Causal pathways of the effects of age and the CCR5-Delta32, CCR2-64I, and SDF-1 3'A alleles on AIDS development

OBJECTIVE: To investigate the causal pathways by which age and the CCR5-Delta32, CCR2-64I, and SDF-1 3'A alleles influence progression to AIDS. DESIGN: Analysis of follow-up data from 2 cohort studies among homosexual men (n=400), having >10 years of follow-up. METHODS: The effects of the 4 cofactors on the CD4 and HIV-1 RNA trajectories after seroconversion were modeled in a random-effects model. A proportional hazards model was used to investigate their effect on the risk of AIDS after correction for CD4 cell count and RNA level. This approach allows investigation as to whether they influence AIDS progression by affecting CD4 count and RNA level or by other pathways. RESULTS: Persons of younger age or having the CCR2-64I or SDF-1 3'A mutation have significantly higher CD4 levels. Persons with the CCR5-Delta32 deletion or CCR2-64I mutation have significantly lower RNA levels. After correction for both CD4 count and RNA level, only the SDF-1 3'A mutation significantly increases the AIDS risk. CONCLUSIONS: Age and the CCR5-Delta32 deletion and CCR2-64I mutation influence AIDS progression by affecting CD4 and HIV-1 RNA. The SDF-1 3'A allele increases the AIDS risk, but this effect is countered by its effect on CD4 and HIV-1 RNA level.     

Sequencing of the alpha-synuclein gene in a large series of cases of familial Parkinson's disease fails to reveal any further mutations. The European Consortium on Genetic Susceptibility in Parkinson's Disease (GSPD)

A mutation in exon 4 of the human alpha-synuclein gene was reported recently in four families with autosomal dominant Parkinson's disease (PD). In order to examine whether mutations in this exon or elsewhere in the gene are common in familial PD, all seven exons of the alpha- synuclein gene were amplified by PCR from index cases of 30 European and American Caucasian kindreds affected with autosomal dominant PD. Each product was sequenced directly and examined for mutations in the open reading frame. No mutations were found in any of the samples examined. We conclude that the A53T change described in the alpha- synuclein gene is a rare cause of PD or may even be a rare variant. Mutations in the regulatory or intronic regions of the gene were not excluded by this study.      

Assessment of vital exhaustion and identification of subjects at increased risk of myocardial infarction in general practice

Vital exhaustion, a state characterized by unusual fatigue, loss of energy, increased irritability, and feelings of demoralization, is one of the cardiovascular risk factors. The authors investigated whether vital exhaustion contributes to the identification of subjects at increased risk of myocardial infarction in general practice. In this prospective cohort study, vital exhaustion was assessed with the Maastricht Interview on Vital Exhaustion. Other cardiovascular risk factors established were age, gender, systolic and diastolic blood pressure, total cholesterol, body mass index, smoking habits, cardiovascular disease, and diabetes mellitus. A Cox regression analysis was used. The subjects were adults (41-66 years) in an average Dutch village population. Outcome measures were fatal and nonfatal myocardial infarction. At the univariate level, vital exhaustion doubled the risk of myocardial infarction. The effect of exhaustion was confounded by gender; women had higher exhaustion scores and a lower incidence of myocardial infarction. With control for gender, age, systolic blood pressure, total cholesterol, smoking habits, self-reported cardiovascular disease, and diabetes mellitus, vital exhaustion almost tripled the risk of myocardial infarction. Assessment of vital exhaustion contributes to the identification of subjects at increased risk of myocardial infarction in general practice.     

