Use of serum retinol-binding protein for prediction of vitamin A deficiency: effects of HIV-1 infection, protein malnutrition, and the acute phase response

BACKGROUND: Serum retinol is the most commonly used indicator of vitamin A status. Retinol is transported in a 1-to-1 complex with retinol-binding protein (RBP). RBP is easy and inexpensive to measure, and studies have shown a high correlation between concentrations of RBP and concentrations of retinol. The performance of RBP in the context of infection or protein malnutrition, however, has not been evaluated. OBJECTIVE: Our aim was to determine whether RBP is a good surrogate measure for retinol in the context of HIV-1 infection, protein malnutrition, and the acute phase response. DESIGN: The relation between RBP and retinol was examined in a cross-sectional study of 600 Kenyan women. RESULTS: There was a high correlation between concentrations of RBP and those of retinol (r = 0.88). When equimolar cutoffs were used, RBP predicted marginal vitamin A status (retinol < 1.05 micro mol/L) with 93% sensitivity and 75% specificity and vitamin A deficiency (retinol < 0.70 micro mol/L) with 91% sensitivity and 94% specificity. Similarly high sensitivities and specificities were found among subgroups with HIV-1 infection, a positive acute phase response, and protein malnutrition. Protein malnutrition and a positive acute phase response were common, especially among HIV-1-infected women, and were independently and synergistically associated with lower RBP concentrations. CONCLUSIONS: Equimolar RBP cutoffs predict vitamin A deficiency with high sensitivity and specificity, even in the context of infection and protein malnutrition. Like retinol, RBP may not accurately identify true vitamin A status under all conditions, because the acute phase response and protein malnutrition depress RBP concentrations. However, RBP may be a simple, inexpensive tool for assessment of vitamin A deficiency in population studies.     

Use of the retinol-binding protein: transthyretin ratio for assessment of vitamin A status during the acute-phase response

The ratio plasma retinol-binding protein (RBP):transthyretin (TTR) has been proposed as a means to improve the assessment of vitamin A status of individuals with concurrent infection or inflammation. We have measured RBP and TTR in stored sera from South African children who had accidentally ingested kerosene. Samples were collected from these children in hospital when suffering acute inflammation and respiratory distress, and from them and neighbourhood control children 3 months later. Vitamin A status was defined by modified relative dose response (MRDR) tests of liver retinol stores at 3 months and by serum retinol concentration both when children were ill and when they were well. Illness was defined as either being in hospital or, at follow-up, as having a raised plasma alpha 1-acid glycoprotein (AGP) level. The RBP:TTR value was significantly decreased by both illness and low liver retinol stores. When the effects on RBP:TTR of illness and vitamin A stores were considered together for the 3-month follow-up samples, only vitamin A status significantly decreased the value. We calculated sensitivity and specificity of the RBP:TTR ratio against established measures of vitamin A status using a cut-off value of 0.3 for RBP:TTR and standard cut-off values for MRDR (0.06) and plasma retinol (0.7 mumol/l). Compared with MRDR, RBP:TTR had sensitivities of 76% and 43% and specificities of 22% and 81% to detect vitamin A deficiency in hospitalized and well children respectively. Compared with plasma retinol, sensitivities were 88% and 44% and specificities were 55% and 64% in hospitalized and well children respectively. Only for the case of clinically well children with biochemical evidence of subclinical inflammation did sensitivity (62% and 100% against MRDR and plasma retinol respectively) and specificity (100% and 60% against MRDR and retinol) approach useful levels for an assessment tool. Overall, although a trend supporting the theory behind the use of the RBP:TTR for assessment of vitamin A status in infection was observed in the current study, the ratio did not provide adequate sensitivity and specificity to be a useful assessment tool.     

HIV-1急性感染期的免疫应答特征

HIV-1感染早期的生物学特征及免疫学应答可能是决定艾滋病病程的一个重要因素.近来有研究发现初始有效的免疫应答可驱动病毒逃逸突变的产生,这使得人们对抵御病毒传播的早期免疫应答和急性期病毒血症的控制有了进一步的认识.强烈的固有免疫应答和获得性免疫应答在感染后即可发生,但对于清除病毒却为时已晚.此文讨论了近年来关于HIV-I感染早期免疫应答动力学和特征方面的研究及其对研制有效预防性疫苗的意义.     

