John A.T. Young & Sumit Chanda on HIV Replication in Human Cells
Fast Moving Front Commentary, January 2011
Top-bottom: John A.T. Young & Sumit Chanda.
Article: Global analysis of host-pathogen interactions that regulate early-stage HIV-1 replication
Authors: Konig, R;Zhou, YY;Elleder, D;Diamond, TL;Bonamy,
GMC;Irelan, JT;Chiang, CY;Tu, BP;De Jesus, PD;Lilley,
CE;Seidel, S;Opaluch, AM;Caldwell, JS;Weitzman, MD;Kuhen,
KL;Bandyopadhyay, S;Ideker, T;Orth, AP;Miraglia,
LJ;Bushman, FD;Young, JA;Chanda,
John A.T. Young & Sumit Chanda talk with ScienceWatch.com and answer a few questions about this month's Fast Moving Fronts paper in the field of Molecular Biology & Genetics.
Why do you think your paper is highly cited?
This was one of the first studies to combine genome-wide RNAi screening and bioinformatics to identify the repertoire of host cellular factors that help facilitate HIV replication in human cells. It represents a significant advance in our understanding of viral-host interactions, providing a blueprint of the machinery that is exploited by the virus. That information, coupled with similar studies of other viral pathogens, forms the basis of additional, more detailed, mechanistic studies and should aid in the design of new antiviral approaches.
Does it describe a new discovery, methodology, or synthesis of knowledge?
This study employed new technologies, genome-wide RNAi screening and bioinformatics, to tackle a fundamentally important question, i.e., what are the host cellular proteins required by HIV to replicate inside our cells? Using this approach, we implicated approximately 300 such proteins and, in doing so, provided, for the first time, a physical and genetic map of host-pathogen interactions that are required for a virus to replicate in a host cell.
Would you summarize the significance of your paper in layman's terms?
An interesting graphic illustrating the systems biology approach toward studying virus infection
View larger figure in tab below.
The human immunodeficiency virus (HIV), the causative agent of AIDS, exploits the protein machinery that exists in our own cells to facilitate its replication and transmission from person to person. This study defined a large number of these cellular proteins that are necessary for different steps of virus replication. This information provides a clearer understanding of the many ways that our cells contribute to HIV replication and also suggests new approaches for developing antiviral treatments.
How did you become involved in this research, and how would you describe the particular challenges, setbacks, and successes that you've encountered along the way?
Dr. Chanda has been involved in the areas of functional genomics and technology for most of his scientific career, and he has more recently developed a keen interest in the systems biology of viral infections. Dr. Young has had a long-standing interest in retrovirus-host interactions and in the use of genetic approaches to identify and characterize the roles played by these factors. Therefore, this was a natural collaboration representing the research interests of both labs.
As with most technological advances, particularly in functional genomics, there are various challenges that remain to be addressed. These include understanding the basis of false negative and positive activities, as well as variances that result from the use of different platforms and experimental conditions.
Furthermore, as the field matures it will be possible to incorporate additional layers of support for involvement of a particular cellular protein or pathway by incorporating rigorously-validated proteomic and metabolomic data into the systems analysis. These are ongoing and evolving challenges, and resolving these issues will enable us to further harness the power of the genome-wide RNAi approach.
Where do you see your research leading in the future?
This type of study launches a number of others aimed at defining the mechanistic roles played by these cellular factors and processes in HIV replication. The information generated by this study could also be highly significant for HIV treatment. Most antiviral approaches that are currently in use target HIV factors and emerging drug resistance is an ongoing problem.
An alternative approach is to instead target cellular factors required by the virus with the hope that drug resistance will be less of a problem in this context. In addition, these results will facilitate our understanding of the effects of individual-to-individual variations of host proteins on disease outcome.
John A.T. Young, Ph.D.
Nomis Foundation Professor
Nomis Center for Immunobiology and Microbial Pathogenesis
The Salk Institute for Biological Studies
La Jolla, CA USA
Dr. Sumit Chanda
Infectious & Inflammatory Disease Center
The Burnham Institute for Medical Research
La Jolla, CA, USA
KEYWORDS: HUMAN-IMMUNODEFICIENCY-VIRUS; SCALE RNAI SCREENS; DNA INTEGRATION; NUCLEAR IMPORT; COMPLEX; PROTEIN; TYPE-1; TRANSCRIPTION; INFECTION; CELLS.