Everyday, Scientist Live turns its eyes to the Web around it and highlights news and research across the Internet. Today we look at how topoisomerase levels affect chemotherapy responses, HIV host evasion, and transmission of West Nile Virus.
ONCOLOGY
Topoisomerase poisons target topoisomerase enzymes and interfere with the unwinding of DNA for transcription, and they are widely used and effective chemotherapeutic agents. Tumors, however, are often insensitive to, or become resistant to, these drugs, and the genetic basis for this resistance is unclear.
To identify genetic factors involved in response to doxorubicin (a front-line chemotherapy agent that targets topoisomerase 2), Darren J. Burgess et al. screened a library of shRNAs-molecules that knock down expression of target genes-in lymphoma cells. They found that shRNAs targeting topoisomerase 2α (Top2A) frequently confer resistance to the drug. Mice injected with Top2A-deficient lymphoma cells and then treated with doxorubicin exhibited resistance to the drug, fewer tumors, and longer overall survival. Mice with a knockdown of topoisomerase 1 (Top1) showed resistance to camptothecin, a topoisomerase 1 poison. Unexpectedly, Top1 knockdown hypersensitized cells to topoisomerase 2 poisons, suggesting a synergy between Top1 suppression and topoisomerase 2 poisoning.
The authors say that their results point to an approach for validating candidate genes and screening for other genetic determinants of drug resistance, and they suggest that levels of topoisomerase enzymes might serve as biomarkers to guide the clinical use of topoisomerase poisons.
- "Topoisomerase levels determine chemotherapy response in vitro and in vivo" Darren J. Burgess, Jason Doles, Lars Zender, Wen Xue, Beicong Ma, W. Richard McCombie, Gregory J. Hannon, Scott W. Lowe, and Michael T. Hemann. PNAS.
VIROLOGY
To ensure their survival, microbial pathogens have evolved diverse strategies to subvert host immune defenses. The human retrovirus HIV-1 has been proposed to hijack the natural endocytic function of dendritic cells (DCs) to infect interacting CD4 T cells in a process termed trans-infection.
Although DCs can be directly infected by certain strains of HIV-1, productive infection of DCs is not required during trans-infection; instead, DCs capture and internalize infectious HIV-1 virions in vesicles for later transmission to CD4 T cells via vesicular exocytosis across the infectious synapse. This model of sequential endocytosis and exocytosis of intact HIV-1 virions has been dubbed the "Trojan horse" model of HIV-1 trans-infection.
While this model gained rapid favor as a strong example of how a pathogen exploits the natural properties of its cellular host, our recent studies challenge this model by showing that the vast majority of virions transmitted in trans originate from the plasma membrane rather than from intracellular vesicles. This review traces the experimental lines of evidence that have contributed to what we view as the "rise and decline" of the Trojan horse model of HIV-1 trans-infection.
- "The Achilles Heel of the Trojan Horse Model of HIV-1 trans-Infection" Cavrois M, Neidleman J, Greene WC (2008) The Achilles Heel of the Trojan Horse Model of HIV-1 trans-Infection. PLoS Pathog 4(6): e1000051. doi:10.1371/journal.ppat.1000051
VIROLOGY
The distribution and intensity of transmission of vector-borne pathogens can be strongly influenced by the competence of vectors. Vector competence, in turn, can be influenced by temperature and viral genetics. West Nile virus (WNV) was introduced into the United States of America in 1999 and subsequently spread throughout much of the Americas.
Previously, we have shown that a novel genotype of WNV, WN02, first detected in 2001, spread across the US and was more efficient than the introduced genotype, NY99, at infecting, disseminating, and being transmitted by Culex mosquitoes. In the current study, we determined the relationship between temperature and time since feeding on the probability of transmitting each genotype of WNV. We found that the advantage of the WN02 genotype increases with the product of time and temperature. Thus, warmer temperatures would have facilitated the invasion of the WN02 genotype. In addition, we found that transmission of WNV accelerated sharply with increasing temperature, T, (best fit by a function of T4) showing that traditional degree-day models underestimate the impact of temperature on WNV transmission.
This laboratory study suggests that both viral evolution and temperature help shape the distribution and intensity of transmission of WNV, and provides a model for predicting the impact of temperature and global warming on WNV transmission.
- "Temperature, Viral Genetics, and the Transmission of West Nile Virus by Culex pipiens Mosquitoes" Kilpatrick AM, Meola MA, Moudy RM, Kramer LD (2008) Temperature, Viral Genetics, and the Transmission of West Nile Virus by Culex pipiens Mosquitoes. PLoS Pathog 4(6): e1000092. doi:10.1371/journal.ppat.1000092