Synthesis of retinol-binding protein and transthyretin in yolk sac and fetus in the rat

Levels of retinol-binding protein (RBP) and transthyretin (TTR) were determined in rat maternal livers, placenta, yolk sac, whole fetuses and fetal livers at different stages of gestation. Yolk sac concentrations of RBP and TTR expressed as micrograms per mg protein were three- to fivefold higher than liver values. TTR (moles) in the whole fetus was higher than RBP at all stages of gestation. Fetal hepatic RBP concentration was relatively constant throughout gestation, where fetal hepatic TTR concentration was low until close to parturition. RBP was observed in fetal microsomes at 12 d gestation. Incorporation of labeled amino acids into both RBP and TTR in vitro was observed in the yolk sac. In the 20-d fetal liver, incorporation to RBP and TTR was observed, whereas at 14 d gestation, incorporation only to RBP was observed. A small amount of synthesis of both proteins was also observed in the placenta. In the fetal circulation at 20-21 d gestation, no TTR-RBP complex was observed; instead a broad peak of RBP was found eluting at 20,000-40,000 daltons on gel chromatography. Incubation of fetal serum with maternal TTR resulted in an RBP peak eluting with an Mr of approximately 40,000. Treatment of the fetal serum with either lysozyme, neuraminidase or endoglycosidase H resulted in a 20,000 dalton RBP peak and following incubation with maternal TTR, a 70,000 dalton RBP-TTR complex was formed. Yolk sac, fetal liver and amniotic fluid on gel filtration exhibited a 40,000-20,000 dalton RBP peak. It is suggested that retinol transport in the fetus may involve RBP and TTR synthesized in the yolk sac as well as in fetal tissue.(ABSTRACT TRUNCATED AT 250 WORDS)     

艾滋病毒1型急性感染研究进展

2009年,据联合国估计在世界范围内约有3320万人感染HIV-1,约有260万人为新发感染,因此,对HIV-1感染的预防迫在眉睫.此文综述了HIV-1传播和急性感染方面的重大进展.     

The molar ratio of serum retinol-binding protein (RBP) to transthyretin (TTR) is not useful to assess vitamin A status during infection in hospitalised children.

OBJECTIVE: To assess the usefulness of the molar ratio of serum retinol-binding protein (RBP) to transthyretin (TTR) to determine vitamin A (VA) status during infection. DESIGN: We took advantage of previously collected data during a randomised double-blind, placebo-controlled clinical trial to conduct a secondary analysis of the RBP/TTR ratio and its relationship to infection and VA status. In this clinical trial, children were randomly assigned to one of three groups and received either one single oral high dose of VA (200 000 IU) on the day of admission and subsequently a placebo daily until discharge or daily oral low doses of VA (5000 IU) from admission until discharge or a placebo daily from admission until discharge. SETTING: Lwiro pediatric hospital, Province of South Kivu, Democratic Republic of Congo. SUBJECTS: A total of 900 children aged 0-72 months hospitalised consecutively between March 1994 and March 1996. MAIN OUTCOME MEASURES: RBP/TTR molar ratio after 7 days hospitalisation. RESULTS: After 7 days hospitalisation, molar RBP:TTR ratio (mean+/-s.d.) of infected children (C-reactive proteins>10 mg/l) was 0.67+/-0.31 in the high-dose group (n=81), 0.74+/-0.44 in the low dose group (n=71) and 0.73+/-0.39 in the placebo group (n=81). These values did not differ significantly (one-way ANOVA P=0.472). In patients with baseline serum retinol concentrations<0.70 micromol/l, changes in RBP:TTR ratio between admission and day 7 were not statistically different in the three groups (one-way ANOVA P=0.548). CONCLUSIONS: In this population of malnourished hospitalised children, molar RBP:TTR ratio does not appear to be useful to assess VA status during infection. SPONSORSHIP: Our research was partially supported by a grant from the Fonds de la Recherche Scientifique et Médicale (contract 3.4505.94) and the David and Alice Van Buuren Foundation.     

