Essential role of the CCL2-CCR2 axis in Mayaro virus-induced disease.

Mayaro virus (MAYV) is an emerging arbovirus member of the Togaviridae family and Alphavirus genus. MAYV infection causes an acute febrile illness accompanied by persistent polyarthralgia and myalgia. Understanding the mechanisms involved in arthritis caused by alphaviruses is necessary to develop specific therapies. In this work, we investigated the role of the CCL2/CCR2 axis in the pathogenesis of MAYV-induced disease. For this, wild-type (WT) C57BL/6J and CCR2-/- mice were infected with MAYV subcutaneously and evaluated for disease development. MAYV infection induced an acute inflammatory disease in WT mice. The immune response profile was characterized by an increase in the production of inflammatory mediators, such as IL-6, TNF, and CCL2. Higher levels of CCL2 at the local and systemic levels were followed by the significant recruitment of CCR2+ macrophages and a cellular response orchestrated by these cells. CCR2-/- mice showed an increase in CXCL-1 levels, followed by a replacement of the macrophage inflammatory infiltrate by neutrophils. Additionally, the absence of the CCR2 receptor protected mice from bone loss induced by MAYV. Accordingly, the silencing of CCL2 chemokine expression in vivo and the pharmacological blockade of CCR2 promoted a partial improvement in disease. Cell culture data support the mechanism underlying the bone pathology of MAYV, in which MAYV infection promotes a pro-osteoclastogenic microenvironment mediated by CCL2, IL-6, and TNF, which induces the migration and differentiation of osteoclast precursor cells. Overall, these data contribute to the understanding of the pathophysiology of MAYV infection and the identification future of specific therapeutic targets in MAYV-induced disease.IMPORTANCEThis work demonstrates the role of the CCL2/CCR2 axis in MAYV-induced disease. The infection of wild-type (WT) C57BL/6J and CCR2-/- mice was associated with high levels of CCL2, an important chemoattractant involved in the recruitment of macrophages, the main precursor of osteoclasts. In the absence of the CCR2 receptor, there is a mitigation of macrophage migration to the target organs of infection and protection of these mice against bone loss induced by MAYV infection. Much evidence has shown that host immune response factors contribute significantly to the tissue damage associated with alphavirus infections. Thus, this work highlights molecular and cellular targets involved in the pathogenesis of arthritis triggered by MAYV and identifies novel therapeutic possibilities directed to the host inflammatory response unleashed by MAYV.

Effectiveness of Medical Nutrition Therapy to Improve Dietary Habits for Promoting Bone Health in People Living with Chronic HIV.

INTRODUCTION: Previous studies have established the risk of bone loss among people living with HIV affected by antiretroviral therapy drug side effects and inadequate nutrient intake. Until recently, there have been limits on using the medical nutrition therapy (MNT) to improve dietary habits for promoting bone health among people living with HIV. This was a randomized controlled trial study aimed to investigate the effectiveness of MNT in improving the bone health in people living with HIV by promoting dietary habits. METHODS: PLHIV at Queen Savang Vadhana Memorial Hospital were randomly grouped (by quota sampling) into the MNT group (intervention group) and the control group. One hundred and thirty PLHIV were recruited to participate in this study by convenient sampling. Sixty-five participants of the MNT group made a total of 6 appointments (for 12 weeks) to meet registered dietitians for receiving MNT to improve dietary habits for improving bone health, while 65 participants in the control group received only routine care at the hospital service center. RESULTS: In general, participants in the MNT group had significant increase in the amounts of calcium, vitamin D, potassium, and phosphorus intakes and length of exercise after the final week compared with before intervention. Also, they had significantly higher amount of nutrient intakes (calcium, vitamin D, potassium, and phosphorus) and length of exercise than the control group after finishing the final week of the experiment. CONCLUSION: In conclusion, MNT is effective for improving food habits and physical activity to promote bone health among people living with HIV.

Elderly HIV-positive women: A gender-based analysis from the Multicenter Italian "GEPPO" Cohort.

