Interleukin-12 (IL-12) is a cytokine that promotes cell-mediated immunity to intracellular pathogens by inducing type 1 helper T cell (TH1) responses and interferon-gamma (IFN-gamma) production. IL-12 binds to high-affinity beta1/beta2 heterodimeric IL-12 receptor (IL-12R) complexes on T cell and natural killer cells. Three unrelated individuals with severe, idiopathic mycobacterial and Salmonella infections were found to lack IL-12Rbeta1 chain expression. Their cells were deficient in IL-12R signaling and IFN-gamma production, and their remaining T cell responses were independent of endogenous IL-12. IL-12Rbeta1 sequence analysis revealed genetic mutations that resulted in premature stop codons in the extracellular domain. The lack of IL-12Rbeta1 expression results in a human immunodeficiency and shows the essential role of IL-12 in resistance to infections due to intracellular bacteria.

Circulating memory B cells are severely reduced in the peripheral blood of HIV-1-infected patients. We investigated whether dysfunctional serologic memory to non-HIV antigens is related to disease progression by evaluating the frequency of memory B cells, plasma IgG, plasma levels of antibodies to measles, and Streptococcus pneumoniae, and enumerating measles-specific antibody-secreting cells in patients with primary, chronic, and long-term nonprogressive HIV-1 infection. We also evaluated the in vitro production of IgM and IgG antibodies against measles and S pneumoniae antigens following polyclonal activation of peripheral blood mononuclear cells (PBMCs) from patients. The percentage of memory B cells correlated with CD4 ؉ T-cell counts in patients, thus representing a marker of disease progression. While patients with primary and chronic infection had severe defects in serologic memory, long-term nonprogressors had memory B-cell frequency and levels of antigen-specific antibodies comparable with controls. We also evaluated the effect of antiretroviral therapy on these serologic memory defects and found that antiretroviral therapy did not restore serologic memory in primary or in chronic infection. We suggest that HIV infection impairs maintenance of long-term serologic immunity to HIV-1-unrelated antigens and this defect is initi- IntroductionThe ability to maintain an intact memory B-cell compartment is an essential component of the immune response to (re-) infections. 1 Maintenance of serologic memory is carried out by plasma cells and memory B cells [1][2][3] ; memory B cells play an essential role in the maintenance of antibody (Ab) levels by rapidly generating secondary immune responses upon reinfection or antigenic stimulation. 4 One of the most deleterious effects of HIV-1 infection is B-lymphocyte hyperactivation, which manifests as hypergammaglobulinemia, increased expression of activation markers, high spontaneous Ab production in vitro, and increased incidence of B-cell lymphomas. 5 Paradoxically, HIV-1-infected persons, especially those in advanced stages of disease, also have impaired humoral immune response to vaccination, and their B cells respond poorly to in vitro stimulation by common mitogens such as SAC and PWM. 5 Earlier studies suggest that naive and memory B cells differentially contribute to B-cell dysfunctions in HIV-1 infection. [6][7][8][9][10] Circulating memory B cells in peripheral blood from patients with chronic HIV-1 infection (CHI) are severely reduced and die by apoptosis. 6,11 Serum Abs against measles, tetanus toxoid, and HIV-1 antigens are significantly reduced in patients with low memory B cells, indicating that this phenotypic alteration may severely affect memory B-cell functions. 10 Recently, we reported that during primary HIV-1 infection (PHI), memory B cells are phenotypically and functionally altered though not significantly reduced in number. 12 These alterations were only partially recovered upon antiretroviral therapy (ART), suggesting that PHI sets the stage ...

Aims To characterize the demographic and pharmacogenetic factors that influence interpatient variability in the plasma concentrations of the HIV non‐nucleoside reverse transcriptase inhibitor efavirenz. Methods Data from all samples analyzed for efavirenz in our TDM service in 2002 and 2003 were reviewed. Information on gender, age, body weight, height, race, hormonal contraceptive use (in a subset of patients), and time between sampling and last intake was recorded. PCR‐restriction fragment length polymorphism analysis was performed to detect the cytochrome P450 2B6 (CYP2B6) C1459T variant (present in CYP2B6*6 and CYP2B6*7) which is associated with low CYP2B6 activity. Results A total of 255 patients were included in this analysis. The median plasma efavirenz concentration was 2.50 (interquartile range: 1.85–3.55) mg l−1. Eight patients (3.1%) were considered to have a subtherapeutic plasma concentration (<1.0 mg l−1) and 48 (18.9%) a toxic efavirenz concentration (>4.0 mg l−1). Gender, time after last intake, and race were the only factors that were significantly related to plasma efavirenz concentration in a multivariate analysis. No influence was observed for body weight, hormonal contraceptive use, and the presence of the CYP2B6 C1459T polymorphism. Conclusions Gender and race are important factors in determining interpatient variability in plasma efavirenz concentrations which were unaffected by the presence of the CYP2B6 C1459T polymorphism. Physicians should be particularly alert for signs of efavirenz‐induced toxicity in females and non‐Caucasian patients.

Antibody effector functions have been shown to be influenced by the structure of the Fc N-glycans. Here we studied the changes in plasma or serum IgG Fc N-glycosylation upon vaccination of 10 Caucasian adults and 10 African children. Serum/plasma IgG was purified by affinity chromatography prior to and at two time points after vaccination. Fc N-glycosylation profiles of individual IgG subclasses were determined for both total IgG and affinity-purified anti-vaccine IgG using a recently developed fast nanoliquid chromatography-electrospray ionization MS (LC-ESI-MS) method. While vaccination had no effect on the glycosylation of total IgG, anti-vaccine IgG showed increased levels of galactosylation and sialylation upon active immunization. Interestingly, the number of sialic acids per galactose increased during the vaccination time course, suggesting a distinct regulation of galactosylation and sialylation. In addition we observed a decrease in the level of IgG1 bisecting N-acetylglucosamine whereas no significant changes were observed for the level of fucosylation. Our data indicate that dependent on the vaccination time point the infectious agent will encounter IgGs with different glycosylation profiles, which are expected to influence the antibody effector functions relevant in immunity.

The clinical data and genotyping results are compatible with either interhuman transmission or an environmental source of infection. More complex models may account for PCP clusters.