HDM TBL 12: Immune response to viral infection

Th1 cells prod.

IFN-gamma to activate CTL & B cells [IgG1 & IgG3]

Innate immunity to viruses

1. TLR3 [dsRNA] & TLR7 [ssRNA] recognize viral RNA inside cells

   1. prod of IFN-alpha and IFN-beta [paracrine]

      1. prod of antiviral proteins

         1. interfere w/ viral replication & upregulate MHC-I

2. induces expression of stress ligands, non-classical MHC-1b MICA & MICB & a decrease/loss of MHC I / HLAE expression

   1. NK cells have both KAR [activation → MICA/MICB] & KIR [inhibitory → MHC-I/HLAE] receptors

      1. killing depends on perforin/granzyme & TNF-alpha

3. IFN-gamma & PRR stim → full activation of DC

   1. DCs express CCR7, secrete IL-12, increasing MHC & CD80/86 [B7] co stim

      1. IL-12 further activates NK cells

4. activated DCs respond to CCL21 made by lymph node cells via CCR7

   1. go to T cell rich paracortex in lymph node

      1. there, DC secretes CCL-18, CCL-19, which along w/ CCL-21 attracts many naive T cells → start adaptive response

Adaptive immunity to viruses

5. naive CD4+ T cells express CCR7 & CCR8 so they go to lymph node paracortex where activated DC presents antigen

6. activated CD4+ Th1 cells secrete IFN-gamma & IL-2, provides signal 3 for naive CD8+ T cells on same DC

7. effector CD8+ CTLs leave lymph node by losing expression of CCR7 & gaining CCR5 → migrate towards CCL5 released by cells at affected site

8. Naive B cells express CxCr5 allowing them to localize to primary follicles in response to CxCL13 made by FDCs

9. free virus & virus bound by C3d/iC3b enter lymph node & bind CR2 [CD21] on FDC

   1. B cell activation

   2. B cells lose CxCR5 & gain CCR7 so it migrates to paracortex

10. in paracortex, activating CD4+ Tfh cells encounter antigen-specific B cells via MHC-II

    1. cells form conjugate & cross-stim

    2. Tfh cell loses CCR7 & gains CxCR5

       1. both Tfh and B cell move back to follicle

          1. B cell rapidly prolif inducing germinal center formation

11. Tfh cells stim B cell thru CD40 ligand & release IL-21 → AID enzyme expression

    1. Class Switch Region [CSR]: AID catalyzes conversion of IgM to other isotypes [like IgG & IgA for viruses]

    2. SHM, memory B cells generated

12. neutralizing antibodies

Human Immunodeficiency Virus [HIV]

• enveloped (+)ssRNA retrovirus

• key proteins prod from 3 poly proteins: gag, pol, env

  • gp120 glycoprotein

  • gp41 glycoprotein

  • nucleocapsid protein: encapsulates RNA

  • matrix proteins: role in viral assemby

  • reverse transcriptase [RT]

  • protease

  • integrase

TLR 3 makes

IFN-beta

TLR7 makes

IFN-beta & IFN-alpha

gp120 glycoprotein

HIV protein

binds to CD4 on T cells

gp41 glycoprotein

HIV protein

fusion & entry into host cells

reverse transcriptase [RT]

converts (+)ssRNA to dsDNA, error-prone

HIV protein

protease

cleaves viral polyproteins to make virions infectious

HIV protein

integrase

cleaves host DNA & ligates viral DNA into host genome

HIV protein

targets of anti-retroviral therapy for HIV

1. Reverse Transcriptase

2. protease

3. integrase

3 stages of HIV infection

1. acute

2. latent

3. reactivation

in HIV infection, B cells …

secrete antibodies IgG1, IgG3, IgA that bind to gp120 during viremic phase or in secretions, neutralizing virus

can activate C’ & damage virions

HIV tissue tropism & life cycle

HIV destroys CD4+ T cells → AIDs

• HIV infects CD4+ T cells or DC/macrophages by attching CD4 [receptor] & CXCR4 or CCR5 [coreceptors]

• envelope fuses w/ host cell membrane, nucleocapsid uncoats releasing ssRNA, RT, & integrase into cytoplasm

  • RT converts genomic ssRNA into dsDNA

• integrase inserts dsDNA into host genomic DNA, forming provirus, allowing virus to remain unseen

