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The Virus-Host Interaction
Virus-host interactions are the drivers of all outcomes of an infection and can occur in the host at
numerous levels; the cell, the individual and also the entire community, helping to drive evolution
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Interactions occur during every stage of the viral life cycle, from the first point
of contact with a cell to when the virus leaves the cell
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The release of interferon is comparable to the rallying of troops, sent out to protect neighbouring
settlements from attack
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In this essay I shall focus upon the virus-host
interactions arising at the entry of viruses into host cells and the subsequent strategies cells have
developed to prevent this invasion
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The consequences of an interaction between a virus and its host partially depend upon the host
proteins that the virus comes into contact with
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The host has a plethora of these restriction factors which
are germ line encoded and are capable of signalling to the innate immune system
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For example,
Interferon-Induced Transmembrane Proteins (IFITM) are membrane bound proteins that aid to block
viral fusion
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Therefore this is a logical stage for host
cells to restrict
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Different viruses have different cell tropisms depending upon their viral
glycoproteins (gp) and the host membrane proteins that these gp’s recognise
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g
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Gp120 has a binding site which recognises the host
receptor CD4, which is present on a number of host immune cells including CD4 T cells, macrophages
and dendritic cells
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The entry of HIV-1 into cells also requires a co-receptor, either
CXCR4 or CCR5
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The
binding of gp120 induces a conformational shift, resulting in the exposure of the hydrophobic
terminus of gp41
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All enveloped viruses must undergo virus-cell fusion into
order to enter a cell, whether at the cell membrane or at the endosome membrane
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HIV-1 gp41 has two heptad repeat
regions, HR1 and HR2, which have repeating amino acids sequences (Furuta et al
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These
sequences interact with each other causing the formation of a trimeric hairpin motif (prehairpin
intermediate) which is inserted into the host membrane
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This conversion of the
fusion peptide into an embedded hairpin is a common feature of all enveloped viruses despite the
diversity of their fusion peptides, and is triggered by either receptor binding, e
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HIV-1, or a low pH,
e
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Influenza A virus
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Subsequently these structures all fold
back into their most energetically stable conformation, which results in hemifusion (figure 1); a
process of merging together small sections of the outer monolayers while the inner monolayers
remain complete (White et al
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This movement provides sufficient energy to allow complete
fusion by merging of the inner monolayers, resulting in pore formation which allows the viral capsid
to be released into the host cell cytoplasm (Chernomordik and Kozlov, 2005)
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The IFITM restriction
factors blocks the fusion of a diverse range of enveloped proteins, with IFITM1 blocking viruses
fusing at the cell surface membrane and IFITM2/3 blocking fusion within endosomes (Fassati, 2014)
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, 2013)
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This
mechanism is not fully characterised yet and there is some debate about the exact stage of
inhibition
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, 2013)
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, 2013)
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, 2014)
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Studies have also suggested that
the virus may become tethered to the interior of the stabilised hemifusion site (Desai et al
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Figure 1 – Diagram showing the steps of HIV-1 viral fusion with a host cell membrane
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(Adapted from Vigant et al
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These proteins have been found to be very effective in inhibiting a number of enveloped viruses
including HIV-1, Influenza A virus, Rabies virus, West Nile virus and Dengue virus (Huang et al
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, 2010; Smith et al
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Irrespective of how the exact mechanism occurs, the host-virus
interaction involving IFITM restriction factors is a crucial first line defence for host cells helping to
prevent infection
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For example, when challenged with
a low pathogenicity Influenza A virus, IFITM3-/- mice suffer from fulminant viral pneumonia, whereas
IFITM3+/+ mice fully recover (Everitt et al
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We also know that like many restriction factors
IFITM proteins are not only induced by IFN but communicate with the IFN type 1 system to produce
additional IFN in a positive feedback loop
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, 2009)
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, 2012; Zhang et al
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A
single nucleotide polymorphism (SNP) is present within a specific location of the IFITM3 gene within
the human population, with possible allele combinations of CC, CT or TT
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3% CC, while
Han Chinese had 25% TT and 25% CC
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People with the CC genotype have
3-4 times increased odds of having severe flu than those who have the CC or CT genotype, leading to
increased complications and mortality
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How does this variation seen in the IFITM3 gene arise? Genetic diversity occurs through the
mechanisms of mutation, selection and recombination
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This makes virus-host interactions key in generating diversity within our species
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For example, IFITM3 proteins have anti-viral functions
