Citations

ABSTRACT The Ref1 and Lv1 postentry restrictions in human and monkey cells have been analyzed for lentiviruses in the primate and ungulate groups, but no data exist for the third (feline) group. We compared feline immunodeficiency virus (FIV) to other restricted (human immunodeficiency virus type 1 [HIV-1], equine infectious anemia virus [EIAV]) and unrestricted (NB-tropic murine leukemia virus [NB-MLV]) retroviruses across wide ranges of viral inputs in cells from multiple primate and nonprimate species. We also characterized restrictions conferred to permissive feline and canine cells engineered to express rhesus and human TRIM5α proteins and performed RNA interference (RNAi) against endogenous TRIM5α. We find that expression of rhesus or human TRIM5α proteins in feline cells restricts FIV, impairing pseudotyped vector transduction and viral replication, but rhesus TRIM5α is more restricting than human TRIM5α. Notably, however, canine cells did not support restriction by human TRIM5α and supported minimal restriction by rhesus TRIM5α, suggesting that these proteins may not function autonomously or that a canine factor interferes. Stable RNAi knockdown of endogenous rhesus TRIM5α resulted in marked increases in FIV and HIV-1 infectivities while having no effect on NB-MLV. A panel of nonprimate cell lines varied widely in susceptibility to lentiviral vector transduction, but normalized FIV and HIV-1 vectors varied concordantly. In contrast, in human and monkey cells, relative restriction of FIV compared to HIV-1 varied from none to substantial, with the greatest relative infectivity deficit for FIV vectors observed in human T-cell lines. Endogenous and introduced TRIM5α restrictions of FIV could be titrated by coinfections with FIV, HIV-1, or EIAV virus-like particles. Arsenic trioxide had complex and TRIM5α-independent enhancing effects on lentiviral but not NB-MLV infection. Implications for human gene therapy are discussed.

ABSTRACTThe attenuation of eosinophilia by the administration of monoclonal antibodies to CCR3 consistently correlates with impairment in worm elimination following primary intraperitonealBrugia pahangiinfections in mice. Host protection was unimpaired in mice deficient in eosinophil peroxidase (EPO) or major basic protein 1 (MBP-1), suggesting that eosinophils are essential in host protection but that neither EPO nor MBP-1 alone is.

Objective— We hypothesized that apolipoprotein E (apoE) −/− /low-density lipoprotein (LDL) −/− double knockout mice might develop vasa vasorum (VV) in association with advanced lesion formation. Methods and Results— Aortas from apoE −/− /LDL −/− mice aged 16, 18, 20, or 80 weeks were infused in situ with Microfil, harvested, and scanned with micro-computed tomography (CT). We characterized plaque volume and CT “density” as well as VV luminal volume along the aorta using Analyze 6.0 software. Results were complemented by a detailed histological plaque classification according to American Heart Association guidelines. From 16 to 80 weeks, plaque volume and VV opacified lumen volume increased with age ( P <0.001). The 3-dimensional micro-CT images of arterial and venous VV trees allowed perfusion territories to be delineated. The spatial location and magnitude of VV density and adventitial inflammation were strongly correlated in advanced atherosclerotic lesions ( r =0.91) and identified as an independent correlate to advanced lesions. At age 80 weeks, VV luminal volume was increased 20-fold compared with animals at age 16 weeks ( P <0.001). Micro-CT showed that adventitial VV communicate with intraplaque microvessels. Conclusion— Our results show that apoE −/− /LDL −/− double knockout mice develop VV and advanced atheromas along the aorta. Lesion volume was closely associated with amount of neovascularization in advanced atheromas.

A number of recently developed and promising approaches to antitumoral immunotherapy are being investigated as potential treatments for advanced prostate cancer. These approaches largely revolve around strategies to increase antigen-specific T-cell activation against prostate tumors as well as precise manipulations of critical co-regulatory receptors that help to maintain and prolong the activity of antigen-presenting cells and T cells that are capable of mediating tumor regression. Herein, we describe the experience with the most recent and promising approaches pertaining to prostate cancer immunotherapy. Additionally, we discuss the mechanistic basis for these approaches as well as current limitations that must still be addressed in order to propel immunotherapy into the forefront of prostate cancer treatment.

Background and Purpose— Mitral annular calcification (MAC) and aortic valve (AV) sclerosis have each been linked to cardiovascular disease. Whether MAC and AV sclerosis are risk factors for stroke independent of other echocardiographic or laboratory predictors has not been established. We evaluated the relationship between MAC, AV sclerosis, and first stroke events in a population-based cohort. Methods— Our study cohort consisted of 2723 American Indians participating in the Strong Heart Study who were free of prevalent cardiovascular disease. Participants underwent standardized clinical, echocardiographic, and laboratory evaluation, and incident stroke was ascertained using validated methods. Results— During a median follow-up of 7 years, 86 strokes occurred. Age- and sex-adjusted incidence rates of stroke were significantly increased for MAC (rate ratio [RR], 3.12; 95% CI, 1.77 to 5.25) but not for AV sclerosis (RR, 1.15; 95% CI, 0.45 to 2.49). MAC was also associated with a reduced time to first stroke events after adjustment for clinical variables and the inflammatory markers C-reactive protein and fibrinogen (hazard ratio [HR], 2.42; 95% CI, 1.39 to 4.21) or the echocardiographic covariates left ventricular hypertrophy and left atrial enlargement (HR, 1.89; 95% CI, 1.04 to 3.41). Individuals with and without AV sclerosis showed no significant difference in stroke-free survival in unadjusted analyses ( P =0.698). Crossing of the survival curves precluded multivariable analysis using Cox models. Conclusions— In this cohort of American Indians without clinical cardiovascular disease, the presence of MAC, but not AV sclerosis, proved to be a strong risk factor for incident stroke after extensive adjustment for other predictors. Individuals exhibiting MAC may benefit from aggressive risk factor modification, but this will require further investigation.