急性HIV-1感染的传播和预防

人免疫缺陷病毒-1(HIV-1)感染的急性期,机体的免疫系统面临巨大的挑战,难以将病毒清除。对病毒入侵后急性前期机体免疫反应及与病毒相互作用的研究,能促进有效的抗病毒药物和疫苗的开发,对于艾滋病的防治将起到积极的作用。     

Determination of a cut-off value for the molar ratio of retinol-binding protein to transthyretin (RBP:TTR) in Bangladeshi patients with low hepatic vitamin A stores

The purpose of this study was to determine a cut-off value of the molar ratio of retinol-binding protein to transthyretin (RBP:TTR) to indicate marginal vitamin A (VA) deficiency. Plasma RBP and TTR were measured by radial immunodiffusion in two groups of patients, i.e., surgical patients with known hepatic VA stores, and a cohort of children residing in a malaria-endemic area of Papua New Guinea who had received placebo or 210 micro mol of VA every 3 mo for 9 mo. A RBP:TTR ratio < or =0.36 selectively detected five of seven patients (71% sensitivity) with hepatic VA stores < or =69.9 nmol/g of tissue (i.e., < or =20 micro g/g), indicative of marginal VA deficiency. Using this cut-off value, 28% (n = 245) of children from Papua New Guinea had marginal VA deficiency before supplementation. After 7 mo, a low ratio persisted in 29% (n = 92) of placebo-treated children but in only 11% (n = 83) of those receiving VA supplements (chi(2), P < 0.01). At the end of the study, 13 mo after initiation or 4 mo after the last dose of VA, the percentage of children with a low ratio was still lower (chi(2), P < 0.02) in the VA group, 42.5% (n = 113) than in the placebo group, 58.6% (n = 118). These results demonstrate that a cut-off value < or =0.36 is indicative of marginal VA deficiency and can be used as an indirect method of VA assessment.     

Presence of HIV-1 Nef specific CD4 T cell response is associated with non-progression in HIV-1 infection

The ex vivo response to three HLA-DR-restricted Nef peptides (Nef 66-97, Nef 133-159, Nef 180-202) and one HLA-DQ-restricted Nef peptide (Nef 56-68) was evaluated in 28 HIV-seropositive patients and 6 Long-term Non-Progressors (LTNPs). Analyzing specific proliferative response and IFN-gamma secretion, patients were identified as high responders, medium responders and non-responders to peptides. As high responder patients, LTNP patients showed strong proliferative response to all the Nef-peptides as strong IFN-gamma secretion. Twenty-four months later, all high responder patients were always without antiretroviral treatment whereas 50% of medium responders and at least 66% of low responder patients followed bi-therapy. CDC classification confirmed also unfavourable evolution for these two last groups. All high responder patients conserved stable CD4 counts, proliferative response to Nef peptides as strong IFN-gamma secretion during this 24-month period. So, early good T CD4 response to peptides of the Nef protein could thus be regarded as a factor of good prognosis in HIV infection and a tool of importance in the decision to put or not a patient under treatment.     

Documented male-to-female transmission of HIV-1 after minimal vaginal exposure in the absence of other cofactors for infection

AIDS cases attributable to heterosexual vaginal intercourse constitute a growing proportion of new AIDS cases in the United States. Major cofactors that possibly increase the efficiency of heterosexual transmission of HIV-1 include genital ulcer disease, multiple sexual exposures, lack of male circumcision, and primary and advanced stages of HIV-1 disease. I report the case of a 33-year-old woman who was recently infected with HIV-1 after one to three nontraumatic episodes of vaginal intercourse with a healthy-appearing, HIV-1-infected, bisexual man. An investigation of her exposure history revealed the precise time frame during which infection occurred. The patient developed a primary HIV-1-infection syndrome and became seropositive for HIV-1 within eight weeks of her last sexual contact with the infected man. An epidemiological and laboratory evaluation of the index patient and her sexual partner identified only one risk factor for enhanced HIV-1 transmission: the patient's use of oral contraceptives. Her partner was immunologically intact, HIV-1 antigen negative, and circumcised. Both of the individuals were from Minnesota, as were their recent sexual partners. This case illustrates that HIV-1 infection by vaginal intercourse can occur in the absence of the major risk factors believed to increase the efficiency of transmission. Even in a low HIV-1 prevalence area like Minnesota, efforts to promote awareness of HIV-1 status, abstinence, non-penetrative sex, or barrier protection need to be expanded and the behaviors adopted by sexually active persons if HIV-1 transmission is to be minimized.     

The magnitude of the acute phase protein response is attenuated by protein deficiency in rats.

