Transcript Virus-Cell Interactions

Virus-Cell Interactions
Cytolytic
(e.g.non-enveloped viruses)
(+) Replication
Non-Cytolytic
(e.g. enveloped viruses)
Pathogenic
(-) Replication
Non-Pathogenic
P
O
L
I
O
V
I
R
U
S
C
Y
T
O
L
Y
T
I
C
E
F
F
E
C
T
B
E
G
I
N
S
A
B
O
U
T
8
H
O
U
R
S
4
L
C
M
V
I
R
U
S
C
E
L
L
S
S
U
R
V
I
V
E
3
2
1
LOG10CEL-ASOCIATEDVIRUSPERCL
0
1
2
3
0
1
0
2
0
3
0
4
0
H
O
U
R
S
A
F
T
E
R
I
N
F
E
C
T
I
O
N
5
0
Productive Viral Replication is not
required for cytopathology
Low pH
Buffer
-
+
Syncytia formation induced by low pH
(LaCrose virus, bunyavirus, RNA enveloped virus)
Viral Env
(Nipah Virus, Paramyxovirus,
-ve strand RNA enveloeped virus)
(Nipah)
(-)
(+)
Syncytia
Cellular responses to virus
attachment

Apoptosis


Reovirus attachment via 1
protein (encoded by S1
genome segment)
Signal Transduction

HIV Env (gp120)
Genome segment
Percent
apoptosis
L1
L2
L3
M1
M2
M3
M4
S1
S2
S3
Virus
strain
3%
6%
2%
1
3
3
1
3
3
1
3
1
1
3
3
1
3
1
1
1
3
1
3
3
1
1
1
1
3
3
1
3
3
T1L (strain
EB145
EB121
1)
97%
48%
1
3
1
3
1
3
1
3
1
3
1
3
1
3
3
3

1
3
1
3
1.HA3
T3D (strain
3)
Signaling cascades
Virus modulation of host cell
Transcription


Generalized vs specific affects on RNA
transcription
Poliovirus



CMV


Generalized reduction in RNA Pol I, II and III activities (rRNA,
mRNA, tRNA)
Shuts down cellular RNA synthesis, promotes viral RNA synthesis
Microarray analyses indicate change in transcription of about 5% of
cellular genes
LCMV

Specific downregulation of growth hormone gene
Infection of infant mice
1
0
0
% Surviving
LCMV causes persistent
nonlytic infection of
GH-producing
6
0
C
O
N
T
R
O
L
L
C
M
V
I
N
F
E
C
T
E
D
4
0
L
C
M
V
I
N
F
E
C
T
E
D
+
G
H
T
R
E
A
T
E
D
PERCNTSUVING
cells in pituitary
8
0
2
0
0
0
1
0
2
0
3
0
4
0
5
0
A
G
E
I
N
D
A
Y
S
Growth hormone is required for normal growth and regulation of glucose metabolism; LCMV infected
Mice leads to retarded growth and hypoglycemia which leads to death before 1 month of age
Specific downregulation of
GH-mRNA, other mRNAs
not affected
(viral interference with
GH-promoter?)
DNA probe
for
Actin
Collagen
TSH
GH
Function of
Prot ein
Relative amount of RNA
Ratio
LCMV/
Uninfected
Uninfected
LCMV
Housekeeping
Housekeeping
0.11
0.96
0.10
0.46
0.9
0.5
Hormone
Hormone
1.72
3.80
0.69
0.24
0.4
0.08
Virus Modification of Host Cell
Protein Synthesis
Poliovirus
encoded
Required
for cap-dependent
translation
Internal Ribosome Entry Site (IRES) allows
direct binding of ribosome complex to mRNA
without the m7G mRNA cap
Cap-independent translation
Virus Induced Alterations in
Cellular Membranes



Blocking or down-regulation of the
cellular receptor for virus
Modulation of MHC expression
Viral proteins that serve as Ion
Channels
Blocking or down-regulation of the
cellular receptor for virus


