Virus-Cell Interactions

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

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

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

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

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?)

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

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: 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

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

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

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 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)

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