We assessed the growth rate and changes in plasma albumin, total protein and alpha 2-macroglobulin concentrations (a major acute phase protein in rats) before and after a subcutaneous injection of turpentine (0.5 mg/kg body wt) in groups of rats receiving one of a series of protein-deficient diets (protein concentrations of 0.5, 1.5, 3.0, 4.5 or 6.0 g/100 g) or a diet containing an adequate level of protein (20 g/100 g) for maximal growth. Increasing protein deficiency in the different groups of animals reduced the basal albumin and total protein concentrations and attenuated the total protein and alpha 2-macroglobulin responses to turpentine. Increasing protein deficiency delayed the time taken for alpha 2-macroglobulin to reach peak concentrations post-injection and its return to basal concentrations. The turpentine-induced hypoalbuminemia was similar in all groups of animals (approximately 10 g/L depression) but restoration to values that were present before turpentine injection was increasingly delayed with increasing protein deficiency. The magnitude of the acute phase response (peak alpha 2-macroglobulin concentration) was found to be directly related to growth rate (r = 0.70, P less than 0.001). We concluded that protein deficiency can alter the pattern and magnitude of the acute phase responses in circulating protein concentrations to an extent that is dependent on the severity of protein deficiency.     

重症医院感染患者急性时相蛋白的临床研究

目的为了探讨急性时相蛋白在重症医院感染患者发病过程中的变化及其诊断价值。方法采用全自动散射比浊定量分析法测定２２例重症医院感染患者ＣＲＰ、α１ＡＴ、α１ＡＧ及ＨＰ的含量和动态变化,并与２６例轻症医院感染患者及２０例正常人对照分析。结果重症医院感染患者首次测定ＣＲＰ、α１ＡＴ、α１ＡＧ及ＨＰ含量均显著高于轻症医院感染组和正常组（Ｐ值分别＜０．０１）。动态观察发现急性时相蛋白随着病情好转逐渐降至正常范围,而６例重症死亡组ＣＲＰ因病情恶化呈上升趋势,但α１ＡＧ、ＨＰ却呈持续性下降。轻症医院感染患者ＣＲＰ、α１ＡＴ、ＨＰ与正常组无明显差异,仅α１ＡＧ差异显著（Ｐ＜０．０５）。结论ＣＲＰ、α１ＡＴ、α１ＡＧ及ＨＰ的定量分析是一种快速、灵敏的检测手段,对于尽早发现医院感染、准确判断其严重程度及预后具有重要价值。ＣＲＰ持续升高,α１ＡＧ和ＨＰ迅速下降则提示病情恶化     

Safety and immunogenicity of an adjuvanted protein therapeutic HIV-1 vaccine in subjects with HIV-1 infection: A randomised placebo-controlled study

The human immunodeficiency virus type-1 (HIV-1) vaccine candidate F4/AS01 has previously been shown to induce potent and persistent polyfunctional CD4⁺ T-cell responses in HIV-1-seronegative volunteers. This placebo-controlled study evaluated two doses of F4/AS01 1-month apart in antiretroviral treatment (ART)-experienced and ART-naïve HIV-1-infected subjects (1:1 randomisation in each cohort). Safety, HIV-1-specific CD4⁺ and CD8⁺ T-cell responses, absolute CD4⁺ T-cell counts and HIV-1 viral load were monitored for 12 months post-vaccination. Reactogenicity was clinically acceptable and no vaccine-related serious adverse events were reported. The frequency of HIV-1-specific CD4⁺ T-cells 2 weeks post-dose 2 was significantly higher in the vaccine group than in the placebo group in both cohorts (p < 0.05). Vaccine-induced HIV-1-specific CD4⁺ T-cells exhibited a polyfunctional phenotype, expressing at least CD40L and IL-2. No increase in HIV-1-specific CD8⁺ T-cells or change in CD8⁺ T-cell activation marker expression profile was detected. Absolute CD4⁺ T-cell counts were variable over time in both cohorts. Viral load remained suppressed in ART-experienced subjects. In ART-naïve subjects, a transient reduction in viral load from baseline was observed 2 weeks after the second F4/AS01 dose, which was concurrent with a higher frequency of HIV-1-specific CD4⁺ T-cells expressing at least IL-2 in this cohort. In conclusion, F4/AS01 showed a clinically acceptable reactogenicity and safety profile, and induced polyfunctional HIV-1-specific CD4⁺ T-cell responses in ART-experienced and ART-naïve subjects. These findings support further clinical investigation of F4/AS01 as a potential HIV-1 vaccine for therapeutic use in individuals with HIV-1 infection.     

