The Nef-Infectivity Enigma: Mechanisms of Enhanced Lentiviral Infection

The Nef protein is an essential factor for lentiviral pathogenesis in humans and other simians. Despite a multitude of functions attributed to this protein, the exact role of Nef in disease progression remains unclear. One of its most intriguing functions is the ability of Nef to enhance the infectivity of viral particles. In this review we will discuss current insights in the mechanism of this well-known, yet poorly understood Nef effect. We will elaborate on effects of Nef, on both virion biogenesis and the early stage of the cellular infection, that might be involved in infectivity enhancement. In addition, we provide an overview of different HIV-1 Nef domains important for optimal infectivity and briefly discuss some possible sources of the frequent discrepancies in the field. Hereby we aim to contribute to a better understanding of this highly conserved and therapeutically attractive Nef function

Sex hormone-binding globulin at the crossroad of body composition, somatotropic axis and insulin/glucose homeostasis in young healthy men

OBJECTIVES:Sex hormone-binding globulin (SHBG) modulates the bioavailability of sex steroids at tissue level. Genetic, hormonal and lifestyle-related factors determine the SHBG levels, and low SHBG levels are a known risk factor for the development of the metabolic syndrome, diabetes and cardiovascular diseases. We investigated to what extent different determinants contribute to the variation in SHBG levels in healthy young men. DESIGN AND PATIENTS: Healthy male siblings (n = 677) aged 25-45 year were recruited in a cross-sectional, population-based study. MEASUREMENTS: Lean and fat mass were measured using dual-energy X-ray absorptiometry (DXA), and immunoassays were used to determine the serum hormonal levels. Additional information about smoking and physical activity was obtained using questionnaires. Carriers of two SHBG polymorphisms, the Asp327Asn polymorphism and the (TAAAA)(n) repeat polymorphism, were identified. RESULTS: Weight, BMI, whole body fat mass and truncal fat mass were negatively associated with SHBG levels. Body composition characteristics did not differ between SHBG genotype groups, indicating that body composition controls SHBG levels rather than the other way around. The associations may be mediated by adipokines because leptin and adiponectin were, respectively, inversely and positively associated with SHBG levels. Insulin and glucose were negatively associated with SHBG levels, as well as IGF-1 and IGF-BP3, while no associations were found with free thyroid hormone status. CONCLUSIONS: In conclusion, we found that fat mass, insulin and IGF-1 levels are important negative determinants of SHBG levels in young healthy men. The association with fat mass could be mediated by the effects of adiponectin and/or leptin on SHBG synthesis

Sex hormone-binding globulin as an independent determinant of cortical bone status in men at the age of peak bone mass

Context: Sex steroids are important determinants of the skeletal development, growth, and maintenance after achievement of peak bone mass. A large fraction of these hormones are bound by SHBG, and previous studies have shown that SHBG could be a determinant of bone characteristics. Objective: We investigated associations of serum SHBG levels with cortical and trabecular bone characteristics in young healthy men. Design and Settings: A total of 677 healthy male siblings aged 25-45 yr were recruited in a cross-sectional, population-based study. Main Outcomes: Areal bone parameters were assessed using dual-energy x-ray absorptiometry. Cortical bone parameters at the tibia and radius and trabecular vBMD at the radius were assessed using peripheral quantitative computed tomography. Serum testosterone, estradiol, and SHBG levels were measured using immunoassays. Results: Regression models including age, height, and weight showed that SHBG levels were positively associated with bone area at the hip and the whole body, but not with areal bone mineral density (BMD). Higher SHBG levels were associated with a larger cortical bone area and periosteal and endosteal circumferences at both the tibia and the radius, whereas trabecular volumetric BMD at the radius was negatively associated with SHBG levels. Associations persisted after adjustment for (free) sex steroid levels. No associations were found with cortical volumetric BMD or cortical thickness. Conclusion: In this population of healthy adult men at the age of peak bone mass, SHBG levels were positively associated with cortical bone size, independently from sex-steroid levels. This suggests a possible independent role of SHBG in the determination of adult bone size. (J Clin Endocrinol Metab 95: 1579-1586, 2010

Relation between fatty acid composition and clinical status or genotype in cystic fibrosis patients

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Birth weight in relation to sex steroid status and body composition in young healthy male siblings

Context: Sex steroid concentrations have a strong genetic determination, but environmental factors and body composition play an important role. From studies in children with intrauterine growth restriction, low birth weight has been associated with altered gonadotropin concentrations. Objective: We aim to investigate sex steroid concentrations in healthy young brothers in relation to birth weight (normal gestational age), body composition, and parental steroid concentrations. Design and Setting: We conducted a cross-sectional, population-based sibling pair study with inclusion of parental data. Participants: A total of 677 men (25-45 yr old) were included in this study, with 296 independent pairs of brothers and 122 fathers. Main Outcomes: We measured testosterone, estradiol, leptin, adiponectin, IGF-I (immunoassays), and free steroid hormones (calculated) in relation to birth weight and changes in body composition (dual-energy x-ray absorptiometry). Results: Birth weight was associated with serum testosterone (P = 0.0004)and SHBG (P = 0.0001), independent from weight, age, or fat mass, whereas no association with (free) estradiol, LH, or FSH was found. Paternal testosterone (P = 0.02), estradiol (P = 0.04), and SHBG (P = 0.0004) were associated with the respective sex steroid concentrations in the brothers. Weight increase (population rank) during life, was associated with lower testosterone (-15%; P < 0.001), independent from current weight and with higher free estradiol concentrations (+8%; P = 0.002), whereas weight decrease was associated with higher testosterone (+13%; P < 0.001). Conclusion: Birth weight and paternal steroid concentrations are associated with testosterone concentrations, independent from adult weight. These findings support the concept of in utero programming across the range of birth weight. (J Clin Endocrinol Metab 95: 1587-1594, 2010

Fat Mass Is Negatively Associated with Cortical Bone Size in Young Healthy Male Siblings

Context: Body weight has been associated with bone mass and bone size through shared genetic determination and environmental influences. Whereas lean mass exerts a positive influence on bone size, the relationship between fat and bone remains unclear. Objective: The objective of the present study was to investigate the individual influence of fat mass and lean mass on volumetric bone density and size in young healthy male siblings at age of peak bone mass. Design: This was a cross-sectional, population-based sibling pair study. Participants: A total of 677 men (25-45 yr) were included in this study with 296 independent pairs of brothers. Main Outcome Measures: Areal and volumetric bone parameters were determined using dual-energy X-ray absorptiometry (DXA) and peripheral quantitative computed tomography (pQCT). Body composition was determined by DXA. Sex steroids, leptin, and adiponectin were determined by immunoassay. Results: Total and regional fat mass were found to be inversely associated with areal bone mass and bonesize, independent from lean mass (radius periosteal circumference beta: - 0.29 +/- 0.04; P < 0.001). Lean mass was positively associated with bone size but inversely with cortical density at both tibia and radius (P < 0.01). The negative association between total fat mass and bone size was independent from sex steroid concentrations. Leptin but not adiponectin was inversely associated with bone size, but this was no longer significant after adjustment for body fat. Conclusions: Increased fat mass is associated with smaller bone size, challenging the view of a high bone mass index as a protective factor for osteoporosis, whereas lean mass was a consistent positive determinant of bone size