Retroviruses and comparative pathology

Retroviruses are RNAviruses that infect and can induce disease in humans and animals. Retroviral infections in small ruminants and horses share common features: when serology is available, infected animals can be seronegative; infected animals inconstantely develop disease; infection and disease can be experimentaly induced. Animal retroviruses are a cause of spontaneous diseases, transmissible among animals and model systems of human diseases.Les rétrovirus sont des virus à ARN qui infectent et sont susceptibles de rendre malade l'homme et l'animal. Les infections rétrovirales des petits ruminants et des équidés ont des caractéristiques communes: lorsqu'il existe un diagnostic sérologique, des animaux infectés peuvent être séronégatifs; les animaux infectés ne sont pas toujours malades; l'infection et la maladie peuvent être reproduits expérimentalement. Au total, les rétrovirus animaux, en particulier des petits ruminants et des équidés, sont une cause de maladies spontanées, transmissibles chez ces animaux et peuvent être utilisés comme modèle de plusieurs maladies humaines

Spontaneous Expression of the c-sis Gene and Release of a Platelet-derived Growth Factorlike Molecule by Human Alveolar Macrophages

Alveolar macrophages from normal individuals and patients with interstitial lung diseases spontaneously expressed a 4.2-kilobase mRNA complementary to the c-sis gene, a proto-oncogene coding for one of the chains of platelet-derived growth factor (PDGF). Concomitantly, these cells released a mediator with the properties of PDGF, including: (a) chemotactic factor for smooth muscle cells whose activity was resistant to heat and acid, but sensitive to reduction; (b) mitogenic (competence) activity for fibroblasts; (c) ability to compete with PDGF for its receptor, and (d) precipitated by an anti-PDGF antibody. While blood monocytes did not contain c-sis mRNA transcripts, monocytes matured in vitro expressed c-sis, consistent with the concept that expression of c-sis occurs during the differentiation of monocytes into alveolar macrophages. Together with the known actions of PDGF, these observations suggest that the c-sis proto-oncogene and its PDGF product are part of the armamentarium available to the alveolar macrophages for normal lung defense and participation in lung inflammation

Development of a Multivariate Prediction Model for Early-Onset Bronchiolitis Obliterans Syndrome and Restrictive Allograft Syndrome in Lung Transplantation.

Chronic lung allograft dysfunction and its main phenotypes, bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS), are major causes of mortality after lung transplantation (LT). RAS and early-onset BOS, developing within 3 years after LT, are associated with particularly inferior clinical outcomes. Prediction models for early-onset BOS and RAS have not been previously described. LT recipients of the French and Swiss transplant cohorts were eligible for inclusion in the SysCLAD cohort if they were alive with at least 2 years of follow-up but less than 3 years, or if they died or were retransplanted at any time less than 3 years. These patients were assessed for early-onset BOS, RAS, or stable allograft function by an adjudication committee. Baseline characteristics, data on surgery, immunosuppression, and year-1 follow-up were collected. Prediction models for BOS and RAS were developed using multivariate logistic regression and multivariate multinomial analysis. Among patients fulfilling the eligibility criteria, we identified 149 stable, 51 BOS, and 30 RAS subjects. The best prediction model for early-onset BOS and RAS included the underlying diagnosis, induction treatment, immunosuppression, and year-1 class II donor-specific antibodies (DSAs). Within this model, class II DSAs were associated with BOS and RAS, whereas pre-LT diagnoses of interstitial lung disease and chronic obstructive pulmonary disease were associated with RAS. Although these findings need further validation, results indicate that specific baseline and year-1 parameters may serve as predictors of BOS or RAS by 3 years post-LT. Their identification may allow intervention or guide risk stratification, aiming for an individualized patient management approach

Alpha-1 antitrypsin deficiency 50 years later

National audienceAlpha-1 antitrypsin deficiency is a frequent genetic disorder associated with pulmonary emphysema in smokers and with liver cirrhosis. Aside from lung or liver transplantation, only replacement therapy can currently slow the progression of emphysema. Progress in the pathogenesis of this disorder (protein misfolding, RER aggregation) is opening the way to new strategies such as proteostasis control. Alpha-1 antitrypsin deficiency remains poorly known and underdiagnosed

[Endogenous porcine retroviruses and xenotransplantation]

Vertebrate DNA contains numerous genomes closely related to retroviruses, i.e. endogenous retroviruses. While most of the retroviruses are pathogenous, endogenous retroviruses have rarely been shown as such. Endogenous retroviruses, as most of the retroviruses, are able to cross 'species barriers'. Porcine endogenous retroviruses were described in 1974. They are expressed in tissues and cells involved in transplantation, endothelial cells, for instance. They are capable of interspecific transmission, expressed in vitro in human cells; no evidence of in vivo interspecific transmission has been reported so far. As far as xenotransplantation is concerned, porcine endogenous retroviruses represent a risk of adaptation to humans of a new form of retrovirus. Such a risk mandates a close monitoring of recipients and their partners. This risk has already been taken with the use of tissues and stable blood-derived products from animals harboring in their genomes endogenous retroviruses

Molecular characterization of field isolates of lentiviruses of small ruminants

Molecular characterization of field isolates of lentiviruses of small ruminants. Workshop on Comparative Approach to Retroviral Vaccine

Genomic heterogeneity of small ruminant lentiviruses: existence of heterogeneous populations in sheep and of the same lentiviral genotypes in sheep and goats

We have recently shown that French small ruminant lentiviruses (SRLV) from sheep are more similar to Caprine Arthritis Encephalitis Virus (CAEV) than to visna maedi virus (VMV) in a conserved region of the pol gene. To extend these results, we have examined sequences from a variable region of the env gene in French SRLV. We found that they were nearly equally distant from both CAEV and VMV strains, suggesting a considerable divergence since the initial introduction of the virus. Analysis of separate clones from individual animals showed that some carry a population of variant viruses. The study of further pol gene sequences from both goats and sheep suggests that viral variants show little or no host species specificity. A phylogenetic tree of pol gene sequences confirmed the presence of a novel genotype of SRLV in France