Analysis of the immune response and viral evolution during the acute phase of SIV infection

Development of an effective vaccine against human immunodeficiency virus (HIV) will require knowledge of the immune responses that correlate with protection. During the acute phase of HIV infection the host immune responses appear to control viral replication. It is thought that virus-specific cellular immunity is intimately involved in this viral control. We have developed a model system to measure the entire T cell response and viral evolution in the face of this onslaught in rhesus macaques during the acute phase of infection with molecularly cloned simian immunodeficiency virus (SIV). We used intracellular cytokine staining (ICS) of peripheral blood mononuclear cells (PBMCs) from animals during the acute phase of viral infection stimulated with peptides spanning the entire protein sequence of SIV to determine which peptides were recognized by CD8 and CD4 positive T cells. Furthermore, we sequenced the entire virus during the acute phase of infection. This approach has proved highly effective for measuring acute phase T cell responses and viral evolution in SIV-infected rhesus macaques and might facilitate the definition of cellular immune responses in HIV-infected humans during the acute phase.     

HIV-1新发感染检测技术在新发感染率估计中的应用

HIV新发感染率是反映HIV流行水平、评估预防控制措施效果和卫生资源分配的重要依据.根据HIV-1 RNA、p24抗原和HIV特异性抗体不同特性,不管是在血清阳转前还是阳转后,利用HIV-1新发感染检测技术,通过单次血清标本检测就可以区分新发感染或既往感染,为HIV-1新发感染率估计提供便捷、实用的方法.     

Use of retinol-binding protein and prealbumin as indicators of the response to nutrition therapy

There is no single available measurement for evaluating the short-term response to nutrition therapy. The ideal parameter should have high sensitivity and specificity and should be unaffected by non-nutritional factors. A literature review suggested that plasma retinol-binding protein and prealbumin concentrations change earlier than albumin and transferrin levels and appear to correlate better with nitrogen balance during nutrition therapy. That conclusion was supported by our own findings in patients receiving total parenteral nutrition and following the transition to oral or enteral feedings. Although concentrations of these plasma proteins have been shown to be affected by stress and renal and hepatic disease, they appear to be more sensitive indicators of the adequacy of nutrition support than other more commonly used assessment parameters.     

Prenatal protein malnutrition induces a phase shift advance of the spontaneous locomotor rhythm and alters the rest/activity ratio in adult rats

Abstract

Evidence is accumulating for significant structural and functional changes within the central nervous system (CNS) following prenatal protein malnutrition. Included among the structures that are likely to be affected are the suprachiasmatic nuclei (SCN) involved in the regulation of locomotor activity, sleep-wake cycle, and drinking behavior. To determine the effects of prenatal protein malnutrition on the spontaneous activity rhythm, 24h radiotelemetric measurements were recorded over an 8-day period. Male offspring of rats provided with protein-deficient (6% casein) or adequate (25% casein) diets for 5 weeks prior to mating and throughout pregnancy were studied. Well nourished rats displayed a rise in activity level during the first hour of the 12h light phase, whereas prenatally malnourished rats displayed this increase during the 12h dark phase, approximately 50min before lights on, reflecting a significant phase advance in this group. In addition, cosinor analysis revealed that the alpha/rho relationship was affected in the previously malnourished group, the activity phase being shorter than in the well-nourished animals. These findings suggest changes in the regulatory systems controlling the locomotor activity rhythm as a consequence of prenatal protein malnutrition. Alterations in entrainment to the light–dark cycle, and/or in the coupling force of the circadian oscillators are all candidate mechanisms.     

Prenatal protein malnutrition induces a phase shift advance of the spontaneous locomotor rhythm and alters the rest/activity ratio in adult rats

Evidence is accumulating for significant structural and functional changes within the central nervous system (CNS) following prenatal protein malnutrition. Included among the structures that are likely to be affected are the suprachiasmatic nuclei (SCN) involved in the regulation of locomotor activity, sleep-wake cycle, and drinking behavior. To determine the effects of prenatal protein malnutrition on the spontaneous activity rhythm, 24 h radiotelemetric measurements were recorded over an 8-day period. Male offspring of rats provided with protein-deficient (6% casein) or adequate (25% casein) diets for 5 weeks prior to mating and throughout pregnancy were studied. Well nourished rats displayed a rise in activity level during the first hour of the 12h light phase, whereas prenatally malnourished rats displayed this increase during the 12h dark phase, approximately 50 min before lights on, reflecting a significant phase advance in this group. In addition, cosinor analysis revealed that the alpha/rho relationship was affected in the previously malnourished group, the activity phase being shorter than in the well-nourished animals. These findings suggest changes in the regulatory systems controlling the locomotor activity rhythm as a consequence of prenatal protein malnutrition. Alterations in entrainment to the light-dark cycle, and/or in the coupling force of the circadian oscillators are all candidate mechanisms.