Downregulation of cognate
receptor can induce
resistance to superinfection
by the same virus; receptor
can also be blocked by
large amouts of shed
envelope in productively
infected cells
Resistance to
superinfection may be used
to classify different
subgroups of ALSV
Subgroup A infected cells become
resistant to superinfection by other
subgroup A viruses due to saturation
of subgroup A receptor, but are still
sensitive to subgroup B viruses which use
a different receptor (and vice versa)
Downregulation of CD4 by HIV
accessory genes: nef and vpu



Nef induces endocytosis
of Env protein already at
the plasma membrane
Env complexes with newly
synthesized CD4 in the ER
Vpu increases degradation
of Env/CD4 complexes
Modulation of MHC expression


MHC Class I-peptide complexes on virally infected cells are
recognized by TCR on cognate CTLs (CD8+ Cytotoxic T
lymphocytes)
Viral evasion of CTL response can involve down-regulation
of MHC I (less peptide presentation to CTLs)


HIV nef
Adenovirus E1A
HIV-1 nef:
Down-modulation of MHC Class I

Advantages:


HIV
Immune evasion; MHC Class I
presents antigens to cytotoxic
T- lymphocytes; alerts innate
and adaptive immune system to
virally infected cells
Evidence:




Nef expression reduces susceptibility
of HIV-infected cells to CTL mediated
lysis in vitro
selectively down-regulates only HLA-A
and HLA-B, which presents antigens to
CTLs;
does NOT down-regulate HLA-C and
HLA-E, which inhibit NK-cell mediated
cell lysis
Thus, efficiency of CTL-mediated lysis
(adaptive immunity) is reduced without
increasing increasing susceptibility to
NK cell lysis
CTL
HIV antigen
MHC Class I
51Cr
100%
HIV Dnef
HIV wt
% Lysis
E (Effector Cell)
CTL
0%
1:2
1:5
1:10
E:T ratio
1:20
HIV antigen
MHC Class I
T (Target Cell)
Adenovirus E1A (early) protein:
Down-modulation of MHC Class I
Tumors in
Adenovirus
Serotype
Tumorigenicity
Normal
Mice
Immu nocomprom ised
mice
MHC Class I
expression
on tumors
Adenovirus 5
Nontumorigenic
NO
YES
High
Adenovirus 12
Tumorigenic
YES
YES
Low
E1A allele lacks ability to
downregulate MHC I
P P
NF-kB
(Stimulates transcription by
binding to enhancer sequences)
Adv E1A
(Inhibits NF-kB activity)
Enhancer
sequences
MHC I
promoter
MHC I gene
Viral proteins that serve as ion
channels



Influenza M2 protein
Acidic pH in endosome
converts M2 protein to
ion channel
Conducting H+ ions into
interior of virus leads to
dissociation of matrix
protein from viral RNP,
allowing genome to be
transcribed
M2 ion
channel
Viruses and the cell cycle



Different viruses replicate optimally in different
phases of the cell cycle
DNA viruses replicate preferentially in S-phase (DNA
replicating phase)

Adenoviruses, papillomaviruses can induce cell cycling to favor

viral replication
HHV-8 (cause of Kaposi’s sarcoma) can expressed constituitively
active form of GPCR--cellular transfromation
HIV replicates best in G2 phase

HIV accessory protein, vpr, arrests cells in G2 phase
Virus Induced Cell death

Necrosis

Intracellular
expression of Ebola
Gp (glycoprotein)
alone can cause
necrotic cell death

Apoptosis

Direct




Reovirus 1 to cellular
receptor
HIV Env gp120 to
coreceptor (CXCR4)
Sindbis Env E2
Indirect

Overcoming the effects
of host cell antiapoptotic genes
(Sindbis virus and bcl-2)
Immune Attack on Virus Infected Cells



CD8+ CTL
Antibody/Complement
NK Cells ADCC