Human immunotypes impose selection on viral genotypes through viral epitope specificity

BACKGROUND: Understanding the genetic interplay between human hosts and infectious pathogens is crucial for how we interpret virulence factors. Here, we tested for associations between HIV and host genetics, and interactive genetic effects on viral load (VL) in HIV+ ART-naive clinical trial participants. METHODS: HIV genomes were sequenced and the encoded amino acid (AA) variants were associated with VL, human single nucleotide polymorphisms (SNPs) and imputed HLA alleles, using generalized linear models with Bonferroni correction. RESULTS: Human (388,501 SNPs) and HIV (3,010 variants) genetic data was available for 2,122 persons. Four HIV variants were associated with VL (p-values<1.66×10 -5). Twelve HIV variants were associated with a range of 1-512 human SNPs (p-value<4.28×10 -11). We found 46 associations between HLA alleles and HIV variants (p-values<1.29×10 -7). We found HIV variants and immunotypes when analyzed separately, were associated with lower VL, whereas the opposite was true when analyzed in concert. Epitope binding prediction showed HLA alleles to be weaker binders of associated HIV AA variants relative to alternative variants on the same position. CONCLUSIONS: Our results show the importance of immunotype specificity on viral antigenic determinants, and the identified genetic interplay puts emphasis that viral and human genetics should be studied in the context of each other

Expression of heat shock protein 90 at the cell surface in human neuroblastoma cells

In addition to the activity of heat shock protein 90 (Hsp90/HSPC) as a chaperone, some recent studies have reported expression of Hsp90 at the cell surface in certain types of cancer and nervous system cells. We study the expression of Hsp90 at the cell surface in human neuroblastoma (NB69) cells. Immunofluorescence experiments labeling with anti-Hsp90 antibodies on both nonpermeabilized cells and live cells detected Hsp90 at the cell surface. Hsp90 was also identified in a membrane fraction from subcellular fractionation. Cell-surface Hsp90 was significantly more expressed in undifferentiated proliferative spherical neuroblastoma cells than in differentiated flattened cells. In addition, spherical cells were significantly more sensitive to Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin compared to flattened cells. This paper describes the first evidence of cell-surface Hsp90 expression in a cancer cell line from nervous tissue and may indicate a novel target for anti-tumoral agents

Lateralisation in Parkinson disease.

Asymmetry of dopaminergic neurodegeneration and subsequent lateralisation of motor symptoms are distinctive features of Parkinson's disease compared to other forms of neurodegenerative or symptomatic parkinsonism. Even 200 years after the first description of the disease, the underlying causes for this striking clinicopathological feature are not yet fully understood. There is increasing evidence that lateralisation of disease is due to a complex interplay of hereditary and environmental factors that are reflected not only in the concept of dominant hemispheres and handedness but also in specific susceptibilities of neuronal subpopulations within the substantia nigra. As a consequence, not only the obvious lateralisation of motor symptoms occurs but also patterns of associated non-motor signs are defined, which include cognitive functions, sleep behaviour or olfaction. Better understanding of the mechanisms contributing to lateralisation of neurodegeneration and the resulting patterns of clinical phenotypes based on bilateral post-mortem brain analyses and clinical studies focusing on right/left hemispheric symptom origin will help to develop more targeted therapeutic approaches, taking into account subtypes of PD as a heterogeneous disorder