Host-Pathogen Strategies #1

MICROBE:

• Frontal attack strategy – agents that cause acute diarrhea, common cold, influenza, etc.

HOST RESPONSE:

• Innate immunity – interferon

• Adaptive immunity – antibody production

• Cellular response – eliminate infected cells

Host-Pathogen Strategy #2

MICROBE:

Stealth attack strategy - agents such as herpes viruses and retroviruses:– Persistence of genetic information in host cells– Modulate cytopathicity in time and space– Evade host immune responses

HOST RESPONSE:

Long term battle between host and pathogen.

HIV Strategies

Stealth attack strategy:

• Forward escape – high mutation rate alters viral recognition by host CTL’s and antibodies

• Timing is everything – glycosylation of viral envelope and last minute unfolding upon cell entry inhibits host antibody attack.

Human Immunodeficiency Virus

• Human retrovirus similar animal lentiviruses

• 10 kb genome

• 16 proteins

• Causative agent of AIDS

http://rds.yahoo.com/S=96062883/K=hiv/v=2/SID=w/l=IVR/SIG=131q4t235/EXP=1114187376/*-http%3A//www.life.umd.edu/CBMG/progrms/department/webpages378h/Adams/daniel.htm

Conserved proteins

All retroviruses need several structural and enzymatic protein coding regions:

• gag – group specific antigen genes

• pol – polymerase genes

• env – envelope genes

http://rds.yahoo.com/S=96062883/K=hiv/v=2/SID=w/l=IVR/SIG=11opqm3ab/EXP=1114187467/*-http%3A//osms.otago.ac.nz/bur_AIDS.htm

HIV Proteins

HIV REGULATORY PROTEINS:• Tat – transcriptional transactivator• Rev – regulator of viron gene expression

HIV ACCESSORY PROTEINS:• Nef – negative effector• Vif – viral infectivity• Vpr – viral protein R• Vpu – viral protein U

http://www.firstcoastnews.com/health/articles/2002-06-27/images/hiv_testing.jpg

Rev – regulates transition between early and late phases of viral gene expression by allowing transport of viral mRNA from the nucleus to the cytoplasm.

Tat & Nef – required for high levels of viral replication and help the virus evade the host immune response.

HIV Host Entry

• Transmission via bodily fluids

• HIV infects T helper cells, macrophages, microglial cells, dendritic cells:– CD4 primary receptor– CCR5 coreceptors present on macrophages, Dendritic

Cells, T cells (HIV R strain)– CSCR4 coreceptor only on T cells (X4 strain)

• R strain predominates early in infection, X4 strain is detected later, T cell counts drop.

HIV Replication

• After internalization, HIV uncoats and RNA is reverse transcribed into cDNA.

• HIV uses IN, MA, and Vpr proteins to enter the nucleus through nuclear pores.

• cDNA is integrated into the host chromosome as an LTR-flanked provirus.

In resting lymphocytes, reverse transcription is inefficient and minimal energy available for viral translocation to nucleus. After activation, T cells are fully permissive.

HIV Transcription• LTR contains enhancer and promoter sequences.

• Upstream Inr initiator and TATA box help position the RNA Polymerase II.

• Other enhancers bind upstream such as NF-KB and ETS factors.

• Regulatory element Tar downstream of Inr binds Tat and makes elongation efficient.

HIV Viral Assembly

• Viral structural and enzymatic proteins are assembled in cholesterol-rich lipid rafts at the plasma membrane.

• Carboxy terminus of Gag is ubiquitylated and recruits TSG101 and PVS4 to release virion progeny.

• Accessory proteins Vpr and Nef, and cellular components MHCI and II are incorporated in new virions. Envelope glycoprotein and cholesterol are necessary for infection of new cells.

Immunological Sanctuaries

• Persistent infections can be established in microglial cells of the CNS and resting T cells.

http://rds.yahoo.com/S=96062883/K=microglial+cell+photo/v=2/SID=w/l=IVR/SIG=11vh83bs0/EXP=1114193053/*-http%3A//www.webvision.med.utah.edu/glia.html

http://rds.yahoo.com/S=96062883/K=t+cell+photo/v=2/SID=w/l=IVR/SIG=13eurb0ob/EXP=1114193181/*-http%3A//www.dynapure.net/kunder/dynal/dynalpub401.nsf/$all/CCDF126C0556FEFAC1256C5400485069

Proviral Latency

• 1990’s: High HIV replication occurs during asymptomatic period, so no viral latency?

• However, lab studies showed that HIV production can still be stimulated under certain conditions.

• Now it is thought that memory T cells and possibly other cells are infected with intact provirus that can be induced after cell activation.

HIV Invisibility• Normally MHC I present viral peptides on host cell that allow

for viral-specific CTL recognition and killing.

• HIV used Nef protein to decrease the expression of MHC I on host cell surfaces.

• Nef interferes with migration of MHC I to cell surface by degradation in endosomes.

• To avoid killing by Natural Killer Cells that target cells without MHC I, HIV selectively inhibits HLA expression so that NK cells inhibitory receptors can still be bound.

HIV Subversion of Host Cells

• HIV enhances apoptosis of bystander cells.

• Nef upregulates Fas Ligand expression on the surface of infected cells, triggering apoptosis in CTL’s and other cells bearing Fas receptors.

• Tat and Env proteins are also involved in apoptosis of bystander cells.

HIV Protection of Infected Cells

• Nef inhibits ASK1 kinase that is involved with apoptosis signalling.

• Nef inactivates the pro-apoptotic Bad protein, thereby blocking mitochondrial release of cytochrome c. (Inhibition of Bad reduces inhibition on anti-apoptotic Bcl-2).

• Nef binds p53 and suppresses the apoptotic actions.

HIV Treatment

HAART – highly active anti-retroviral therapy

• Helps to control viremia during treatment.

• After treatment, viremia usually returns.

• It could take longer than a human’s lifetime to completely clear infection!

• HIV is constantly evolving to evade the host immune response.

Newer HIV Approaches

STI – structural treatment interuption:– Drug holiday to reduce cost and side effects, as well as to

expose immune system to short periods of viremia.

HAART-cytokine combo treatment:– Cytokines such as IL-2 and antibodies to activate T cell

receptors, so that viruses come out of latency to face the immune response and drug therapy.

Gene therapy to create viral-resistant cells?

Methods of HIV Evasion

• Prevent host defenses from eliminating virus.

• Immunologic sanctuaries.

• Proviral latency.

• Altered antigen processing and presentation.

• Counter-attack against host lymphocytes.