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