De visie van Europese farmaciestudenten op studie en beroep

In view of the mutual recognition of the pharmacy degree in the European Community, a survey was held in the spring of 1979 in Cardiff (United Kingdom), Frankfurt (Federal Republic of Germany) and Leiden (The Netherlands) among 70, 47 and 51 senior pharmacy students respectively. They were asked for their personal background and their opinions on the following subjects: the study of pharmacy, duties of the retail pharmacist, presentation of information to physicians and patients, the consumption of medicines, the working conditions for retail pharmacists and the mutual recognition of pharmacy qualifications within the EC. Questions on these subjects were presented in the form of a questionnaire. The responses were analysed by means of a number of computer programs, including that of Homals-1, a technique for the multidimensional analysis of categoric data. The results reflect the views in each separate city as well as the differences between the cities. For example, students in all three cities were unanimous in their views that providing information to patients and physicians should be one of the major activities of the pharmacist, which, according to the students, is not the case at the present time. With respect to mutual recognition, a number of objections were raised by students in Leiden, while Cardiff students had no objections and students from Frankfurt took an intermediate position.Samenvatting Met het oog op een wederzijdse erkenning van het apothekersdiploma in de Europese Gemeenschap, zijn in het voorjaar van 1979 in Cardiff (Verenigd Koninkrijk), Frankfurt (Bondsrepubliek Duitsland) en Leiden (Nederland) respectievelijk 70, 47 en 51 ouderejaars farmaciestudenten geënquÊteerd. Gevraagd is naar hun persoonlijke achtergrond en naar hun mening over de farmaciestudie, de taken van de officine apotheker, de voorlichting aan arts en patiënt, de geneesmiddelenconsumptie, de werkomstandigheden van de officine apotheker en de wederzijdse erkenning van het apothekersdiploma in de EG. Vragen over genoemde onderwerpen werden gesteld door middel van een vragenlijst. Voor de analyse van de antwoorden werd gebruik gemaakt van een aantal computerprogramma's waaronder Homals-1, een techniek voor de meer-dimensionale analyse van categorische gegevens. De resultaten geven de meningen in iedere stad afzonderlijk weer, alsmede de verschillen tussen de steden. Zo bestaat in alle steden de opvatting dat het voorlichten van patiënten en artsen tot de belangrijkste werkzaamheden van de apotheker zou moeten behoren, hetgeen volgens de Studenten nu nog niet het geval is. Ten aanzien van een wederzijdse erkenning hebben de Leidse Studenten veel bezwaar, Studenten uit Cardiff geen bezwaar en Studenten uit Frankfurt nemen een tussenpositie in.

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Naar het bijvakverslag Onderzoek Farmacie in de EG, Subfaculteit Farmacie, Rijksuniversiteit Leiden, Wassenaarseweg 76, 2300 RA Leiden.     

Effects of CCR5-Delta32 and CCR2-64I alleles on HIV-1 disease progression: the protection varies with duration of infection

OBJECTIVE: To examine temporal variation in the effects of CCR5-Delta32 and CCR2-64I chemokine receptor gene polymorphisms on HIV-1 disease progression. DESIGN: Pooled analysis of individual patient data from 10 cohorts of HIV-1 seroconverters from the United States, Europe, and Australia. METHODS: We studied HIV-1 seroconverters of European (n = 1635) or African (n = 215) ancestry who had been genotyped for CCR5-Delta32 and CCR2-64I. We used Cox proportional hazards models with time-varying coefficients to determine whether the genetic protection against AIDS (1987 case definition) and death varied with time since seroconversion. RESULTS: Protection against AIDS conferred by CCR5-Delta32 held constant at a 31% (RH 0.69, 95% CI 0.54, 0.88) reduction in risk over the course of HIV-1 infection, whereas protection against death held constant at a 39% reduction in risk (RH 0.61, 95% CI 0.45, 0.88). When the period from AIDS to death was isolated, the survival benefit of CCR5-Delta32 diminished 2 years after AIDS. Protection against AIDS conferred by CCR2-64I was greatest early in the disease course. Compared with individuals without CCR5-Delta32 or CCR2-64I, individuals with one or two copies of CCR2-64I had a 58% lower risk of AIDS during the first 4 years after seroconversion (RH 0.42, 95% CI 0.23, 0.76), a 19% lower risk during the subsequent 4 years (RH 0.81, 95% CI 0.59, 1.12), and no significant protection thereafter. CONCLUSION: The protection against AIDS provided by CCR5-Delta32 is continuous during the course of infection. In contrast, the protection provided by CCR2-64I is greatest early in the course of infection.     

