1. Virus-Cell Interactions

2. Cytolytic
(e.g.non-enveloped viruses)
(+) Replication
Non-Cytolytic
(e.g. enveloped viruses)
Pathogenic
(-) Replication
Non-Pathogenic

4. Productive Viral Replication is not required for cytopathology
Low pH
Buffer - +
Syncytia formation induced by low pH
(LaCrose virus, bunyavirus, RNA enveloped virus)

5. Viral Env (-) (+) (Nipah) Syncytia (Nipah Virus, Paramyxovirus,
-ve strand RNA enveloeped virus)
Viral Env
(Nipah)
(-)
(+)
Syncytia

6. Cellular responses to virus attachment
Apoptosis
Reovirus attachment via 1 protein (encoded by S1 genome segment)
Signal Transduction
HIV Env (gp120)
(strain 1)
(strain 3)
Signaling cascades

7. Virus modulation of host cell Transcription
Generalized vs specific affects on RNA transcription
Poliovirus
Generalized reduction in RNA Pol I, II and III activities (rRNA, mRNA, tRNA)
Shuts down cellular RNA synthesis, promotes viral RNA synthesis
CMV
Microarray analyses indicate change in transcription of about 5% of cellular genes
LCMV
Specific downregulation of growth hormone gene

8. Infection of infant mice
LCMV causes persistent
nonlytic infection of
GH-producing
cells in pituitary
% Surviving
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?)

9. Virus Modification of Host Cell Protein Synthesis
Internal Ribosome Entry Site (IRES) allows
direct binding of ribosome complex to mRNA
without the m7G mRNA cap
Poliovirus
encoded
Required
for cap-dependent
translation
Cap-independent translation

10. 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

11. 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)

12. 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

13. 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

14. HIV-1 nef: Down-modulation of MHC Class I
Advantages:
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
HIV
CTL
MHC Class I
HIV antigen
51Cr

15. 100% HIV Dnef HIV wt % Lysis CTL HIV antigen E (Effector Cell)
MHC Class I
HIV antigen
E (Effector Cell)
T (Target Cell) 0%
1:2
1:5
1:10
1:20
E:T ratio

16. Adenovirus E1A (early) protein: Down-modulation of MHC Class I
E1A allele lacks ability to
downregulate MHC I P
NF-kB
(Stimulates transcription by
binding to enhancer sequences)
Adv E1A
(Inhibits NF-kB activity)
MHC I
promoter
Enhancer
sequences
MHC I gene

17. 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

18. 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

19. Virus Induced Cell death
Necrosis
Intracellular expression of Ebola Gp (glycoprotein) alone can cause necrotic cell death
Apoptosis
Direct
Reovirus s1 to cellular receptor
HIV Env gp120 to coreceptor (CXCR4)
Sindbis Env E2
Indirect
Overcoming the effects of host cell anti-apoptotic genes (Sindbis virus and bcl-2)

20. Immune Attack on Virus Infected Cells
CD8+ CTL
Antibody/Complement
NK Cells ADCC