Monday, December 5, 2016

The Art of Viral Shape Shifting

Viruses are obligate parasites that must infect a host organism in order to replicate, but their hosts utilize mechanisms to restrict virus replication in order to minimize the deleterious effects.  The interplay between virus and host leads to a dynamic evolutionary relationship, termed the Red Queen hypothesis (1).  In order to survive, if the virus or host adapts then so must the other, but this selective pressure does not translate into enhanced reproductive capabilities and so the status quo is maintained.  Therefore, over the course of evolutionary history, humans and their predecessors developed a number of mechanisms to combat invaders, such as interferon induced transmembrane proteins (IFITMs).  IFITMs are a part of the innate immune system, which is also known as the non-specific immune system and is the initial defense mechanism against pathogens.  Although not completely understood, IFITMs inhibit the entry of viruses into cells.  However, there is not a single means of viral entry, but rather a number of different processes employed by different types of viruses.  Human immunodeficiency virus (HIV) is an enveloped retrovirus meaning it has a proteinaceous coat surrounded by a lipid membrane and the ability to integrate into the human genome (2).  Due to the envelope, HIV can enter through a process known as fusion.  Fusion is where the viral receptors bind to cell surface receptors in order to join with the cell membrane and thereby get the viral genome into the cell.  Also, as an RNA virus with a high mutation rate, HIV is able to easily adapt to selective pressures, which makes it difficult for the immune system to combat the virus once an individual is infected.
            A paper published in Cell Host and Microbe sought to further the understanding of IFITM mediated restriction of HIV (3).  Foster et al. first examined the infectivity, as measured by a reporter gene, of HIV-1 when IFITMs were induced in a cell line engineered to not express IFITMs without production of interferon, a signaling component of the immune system (4).  The data indicated that sensitivity to IFITMs was partly a factor of receptor binding.  To confirm their results, the receptors of different HIV-1 strains were expressed on another enveloped virus.  No significant differences in infectivity were observed compared to the initial assays with HIV-1, which indicated that IFITMs function to inhibit envelope mediated viral entry.  An interesting corollary finding was that all viruses resistant to IFITMs were transmission founders, viruses that are involved in the primary infection after transmission.  Further investigation demonstrated that the progeny of transmission founders, based on sequence similarity, were sensitive to IFITMs after 6 months.  The most rational explanation for the development of IFITM sensitivity during the progression of HIV infection relates to the ability of the RNA virus to easily adapt in response to selective pressures from the immune system.  As different components of the immune system target the virus, it acquires mutations required to escape. Throughout the course of HIV infection, the accumulation of mutations in receptor coding genes facilitates survival, but also result in sensitivity to IFITMs.  To test this hypothesis, the authors blocked specific receptors and then tested sensitivity to IFITMs.  It was found that forced selection for particular receptor binding could alter the phenotype between transmission founder and the 6-month progeny.  Foster et al. provided evidence that IFITM mediated restriction of HIV is depended on receptor usage that affects viral entry. 
Figure 3B: Resistance to IFITM3 restriction of HIV-1 replication, as quantified by a reporter gene, for multiple strains of the transmission founder (T/F) and 6 month molecular clones (6mo).  

            The work of Foster et al. correlates strongly with the notion that HIV is a quasispecies (5).  A viral quasispecies is a group of viruses all related by the mutation of a particular viral genome otherwise known as sequence space.  HIV-1 constitutes a quasispecies because the authors demonstrates that the receptors on the virus’ envelope exhibit variability when adapting to the immune system, which indicates that the HIV genomic sequence has a wide array of potential variants (6).  As a quasispecies, HIV-1 is subject to the quasispecies effect, or survival of the flattest.  Survival of the flattest postulates that viruses, which are the best at adapting to a large set of circumstances but concurrently retain a high replicative capacity, will outcompete other viruses (6).  Based on survival of the flattest, the immune system is challenged by a virus like HIV-1, which can essentially adapt to any defense mechanism. 

            If the human immune system has trouble dealing with HIV-1 infection, then utilizing specific drugs to treat infected individuals will give the best chance of clearing the virus.  Under most circumstances drug based therapy is static meaning a specific aliment is treated with a specific drug.  However, the research of Foster et al. has implications that the best standard of treatment for HIV-1 might not be a single drug or drug cocktail.  Over the course of an infection, as the HIV virus mutates, the treatment should differ depending on the state of pathogenesis.  Since related viruses have distinct characteristics the treatment for one is probably not adequate for the other.  If transmission founders are resistant to IFITMs, it wouldn’t make sense to treat with a drug that stimulates production of IFITMs.  Ultimately in the future, HIV-1 should be treated based on sequence.  An infected individual would have their virus sequenced at regular intervals and based on the results of sequencing the treatment could be altered. 


1. Clarke, D. K., Duarte, E. A., Elena, S. F., Moya, A., Domingo, E., & Holland, J. (1994). The red queen reigns in the kingdom of RNA viruses. Proceedings of the National Academy of Sciences, 91(11), 4821-4824. doi:10.1073/pnas.91.11.4821

2. HIV/AIDS Basics. (n.d.). Retrieved December 05, 2016, from https://www.aids.gov/hiv-aids-basics/

3. Foster, T., Wilson, H., Iyer, S., Coss, K., Doores, K., Smith, S., . . . Neil, S. (2016). Resistance of Transmitted Founder HIV-1 to IFITM-Mediated Restriction. Cell Host & Microbe, 20(4), 429-442. doi:10.1016/j.chom.2016.08.006

4. Dual-Light® Luciferase & β-Galactosidase Reporter Gene Assay System. (n.d.). Retrieved December 05, 2016, from https://www.thermofisher.com/order/catalog/product/T1003

5. Nowak, M. A. (n.d.). What is a Quasispecies. Retrieved December 5, 2016, from http://ped.fas.harvard.edu/files/ped/files/tee92_0.pdf

6. Lauring, A. S., & Andino, R. (2010). Quasispecies Theory and the Behavior of RNA Viruses. PLoS Pathogens, 6(7). doi:10.1371/journal.ppat.1001005

No comments:

Post a Comment