BACKGROUND: HIV-positive patients are facing age-and disease-related comorbidities. Since gender differences in viro-immunological, clinical and therapeutic features have been described, aim of this analysis was to explore such differences in elderly HIV-positive females compared to males coming from the same cohort. DESIGN: Cross-sectional study. SETTING: Ten Infectious Diseases Center participating to a new multicenter Italian geriatric Cohort aiming at describing health transition over time in HIV-positive individuals. PARTICIPANTS: HIV-positive patients aged ≥65 years old. MEASUREMENTS: We recorded clinical, viro-immunological and therapeutical data. RESULTS: We included 210 women (17%) out of 1237 patients. Compared to males, elderly females were less likely to present a HIV-RNA <50 copies/mL (74.3% vs. 81.8%, OR 0.64, 95%CI 0.44-0.93); they showed higher CD4+/CD8+ ratio (p = 0.016). Combined antiretroviral therapy (cART) strategies were similar between genders (p>0.05), although women were less likely to be treated with protease Inhibitors (PIs) (p = 0.05); specifically, in triple-drug regimens females received less PIs (28% vs 38% p = 0.022) and more integrase inhibitors (30% vs. 20% p = 0.012). Bone disease was more common in females (p<0.001) while males presented more frequently cardiovascular disease (CVD) (p<0.001). In females with bone disease, PIs and boosted regimens (38% vs. 53.7% p = 0.026 and 30.4 vs 44.0% p = 0.048 respectively) were prescribed less frequently. Polypharmacy was common and similar in both genders (20% vs. 22.8%, p = >0.05). A higher use of lipid-lowering drugs (20.5% vs. 14.8%, p = 0.04) was observed in females and yet they were less likely to receive anti-thrombotic agents (18.6% vs. 26.3%, p = 0.019) even when CVD was recorded (57.1% vs. 83.1%, p = 0.018). In multivariate analysis, we found that female gender was independently associated with a higher CD4+/CD8+ ratio but not with virological suppression. CONCLUSIONS: Elderly HIV-positive women display a worse virologic response despite a better immune reconstitution compared to males. The burden of comorbidities as well as the medications received (including cART) may slightly differ according to gender. Our data suggest that more efforts and focused interventions are needed in this population.

Human Immunodeficiency Virus Infection and the Endocrine System.

In the current era of effective antiretroviral therapies (ARTs), human immunodeficiency virus (HIV) infection became a chronic disorder that requires long term follow-up. Among other medical issues, these patients may develop endocrine problems, specific to HIV infection and its treatment. The purpose of this review is to give an overview of common endocrine complications associated with HIV infection, and to propose diagnostic and therapeutic strategies. HIV can affect the endocrine system at several levels. Adrenal and gonadal dysfunction, osteoporosis with increased fracture risk, dyslipidemia with increased cardiovascular risk, are some of the endocrine disorders prevalent in HIV-infected patients that may negatively influence quality of life, and increase morbidity and mortality. While ARTs have dramatically increased life expectancy in the HIV-infected population, they are not devoid of adverse effects, including endocrine dysfunction. Physicians caring for HIV-infected patients should be knowledgeable and exercise a high index of suspicion for the diagnosis of endocrine abnormalities, and in particular be aware of those that can be life threatening. Endocrine evaluation should follow the same strategies as in the general population, including prevention, early detection, and treatment.

HIV infection, inflammation, immunosenescence, and aging.

Although antiretroviral therapy for HIV infection prevents AIDS-related complications and prolongs life, it does not fully restore health. Long-term treated patients remain at higher than expected risk for a number of complications typically associated with aging, including cardiovascular disease, cancer, osteoporosis, and other end-organ diseases. The potential effect of HIV on health is perhaps most clearly exhibited by a number of immunologic abnormalities that persist despite effective suppression of HIV replication. These changes are consistent with some of the changes to the adaptive immune system that are seen in the very old ("immunosenescence") and that are likely related in part to persistent inflammation. HIV-associated inflammation and immunosenescence have been implicated as causally related to the premature onset of other end-organ diseases. Novel therapeutic strategies aimed at preventing or reversing these immunologic defects may be necessary if HIV-infected patients are to achieve normal life span.

[Rosai-Dorfman disease: clinicopathologic, immunohistochemical and etiologic study of 16 cases].

