Host factor transcriptional regulation contributes to preferential expression of HIV type 1 in IL-4-producing CD4 T cells.

HIV type 1 (HIV-1) replicates preferentially in IL-4-producing CD4 T cells for unclear reasons. We show increased HIV-1 expression is irrespective of viral tropism for chemokine receptors as previously suggested, but rather transcription of the HIV-1 long terminal repeat (LTR) is increased in IL-4-producing CD4 T cells. Increased expression of HIV-1 message is also confirmed in IL-4-producing CD4 T cells from HIV-1-infected individuals ex vivo. In exploring a transcriptional mechanism, we identify a novel c-maf (required for IL-4 expression) transcription factor binding site just upstream of the dual NF-κB/NFAT binding sites in the proximal HIV-1 LTR. We demonstrate that c-maf binds this site in vivo and synergistically augments HIV-1 transcription in cooperation with NFAT2 and NF-κB p65, but not NFAT1 or NF-κB p50. Conversely, small interfering RNA inhibition of c-maf reduces HIV-1 transcription in IL-4-producing T cells. Thus, c-maf increases HIV-1 expression in IL-4-producing CD4 T cells by binding the proximal HIV-1 LTR and augmenting HIV-1 transcription in partnership with NFAT2 and NF-κB p65 specifically. This has important implications for selective targeting of transcription factors during HIV-1 infection because, over the course of HIV-1 progression/AIDS, IL-4-producing T cells frequently predominate and substantially contribute to disease pathology.

Growing pains: a noninflammatory pain syndrome of early childhood.

The term 'growing pains' has been used for almost 200 years to refer to the often severe, generally bilateral lower-extremity nocturnal pains experienced by up to one-third of all children at some time during early childhood. No clear mechanism has yet been identified that explains these pains, but there is an increasing body of evidence indicating that several factors, individually or in combination, might be responsible for this phenomenon. These include mechanical factors, such as joint hypermobility and flat feet, decreased pain thresholds, reduced bone strength, and emotional factors involving the patient's family and other social stressors. Correct diagnosis of growing pains requires a thorough patient history and physical examination. The diagnosis can be safely established without unnecessary laboratory investigations or imaging; however, identification of one or more clinical cautionary signs, such as unilateral pain, morning stiffness, joint swelling and systemic symptoms (e.g. fever, weight loss and malaise), should trigger an extended evaluation to exclude other more serious conditions that might also present with limb pain. Once the diagnosis has been established, conservative management, using symptomatic pain medications, massage and other supportive measures, should be employed until the syndrome self-resolves with time.

Genetic effects on age-dependent onset and islet cell autoantibody markers in type 1 diabetes.

Age-dependent associations between type 1 diabetes risk genes HLA, INS VNTR, and CTLA-4 and autoantibodies to GAD65 (GADAs), ICA512/IA-2, insulin, and islet cells were determined by logistic regression analysis in 971 incident patients with type 1 diabetes and 702 control subjects aged 0-34 years. GADAs were associated with HLA-DQ2 in young but not in older patients (P = 0.009). Autoantibodies to insulin were negatively associated with age (P < 0.0001) but positively associated with DQ8 (P = 0.03) and with INS VNTR (P = 0.04), supporting possible immune tolerance induction. ICA512/IA-2 were negatively associated with age (P < 0.0001) and with DQ2 (P < 0.0001) but positively associated with DQ8 (P = 0.04). Males were more likely than females to be negative for GADA (P < 0.0001), autoantibodies to islet cells (P = 0.04), and all four autoantibody markers (P = 0.004). The CTLA-4 3' end microsatellite marker was not associated with any of the autoantibodies. We conclude that age and genetic factors such as HLA-DQ and INS VNTR need to be combined with islet autoantibody markers when evaluating the risk for type 1 diabetes development.