution inflammatory syndrome (IRIS) is a considerable problem in the treatment of HIV-infected patients. To identify immunologic correlates of IRIS, we characterized T-cell phenotypic markers and serum cytokine levels in HIV patients with a range of different AIDS-defining illnesses, before and at regular time points after initiation of antiretroviral therapy. Patients developing IRIS episodes displayed higher frequencies of effector memory, PD-1(+), HLA-DR(+), and Ki67(+) CD4(+) T cells than patients without IRIS.

CD4+ T cell responses to interleukin-2 administration in HIV-infected patients are directly related to the baseline level of immune activation.

Background: Intermittent interleukin (IL)-2 administration to human immunodeficiency virus (HIV)-infected patients leads to CD4(+) T cell expansions. The factors potentially affecting these expansions were investigated in the present study.

Methods: A matched (for baseline CD4(+) T cell count) case-control study was designed.

Random-effects model for meta-analysis of clinical trials: an update.

The random-effects model is often used for meta-analysis of clinical studies. The method explicitly accounts for the heterogeneity of studies through a statistical parameter representing the inter-study variation. We discuss several iterative and non-iterative alternative methods for estimating the inter-study variance and hence the overall population treatment effect.

Incomplete CD4 T cell recovery in HIV-1 infection after 12 months of highly active antiretroviral therapy is associated with ongoing increased CD4 T cell activation and turnover.

To evaluate the relationship between T cell turnover, immune activation, and CD4 recovery in HIV infection, 32 antiretroviral-naive HIV-1-infected patients were studied before and after initiation of highly active antiretroviral therapy (HAART). Elevated CD4 and CD8 T cell turnover (measured by Ki67) in HIV infection decreased with HAART in blood and lymphoid tissue. Increased peripheral CD4 T cell turnover was strongly associated with immune activation even after viral suppression to less than 50 copies/mL (R = 0.