ZNRD1 (zinc ribbon domain-containing 1) is a host cellular factor that influences HIV-1 replication and disease progression.

BACKGROUND: Human immunodeficiency virus (HIV) takes advantage of multiple host proteins to support its own replication. The gene ZNRD1 (zinc ribbon domain-containing 1) has been identified as encoding a potential host factor that influenced disease progression in HIV-positive individuals in a genomewide association study and also significantly affected HIV replication in a large-scale in vitro short interfering RNA (siRNA) screen. Genes and polymorphisms identified by large-scale analysis need to be followed up by means of functional assays and resequencing efforts to more precisely map causal genes. METHODS: Genotyping and ZNRD1 gene resequencing for 208 HIV-positive subjects (119 who experienced long-term nonprogression [LTNP] and 89 who experienced normal disease progression) was done by either TaqMan genotyping assays or direct sequencing. Genetic association analysis was performed with the SNPassoc package and Haploview software. siRNA and short hairpin RNA (shRNA) specifically targeting ZNRD1 were used to transiently or stably down-regulate ZNRD1 expression in both lymphoid and nonlymphoid cells. Cells were infected with X4 and R5 HIV strains, and efficiency of infection was assessed by reporter gene assay or p24 assay. RESULTS: Genetic association analysis found a strong statistically significant correlation with the LTNP phenotype (single-nucleotide polymorphism rs1048412; [Formula: see text]), independently of HLA-A10 influence. siRNA-based functional analysis showed that ZNRD1 down-regulation by siRNA or shRNA impaired HIV-1 replication at the transcription level in both lymphoid and nonlymphoid cells. CONCLUSION: Genetic association analysis unequivocally identified ZNRD1 as an independent marker of LTNP to AIDS. Moreover, in vitro experiments pointed to viral transcription as the inhibited step. Thus, our data strongly suggest that ZNRD1 is a host cellular factor that influences HIV-1 replication and disease progression in HIV-positive individuals.

Stable isotope compositions of mammoth teeth from Niederweningen, Switzerland: Implications for the Late Pleistocene climate, environment, and diet

Oxygen and carbon isotope compositions of well-preserved mammoth teeth from the Middle Wurmian (40-70 ka) peat layer of Niederweningen, the most important mammoth site in Switzerland, were analysed to reconstruct Late Pleistocene palaeoclimatic and palaeoenvironmental conditions. Drinking water (delta(18)O values of approximately -12.3 +/- 0.9 parts per thousand were calculated front oxygen isotope compositions of mammoth tooth enamel apatite using a species-specific calibration for modern elephants. These delta(18)O(H2O) values reflect the mean oxygen isotope composition of the palaeo-precipitation and are similar to those directly measured for fate Pleistocene groundwater from aquifers in northern Switzerland and southern Germany. Using a present-day delta(18)O(H2)o-precipitation-air temperature relation for Switzerland, a mean annual air temperature (MAT) of around 4.3 +/- 2.1 degrees C can be calculated for the Middle Wurmian at this site. This MAT is in good agreement with palaeotemperature estimates on the basis of Middle Wurmian groundwater recharge temperatures and beetle assemblages. Hence, the climatic conditions in this region were around 4 degrees C cooler during the Middle Wurmian interstadial phase, around 45-50ka BP, than they are today. During this period the mammoths from Niederweningen lived in an open tundra-like, C(3) plant-dominated environment as indicated by enamel (delta(13)C values of -11.5 +/- 0.3 parts per thousand and pollen and macroplant fossils found in the embedding peat. The low variability of enamel delta(13)C and delta(18)O values from different mammoth teeth reflects similar environmental conditions and supports a relatively small time frame for the fossil assemblage. (C) 2006 Elsevier Ltd and INQUA. All rights reserved.