Regulation of stimulated integrin surface expression in human neutrophils by tyrosine phosphorylation

The control of the adhesive properties of human neutrophils is an essential element of their defense function. One level at which this control is exerted involves the upregulation of the surface expression of beta 2-integrins. In this study, we have examined the potential involvement of tyrosine phosphorylation in the latter process. Two inhibitors of tyrosine kinases with differing modes of action, erbstatin and herbimycin A, were found to inhibit the expression of CD11b and CD18 stimulated by chemotactic factors (fMet-Leu-Phe or leukotriene B4) or growth factors (tumor necrosis factor alpha). This inhibition was not shared by an inactive analog of erbstatin or by the protein kinase C inhibitor Ro 31-8330. Erbstatin also inhibited the unveiling of activation-specific neoepitopes detected by antibody CBRM1/5. Pretreatment of neutrophils (but not of endothelial cells) with erbstatin inhibited the stimulation of neutrophils' adherence to endothelial cells induced by fMet-Leu-Phe. Augmentation of tyrosine phosphorylation by inhibiting tyrosine phosphatases using hydroperoxyvanadate led to an increased surface expression of CD11b and CD18 and enhanced the adhesion of neutrophils to endothelial cells. Finally, the leumedin NPC 15669, which had previously been shown to inhibit stimulated CD11b expression and neutrophil adherence to endothelial cells and to exhibit anti-inflammatory properties in various in vivo models of inflammation, inhibited the stimulation of tyrosine, phosphorylation induced by fMet-Leu-Phe. Taken together, these data establish a strong correlation between tyrosine phosphorylation and integrin upregulation in stimulated human neutrophils.     

In vivo HIV-1 infection of CD45RA(+)CD4(+) T cells is established primarily by syncytium-inducing variants and correlates with the rate of CD4(+) T cell decline

Switch from non-syncytium-inducing (NSI) to syncytium-inducing (SI) HIV type 1 (HIV-1) is associated with accelerated CD4(+) T cell depletion, which might partially be explained by higher virulence of SI variants compared with NSI variants. Because NSI and SI variants use different coreceptors for entry of target cells, altered tropism might offer an explanation for increased pathogenesis associated with SI HIV-1 infection. To investigate whether SI and NSI HIV-1 variants infect different CD4(+) T cell subsets in vivo, the distribution of SI and NSI variants over CD4(+) memory (CD45RA(-)RO(+)) and naive (CD45RA(+)RO(-)) cells was studied by using limiting dilution cultures. In contrast to NSI variants that were mainly present in CD45RO(+) cells, SI variants were equally distributed over CD45RO(+) and CD45RA(+) cells. Infection of memory cells by both NSI and SI HIV-1 and infection of naive cells primarily by SI HIV-1 corresponded closely with the differential cell surface expression of CXCR4 and CCR5. The frequency of SI-infected CD45RA(+) CD4(+) T cells, but not the frequency of NSI- or SI-infected CD45RO(+) CD4(+) T cells, correlated with the rate of CD4(+) T cell depletion. Infection of naive cells by SI HIV-1 may interfere with CD4(+) T cell production and thus account for rapid CD4(+) T cell depletion.     

Correlates of resistance to HIV-1 infection in homosexual men with high-risk sexual behaviour

OBJECTIVE: To investigate possible correlates of HIV resistance in participants from the Amsterdam Cohort of Homosexual men who have remained HIV seronegative despite high-risk sexual behaviour. DESIGN/METHODS: We studied in vitro HIV-1 susceptibility and adaptive and innate immunity in 29 high-risk seronegative (HRSN) and 15 HIV-negative pre-seroconversion (pre-SC) homosexual men from the same Amsterdam Cohort Study (ACS) who seroconverted to HIV-1 positive during active follow-up. Host genetics were compared between HRSN and HIV-positive ACS participants. RESULTS: We found lower in vitro susceptibility for a CCR5-using (R5) HIV-1 variant, higher RANTES production levels, but no difference in coreceptor expression in HRSN as compared with pre-SC controls. Reduced R5 in vitro susceptibility of two HRSN tested was restored to normal levels by addition of antibodies against beta-chemokines. A higher proportion of HRSN carried the SDF-1 3'A variant and HLA-A*11, A*31 and Cw*15 alleles. ELIspot analysis with HIV-1 peptide stimulation revealed low frequencies of HIV-1-specific CD8 interferon-gamma producing cytotoxic T cells in both HRSN and pre-SC controls. CONCLUSIONS: Low in vitro R5 susceptibility of cells from the HRSN men was due to beta-chemokine mediated inhibition of virus replication. The presence of HIV-1 specific cytotoxic T cells in both HRSN and pre-SC participants may signify exposure to the virus rather than protection from infection. Host genetic characteristics and other factors affecting innate immunity may contribute to differential resistance to HIV-1 infection among exposed seronegative individuals.