OBJECTIVES: To study the clinicopathologic features of Rosai-Dorfman disease (RDD), expression of various antigens, human herpes virus type 8 (HHV8), human papillomavirus (HPV)-DNA and Epstein-Barr virus (EBV)-mRNA, and compare the findings with those in the literature. METHODS: The clinicopathologic findings of 16 Rosai-Dorfman disease cases were retrospectively reviewed. Immunohistochemical study for S-100 protein, CD68 (PG-M1), CD163, CD21, CD1a, CD20, CD45RO, CD4, CD8, M-CSF and HHV8 was carried out in 9 of the 16 cases. In-situ hybridization for EBV-mRNA and HPV-DNA was also performed. RESULTS: The male-to-female ratio of the patients was 4.33:1. Amongst the 16 cases studied, 62.5% (10/16) presented nodal RDD, with cervical lymph node predominantly involved. Half of these cases had affected lymph nodes in more than one anatomic site. Extranodal RDD represented 37.5% (6/16) of the cases. The relapse rate of extranodal RDD was higher than that of nodal RDD. Histologically, nodal RDD was characterized by dilated sinuses filled with large polygonal histiocytes which contained lymphocytes and plasma cells. For extranodal lesions, various degrees of stromal fibrosis were seen in association with mixed inflammatory cells (especially plasma cells). The large polygonal histiocytes varied in number and were distributed in clusters or patches. Immunohistochemical study showed that the abnormal histiocytes were strongly positive for S-100 protein. They also expressed CD68, CD163 and M-CSF, but were negative for CD1a, CD21 and HHV8. The lymphocytes in cytoplasm of these histiocytes were positive for both T and B cell markers (with T cell predominance, including a mixture of CD4- and CD8-positive cells). HPV-DNA and EBV-mRNA were not detected by in-situ hybridization. To date, 62 cases of RDD have been reported in mainland China, including 34 cases of nodal RDD and 18 cases of extranodal RDD. The remaining 10 cases involved both lymph nodes and extranodal sites. Compared with overseas reports, RDD occurring in China tended to affect older patients and with slight male predilection. CONCLUSIONS: Rosai-Dorfman disease is relatively rare in China. Pathologic diagnosis of extranodal RDD may be difficult. The demographic data of RDD in China, including age and sex of patients, are different from those in the literature.

Acquired osteosclerosis associated with intravenous drug use and hepatitis C infection.

Hepatitis C has recently been recognized as a secondary cause of osteosclerosis; a further example, the first outside of North America, is described. A 37-year-old man with a history of intravenous drug use and known to be hepatitis C antibody positive presented with bone pain. Radiographs and magnetic resonance imaging demonstrated an increase in cortical and trabecular bone that on biopsy was of a normal lamellar pattern but markedly sclerotic. Biochemical markers of bone formation (serum osteocalcin) and resorption (urinary hydroxyproline excretion rate) were both markedly elevated. Pain lessened following administration of pamidronate. Biochemical markers of bone turnover fell towards their reference ranges 12 months after initiating pamidronate therapy but without significant change in bone mineral density. Osteosclerosis is a rare complication of hepatitis C infection, the symptoms of which are controllable with diphosphonate therapy.

Retroviruses and bone diseases.

In 1980, retroviruses were shown to be pathogenic to humans, and experimentation on animals involving retroviruses as causal agents of tumors and degenerative diseases of bone, brain, and lung gained interest. Osteopetrosis, which can be either inherited in rodents or retrovirally induced in cats, is exemplary. Because of replication cycle, retroviruses can be propagated not only as infectious agents but also as cellular genes. If a retroviral infection occurs in germ line cells, the viral genes, which must integrate in the host's DNA, can be passed on to the progeny and inherited as Mendelian characteristics. Therefore, a retroviral etiology could account for diseases that present either as sporadic (infectious) or familial (inherited), although they may be similar in their clinical manifestations. This approach led to the finding of 2 new human retroviruses: 1 in a patient who had sporadic benign osteopetrosis, and the other in a patient who had sporadic paraarticular osteoma. In both patients, the retrovirus was isolated from mononuclear blood cells, not from bone cells, because of the links between bone and the immune system. A systematic search for retroviruses in patients who have sporadic bone disease, which also may appear as inherited disease, has yet to be performed. Patients with sporadic disease could be managed by antiretroviral agents such as Zidovudin.

Metaphyseal bone lesions in young dogs with systemic canine distemper virus infection.

Bone lesions, restricted to the metaphyses of long bones, were observed in young dogs with systemic distemper following experimental and spontaneous infection. Canine distemper virus (CDV) antigen was found immunocytochemically in hematopoietic marrow cells, osteoclasts, osteoblasts and rarely in osteocytes. In experimentally infected dogs, viral antigen was demonstrated in the metaphysis between 5 and 36 days after infection. Associated lesions, characterized by necrosis of osteoclasts, persistence of primary spongiosa and atrophy and necrosis of osteoblasts and marrow cells, were mild and most prominent between 8 and 32 days postinfection. Metaphyseal osteosclerosis (MO) of the long bones, varying from mild to severe, was observed macroscopically in 8 (19%) out of 42 dogs with spontaneous distemper. Affected animals were between 3 and 6 months of age and belonged mainly to the large breeds. In these animals, MO was characterized histologically by persistence of primary spongiosa, loss of bone marrow cells and necrosis of osteoclasts and bone marrow cells varying from mild to severe. Summarized, CDV-associated bone lesions were only transient and there were no indications of viral persistence in bones of dogs experimentally infected with CDV. Although no clinical signs related to the bones were observed, the present study reveals that infection of metaphyseal bone cells is common in young dogs with systemic distemper and occurrence of viral antigen in these cells results in defects in bone modelling.