• when T cell divides, host RNA polymerase transcribes provirus into mRNA & genomic RNA

• virions assembled, bud off from cells and enter blood

  • protease cleaves viral proteins, maturing virus so it can now infect other CD4+ T cells

Maraviroc

CCR5 antagonist in HIV life cycle

Abacavir

RT inhibitor in HIV life cycle

Bictegravir

integrase inhibitor in HIV life cycle

Atazanavir

protease inhibitor in HIV life cycle

immune evasion tactics

1. CD4+ T cell depletion

2. MHC-I downregulation [HLA-A & HLA-B] by Nef

   1. virally infected cells cannot be removed by CTL

3. Latency

4. Antigenic variability

   1. RT enzyme low fidelity

5. Drug resistance

   1. RT enzyme low fidelity

When Nef is mutated

slow progression of HIV / to AIDS

protective alleles against HIV

CCR5Δ32 co receptor is mutated, infection of host cells interfered → individuals don’t progress to AIDs or take a long time

*heterozygous mutation = Long-term non progressor

*homozygous mutation = don’t get HIV infection at all

HLAB*5701

confers susceptibility to adverse drug reactions to abacavir [RT inhibitor] in HIV

influenza virus [Flu]

• enveloped, ~8 segmented, (-)ssRNA virus w/ helical capsid

• transmission via respiratory droplets

• 3 types:

  • A: diff combos of Neuraminidase [N] & Hemagglutinin [H]; causes global pandemics, extreme antigenic variation from antigenic shift

  • B: causes epidemics, minor antigenic variation due to antigenic drift

  • C: mild disease, not issue

• A & C originate zoonotically from birds & swine

Hemagglutinin [HA]

influenza pathogenesis

binds to sialic acid residues on host cell, promoting entry of virus

neuraminidase [NA]

influenza pathogenesis

enables virion release from cells by hydrolyzing sialic acid

RNA dependent RNA polymerase [RdRp]

part of influenza virus; initiates RNA synth to prod mRNA & (-)ssRNA

antigenic drift

flu virus

• RNA pol low fidelity → random mutations in epitopes for N & H genes → seasonal epidemics

antigenic shift

flu virus

• re-assortment of viral genome segments [coding HA, NA], like btwn human and swine strains → pandemics

primary viral pneumonia

flu virus infection → severe alveolar inflamm → acute respiratory distress sydrome [ARDS]

secondary bacterial pneumonia

superinfection from virus → systemic inflammatory response syndrome [SIRS]

WORSE

Herpes Simplex-Virus-1

• enveloped, dsDNA virus w/ icosahedral nucleocapsid

• associated w/ painful lesions/cold sores, genital herpes, ocular keratitis, encephalitis [temporal lobe]

Herpesviridae members

• HSV-1 = cold sores

• HSV-2 = genital herpes

• Varicella-zoster virus [chickenpox]

• cytomegalovirus [CMV]

• EBV

  • associated w/ hematological cancers & nasopharyngeal carcinoma

• HHV-6

• HHV-8

• CMV & EBV associated w/ post-transplant lymphoproliferative disorders [nonmalignant]

ALL herpes viruses establish life-long latent infections in host

HSV-1: Tissue tropism and life cycle

• HSV-1 infects mucosal & cutaneous epithelium, typically on or around mouth

• initially replicates via lytic cycle, shedding virus

• then penetrates underlying sensory nerve endings, infects neurons, & undergoes migration to trigeminal ganglion, where it remains latent

• reactivation → new lytic infection & shedding of virus

• HSV-1 membrane proteins bind to receptors on keratinocytes & HVEM [intestinal epithelial cells] on mucosal epithelial cells

  • HVEM = herpes virus entry mediator

HSV-1 Pathogenesis

• ICP-47 binds to TAP complex, blocking entry of antigenic peptides into ER, preventing MHC-I presentation of HSV-1 peptides to CTL

• gC binds to complement C3b, inhibiting opsonization and C’ mediated lysis

• virion host shutoff [VHS] blocks IFN response and causes cell death

• thymidine kinase [TK] phosphorylates thymidine to form dNTP, to support viral DNA replication

• latency associated transcript [LAT]

  • promotes latency in trigeminal basal ganglia