Accelerated coronary atherosclerosis and arteriosclerosis in young human-immunodeficiency-virus-positive patients

OBJECTIVE: To determine the type of lesions observed in young patients infected with human immunodeficiency virus-1 (HIV-1). DESIGN: Examination of coronary networks in corpses of 13 men and two women who had died aged 23-32 years after having been infected with HIV-1 virus, having been seropositive for 2-5 years. Causes of death were infectious complications (five cases), infection with cytomegalovirus leading to gastro-intestinal haemorrhaging (one case), infection with cytomegalovirus and Kaposi's sarcoma (one case), overdoses of drugs (five cases) and sudden death (three cases). METHODS: The pathological analysis was carried out on the proximal and distal coronary networks. In order to characterize the lesions better, the cells and the cytokines involved were characterized by immunohistochemistry. RESULTS: In all 15 cases we observed thickening of intima in the proximal network at least as great as that of the media, caused by a proliferation of secreting cells, phenotypically identified as smooth muscle cells, with exaggerated production of elastic fibres and in association with an increase in the expression of tumor necrosis factor-alpha and interleukin-1 alpha. In nine cases, atherosclerosis had developed from and on the surface of this proliferation and in four cases arteriosclerosis had an unusual appearance, in the form of mamillated vegetations with endoluminal protrusions. A similar proliferation was found in the distal network in four cases, but with a significantly smaller proportion of elastic fibres. CONCLUSIONS: The lesions we examined in these young HIV-1-infected patients presented particular features and were intermediate between the lesions observed during common coronary atherosclerosis and atherosclerosis associated with chronic rejection of cardiac transplants

RT-PCR detection of lentiviruses in milk or mammary secretions of sheep or goats from infected flocks

Using Smart Source ParsingIn this study we evaluated a reverse transcriptase polymerase chain reaction (RT-PCR) technique for detecting lentiviral infection in milk or mammary secretions from small ruminants. Initial observations on seven goats infected with cloned caprine arthritis-encephalitis virus (CAEV) showed that RT-PCR on milk cells is as reliable as coculture for detecting viral infection, and is quicker and simpler. With a suitable choice of redundant primers followed by a semi-nested amplification, it proved possible to detect the virus in milk samples from naturally infected French sheep (8/8) or goats (9/9), and viral sub-groups could be identified by hybridization with discriminatory probes. All seropositive animals gave positive amplifications, as did one seronegative goat from a contaminated herd, suggesting greater sensitivity for RT-PCR. None of eight goats from a long-established seronegative herd ever gave a positive RT-PCR amplification. This technique provides a simple means for rapidly identifying potentially infectious animals and for epidemiological investigations, as long as the primers are selected according to the genetic structure of the local viral population

Quand le pneumologue doit-il envisager la greffe pulmonaire pour un de ses patients ? Critères d’inscription en liste d’attente : mucoviscidose, HTAP et maladies systémiques (sarcoïdose, histiocytose langerhansienne, lymphangioleïomyomatose et connectivites)

National audienceIntroduction Placing a patient on the national lung transplant waiting list remains a difficult matter, and is more a question of timing than selection of the candidate according to disease-specific criteria. Back-ground The listing criteria for cystic fibrosis are FEV1 less than 30% of the predicted value, hypoxaemia with a PaO2 less than 55 mm Hg and hypercapnia with a PaCO2 over 50 mm Hg. The rate of decline of FEV1, increasing antibiotic requirements and life threatening complications can all accelerate the listing procedure. For primary pulmonary hypertension the criteria are persistent dyspnoea, NYHA grade III or IVA, despite epoprostenol treatment and a 6 minute walk test of less than 250 metres. Sarcoidosis, lymphangioleiomyomatosis, histiocytosis X and connective tissue diseases are rare indications for which the listing criteria are similar to those for the more usual respiratory diseases. View points Further therapeutic advances, increased numbers of available organs and changes in the allocation rules will necessitate periodical updates of these selection and listing criteria. Conclusion The optimal time for placing lung transplantation patients who have been referred early in the course of their disease on the waiting list will be determined by clinical experience and individual patient follow-up.Introduction L’inscription d’un patient sur la liste nationale d’attente de transplantation pulmonaire reste une question délicate non tant par les critères de sélection des candidats que par le choix du moment. État des connaissances Les critères d’inscription pour la mucoviscidose sont définis par un VEMS inférieur à 30 % de la valeur théorique, une hypoxémie inférieure à 55 mmHg et une hypercapnie supérieure à 50 mmHg. La vitesse du déclin du VEMS, l’antibiodépendance et une complication mettant en jeu le pronostic vital accélèrent l’inscription. Les contre-indications restent relatives. Ceux de l’hypertension artérielle pulmonaire sont une dyspnée stade III ou IV NHYA persistante après traitement par époprosténol et un périmètre de marche inférieur à 250 mètres. La sarcoïdose, la lymphangioleïomyomatose, l’histiocytose et les connectivites sont des indications rares dont les critères d’inscription rejoignent ceux des autres pathologies respiratoires plus classiques. Perspectives Les innovations thérapeutiques, l’augmentation des greffons disponibles et les changements des règles d’allocations des greffons devront faire réévaluer les critères de sélection des patients et d’inscription sur la liste d’attente. Conclusion L’expérience clinique et le suivi de chaque patient restent des éléments primordiaux pour juger du moment opportun d’inscription sur liste de transplantation de patients adressés suffisamment tôt aux centres spécialisés