Pvr regulates cyst stem cell division in the Drosophila testis niche, and has functions distinct from Egfr.

Regulation of the rate of stem cell division is one of the key determinants of the abundance of differentiating progeny in stem cell-supported tissues, and mis-regulation can lead to tumorigenesis. The well-studied Drosophila testis niche is an excellent model system to study the regulation of stem cell division in vivo. This niche supports two stem cell populations-the germline stem cells (GSCs) and cyst stem cells (CySCs), which cluster around a group of cells called the hub. The differentiating cells of these two stem cell populations cooperate together to produce sperm. Signal transduction initiated by the epidermal growth factor receptor (Egfr) is a key regulatory pathway in the cyst lineage, and much of the study of this stem cell population has centered around understanding the complexities of the requirements for Egfr signaling. We examined another receptor tyrosine kinase, Pvr, the sole Drosophila PDGF/VEGF homolog, and found that it accumulates in the cyst lineage cells of the testis, while its ligand Pvf1 accumulates in the hub. Pvr inhibition caused a reduction in both CySC numbers and the proportion of CySCs in S phase, similar to Egfr inhibition. However, testes with Pvr inhibition exhibited a low-penetrance non-autonomous germ cell differentiation defect distinct from that observed with Egfr inhibition. Cyst cells with constitutively activated Pvr failed to support germ cell differentiation, as observed with constitutively activated Egfr. However, constitutively activated Pvr promoted tumorous accumulation of cyst cells outside of the niche, a phenotype not observed with constitutively activated Egfr. Thus, Egfr and Pvr have some receptor-specific functions and some shared functions in the cyst lineage cells of the testis.

Human Immunodeficiency Virus nef signature sequences are associated with pulmonary hypertension.

Severe pulmonary hypertension (PH) associated with vascular remodeling is a long-term complication of HIV infection (HIV-PH) affecting 1/200 infected individuals vs. 1/200,000 frequency in the uninfected population. Factors accounting for increased PH susceptibility in HIV-infected individuals are unknown. Rhesus macaques infected with chimeric SHIVnef virions but not with SIV display PH-like pulmonary vascular remodeling suggesting that HIV-Nef is associated with PH; these monkeys showed changes in nef sequences that correlated with pathogenesis after passage in vivo. We further examined whether HIV-nef alleles in HIV-PH subjects have signature sequences associated with the disease phenotype. We evaluated specimens from participants with and without HIV-PH from European Registries and validated results with samples collected as part of the Lung-HIV Studies in San Francisco. We found that 10 polymorphisms in nef were overrepresented in blood cells or lung tissue specimens from European HIV-PH individuals but significantly less frequent in HIV-infected individuals without PH. These polymorphisms mapped to known functional domains in Nef. In the validation cohort, 7/10 polymorphisms in the HIV-nef gene were confirmed; these polymorphisms arose independently from viral load, CD4(+) T cell counts, length of infection, and antiretroviral therapy status. Two out of 10 polymorphisms were previously reported in macaques with PH-like pulmonary vascular remodeling. Cloned recombinant Nef proteins from clinical samples down-regulated CD4, suggesting that these primary isolates are functional. This study offers new insights into the association between Nef polymorphisms in functional domains and the HIV-PH phenotype. The utility of these polymorphisms as predictors of PH should be examined in a larger population.