Tree Shrew Cells Transduced with Human CD4 and CCR5 Support Early Steps of HIV-1 Replication, but Viral Infectivity Is Restricted by APOBEC3.

The host range of human immunodeficiency virus type 1 (HIV-1) is narrow. Therefore, using ordinary animal models to study HIV-1 replication, pathogenesis, and therapy is impractical. The lack of applicable animal models for HIV-1 research spurred our investigation on whether tree shrews (Tupaia belangeri chinensis), which are susceptible to many types of human viruses, can act as an animal model for HIV-1. Here, we report that tree shrew primary cells are refractory to wild-type HIV-1 but support the early replication steps of HIV-1 pseudotyped with the vesicular stomatitis virus glycoprotein envelope (VSV-G), which can bypass entry receptors. The exogenous expression of human CD4 renders the tree shrew cell line infectible to X4-tropic HIV-1IIIB, suggesting that tree shrew CXCR4 is a functional HIV-1 coreceptor. However, tree shrew cells did not produce infectious HIV-1 progeny virions, even with the human CD4 receptor. Subsequently, we identified tree shrew (ts) apolipoprotein B editing catalytic polypeptide 3 (tsAPOBEC3) proteins as active inhibitors of HIV-1 particle infectivity, with virus infectivity reduced 10- to 1,000-fold. Unlike human APOBEC3G, the tsA3Z2c-Z1b protein was not degraded by the HIV-1 viral infectivity factor (Vif) but markedly restricted HIV-1 replication through mutagenicity and reverse transcription inhibition. The pooled knockout of tsA3Z2c-Z1b partially restored the infectivity of the HIV-1 progeny. This work suggests that tsAPOBEC3 proteins serve as an additional barrier to the development of HIV-1 tree shrew models, even when virus entry is overcome by exogenous expression of human CD4. IMPORTANCE The development of animal models is critical for studying human diseases and their pathogenesis and for evaluating drug and vaccine efficacy. For improved AIDS research, the ideal animal model of HIV-1 infection should be a small laboratory mammal that closely mimics virus replication in humans. Tree shrews exhibit considerable potential as animal models for the study of human diseases and therapeutic responses. Here, we report that human CD4-expressing tree shrew cells support the early steps of HIV-1 replication and that tree shrew CXCR4 is a functional coreceptor of HIV-1. However, tree shrew cells harbor additional restrictions that lead to the production of HIV-1 virions with low infectivity. Thus, the tsAPOBEC3 proteins are partial barriers to developing tree shrews as an HIV-1 model. Our results provide insight into the genetic basis of HIV inhibition in tree shrews and build a foundation for the establishment of gene-edited tree shrew HIV-1-infected models.

Spatial illustration of health-care workforce accessibility index in China: How far has our 2009 health-care reform brought us?

OBJECTIVE: The objective of the study was to evaluate the effectiveness of China's health-care reform from 2009 to 2011 by examining China's annual health-care workforce statistics of 2008 and 2011. DESIGN: The design of the study was a secondary data analysis. MAIN OUTCOME MEASURE: The main outcome measure used was the Primary Health Care Worker Accessibility Index (PHCWA). RESULTS: The statistics illustrated the impact health-care reform had on the provision of primary health care in rural areas. The results showed that the health-care reform of 2009 generally improved access to the primary health-care workforce in all 28 areas (range of increase: 13.18-324.0%). However, an increasing disparity in regional health care based on the increase of the standard deviations of PHCWA (range of increase: 36.44-77.10%) may be an issue that policy-makers and analysts will have to face. CONCLUSIONS: Concerted policy efforts from both the provincial and central governments are needed to narrow the gaps. Regional development should not only focus on the economic aspect, but also account for the fact that the adequate provision of primary health care is part of the infrastructure that makes development possible and sustainable.