against numerous viruses; therefore the TT allele may have inferred better protection against a
specific virus circulating within the Han Chinese in the past, leading to positive selection and fixation
within that population
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IFITM proteins are part of a large and diverse family of
proteins which have an array of functions besides immunity related (IR) roles, e
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they control cell
proliferation and the promotion of bone matrix maturation (Hickford et al
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This wide range of
beneficial functions would have keep IFITM proteins under positive selection, accounting for their
appearance in high numbers of vertebrates
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The dynamics of IR-IFITM evolution are not
completely known; however IFITM1/2/3 appears in most mammals, suggestive of numerous positive
selection events (Bailey et al
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The numbers of mammalian species that have evolved with
these highly conserved IR-IFITM genes displays their importance in protecting the host from viral
infections, and suggest their evolution is owed to their broad anti-viral properties (Zhang et al
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These IFITM restriction factors are very advantageous in the fact that they block the very first
stage of the enveloped viral life cycle preventing all further stages, and they are capable of inhibiting

a number of different viruses
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IFITM genes in humans and
chickens share less than 50% amino acid sequence identity and are separated by 310 million years of
evolution; however they are found within these conserved locations and act in the same manner
(Smith et al
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It is incredible that virus-host interactions within different species have led to a
series of mutations and fixation events which have resulted in similar functioning proteins after so
many years of evolution
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The host
is an extremely hostile environment and viruses have to over-come a multitude of restriction factors
like IFITM and other immune sensors, at every step of their replication
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, 2004)
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In conclusion, viral fusion and entry is an essential step in the viral life cycle, leading to cytoplasmic
entry and subsequent viral genome replication
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The host itself has a whole arsenal of countermeasures
to try to prevent this viral transmission, including the Interferon-Induced Transmembrane Proteins
located within the plasma membrane and endosome membrane of cells
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It is the snug
interplay between viruses and their host that can drive positive selection leading to the evolution of
both organisms
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Indeed, these virus-host interactions are the drivers of
evolution and are partly responsible for the species we are today
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The antiviral effector IFITM3
disrupts intracellular cholesterol homeostasis to block viral entry
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2013;13:452–464
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IFITM-Family Proteins: The Cell's First Line of Antiviral Defense
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2014;1:261-283
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The IFITM proteins mediate cellular resistance to influenza A H1N1
virus, West Nile virus, and dengue virus
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2009;139(7):1243-54
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Membrane hemifusion: crossing a chasm in two leaps
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2005;123(3):375-82
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IFITM3 Restricts Influenza A Virus Entry by
Blocking the Formation of Fusion Pores following Virus-Endosome Hemifusion
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2014;10(4)
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IFITM3 restricts the morbidity
and mortality associated with influenza
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2012;484(7395):519-23
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Fuse me IFITM can! Retrovir
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Furuta RA, Wild CT, Weng Y, Weiss CD
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Nat
Struct Biol
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Hickford D, Frankenberg S, Shaw G, Renfree MB
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BMC Genomics
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Huang IC, Bailey CC, Weyer JL, Radoshitzky SR, Becker MM, Chiang JJ, Brass AL, Ahmed AA, Chi X, Dong L,
Longobardi LE, Boltz D, Kuhn JH, Elledge SJ, Bavari S, Denison MR, Choe H, Farzan M
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PLoS Pathog
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Jiang D, Weidner JM, Qing M, Pan XB, Guo H, Xu C, Zhang X, Birk A, Chang J, Shi PY, Block TM, Guo JT
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J Virol
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Li K, Markosyan RM, Zheng YM, Golfetto O, Bungart B, Li M, Ding S, He Y, Liang C, James C
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IFITM Proteins Restrict Viral Membrane Hemifusion
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2013;9(1)
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The causes and consequences of HIV evolution
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2004;5:52-61
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Chicken interferoninducible transmembrane protein 3 restricts influenza viruses and lyssaviruses in vitro
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2013;87:12957–
66
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Broad-spectrum antivirals against viral fusion
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2015;13:426–437
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Structures and Mechanisms of Viral Membrane Fusion
Proteins; Multiple Variations on a Common Theme
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2008;43(3):189–219
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Evolutionary dynamics of the interferon-induced transmembrane gene
family in vertebrates
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2012;7(11)
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Interferon-induced transmembrane protein-3 genetic variant rs12252-C is
associated with severe influenza in Chinese individuals
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2013;4:1418

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