Viral Tropism and Cellular Receptors

Viral Tropism A specific pathologic “signature” left by a viral infection, usually

related to its ability to replicate only in specific cell types Samllpox (scarring from recovered scabes) Polio (paralytic attack) Yellow Fever (acute jaundice) Rhinovirus (common cold)

Mechanisms of tropism Cellular receptors; differential expression limits viral entry into

specific cell types that express the cellular receptor Post-entry factors; cell type must be permissive for viral replication

Transcription and translation machinery compatible with viral life cycle Innate anti-viral defenses can be overcomed by viral encoded proteins or

these defenses do not affect viral life cycle

For lipid enveloped viruses, a specific viral envelope Attachment Protein (usually glycosylated) interacts with the cognate cell surfcae receptor to bring aboutfusion of the virus membrane and the host-cell membrane

Varieties of Viral Receptors

Attachment and entry are distinct events, and may be mediated by different receptors

Varieties of Viral Receptors For some viruses, attachment and entry receptors are

complementary but distinct Herpes Simplex Virus 1 (“cold sores”) Herpes Simplex Virus 2 (genital lesions)

Cellular attachment is primarily via heparan sulfate, but productive entry into the cell requires a coreceptor and interaction with a different envelope glycoprotein

Herpes Virus has 11 membrane glycoproteins, four of which are involved in attachment and entry

gB, gC (attachment--interacts with heparan sulfate) gD, gH/gL (entry--interacts with coreceptor)

Expression of these receptors in the right place and combination can account for some of HSV tropism

Many coreceptors have been described

Entry receptors for Herpes Simplex Viruses

Alternate Tissue Name Designation HSV-1 HSV-2 Expression

hTR2 HveA + + Lung, Liver, kidney, Heart, Brain, Placenta

hNectin1δ HveC + + , , ,Brain Spinal Cord Prostate

, Placenta Liver3- - O sulphated + - , , ,Liver Placenta HeartHS , Kidney Pancreas

2hNectin α HveB - +/- , , Placenta Prostate

Endothelial cells155CD HveD - + , , ,Brain Intestine Peyer's Patches

-T cells

Varieties of Viral Receptors For some viruses, attachment and entry receptors are

complementary but distinct HIV-1 (only one envelope glycoprotein)

Requires a primary receptor (CD4) and a coreceptor (chemokine receptor) for viral entry

Sequential interaction of the virus envelope glycoprotein with CD4 and coreceptor results in fusion between the virus and host cell membrane

CD4+CD4+MacrophagesT cell LinePrimary T cells CD4+M-tropic T-tropicCCR5+CXCR4+CCR5+CXCR4+

Use of Different Coreceptors Largely Accounts for Viral Tropism (HIV)

CD4+CD4+MacrophagesT cell LinePrimary T cells CD4+M-tropic T-tropicCCR5+CXCR4+CCR5+CXCR4+

Use of Different Coreceptors Largely Accounts for Viral Tropism (HIV)

ccr5/ccr581% of CaucasianGet infected normallyProgress to AIDS normally

ccr5/32ccr515-18% of Caucasians Get infected normallyBut progress to AIDS 2-4 years more slowly

32ccr5 /32ccr51% of CaucasiansHighly Resistant to InfectionLoss of CCR5 function but otherwise normal (no side effects)

This makes CCR5 an attractive drug target

Varieties of Viral Receptors For some viruses, attachment

and entry receptors are the same, but membrane fusion is not at the cell surface, membrane fusion is triggered by low pH in endosomes

Influenza HA glycoprotein binds to

sialic acid receptor on cell surface

Virus and receptor are endocytosed

Low pH in endosomes trigger conformational changes in HA which results in membrane fusion

Fusion Peptide

Viral Receptors: Some Principles

A variety of molecules, including glycoproteins, glycolipids, and glycosaminoglycans, can serve as viral receptors.

Different viruses employ different cellular receptors. A given virus isolate may employ several alternate cellular molecules

as receptors. In some instances, viral entry requires two or more different co-

receptors on the cell surface. Usually, both co-receptors are necessary and neither alone is sufficient.

Different isolates of the same virus may prefer different receptors. A specific virus isolate may alter its receptor preference by selection of a mutant VAP during serial passage in animals or cell cultures.

The domain of the receptor that binds the virus may be either a polypeptide sequence or a carbohydrate moiety, often located at the external tip of the receptor molecule.

Not all cells that express the viral receptor are capable of supporting the complete cycle of viral replication.

Viral Tropism & Pathogenesis Viral receptor expression is the primary but not

the only determinant of viral tropism Polio virus

Paralysis Parvovirus B19

Exanthem subitum Pure red cell aplasia

LCMV

Poliovirus Family:Picornaviridae (small (+) RNAvirus); Genus: Enterovirus

Infects only primates (human & non-human) Virus bind more avidly to homogenates from primate vs non-

primate tissues Viral RNA infectious for single round in non-primate tissue (by

passing the entry block) PVR--CD155 (Ig Superfamily)

High conservation amongst Primates Replicates in gut, excreted in feces

Fecal-oral transmission; hygiene issues; swimming pools Viral invasion of CNS; also replicates preferentially in anterior

horn cells--lower motor neurons of spinal cord; results in flaccid paralysis

Tissue Cells PVRexpression

PoliovirusReplication

Cellulardestruction

Central nervoussystem

ThymusKidneyLungAdrenal

IntestineSpleenSkeletal muscle

Neurons Anterior horn spinal cord Posterior horn spinal cord Medulla Cerebellum Midbrain Forebrain

T lymphocytesEpithelial, tubule cellsAlveolar cellsEndrocrine cells

ManyLymphocytesMyocytes

HighHighHighHighHighHigh

HighHighHighHigh

LowLowLow

HighHighHigh

ModerateModerateModerate

NoneNoneNoneNone

NoneNone

Moderate

SevereMinimalModerateMinimalMinimalMinimal

NoneNoneNoneNone

NoneNoneNone

Receptor expression is necessary but not sufficient to explain viral tropism

Polivirus Receptor Expression and Viral RNA expression

Parvovirus B19Family: Parvoviridae (ssDNA virus)

Tropism for red cell progenitors in bone marrow Receptor is a glycoshingolipid on the

erythrocyte P antigen--also present on cells of mesenchymal origin

Virus replicates only in actively dividing cells, not in terminally differentiated RBCs

Therefore, tropism is limited to actively dividing cells with high receptor expression

(erythrocyte precursors)

Platelets Macrophages

Granulocytes

RBCs

Lymphocytic Choriomeningitis VirusFamily: Arenaviridae (minus-strand RNA virus)

Different strains of LCMV exhibit different tropism Armstrong strain--neurotropic Clone13 strain--hepatotropic (liver) and spleen-tropic

Both strains use the same receptor

(α-dystroglycan), but differ by one amino acid in the viral envelope glycoprotein

One amino acid change confers high or low affinity binding of viral envelope to cellular receptor

Other determinants of viral tropism

Cellular protease requirement Temperature of replication Acid Lability Transcriptional control

Cellular protease requirement

Plasma membrane

proteasecleavage

Secreted proteaseFusion Competent

Fusion Incompetent

Fusion Competent

Virulent(NCD Virus)

Avirulent(NCD Virus)

Temperature of replication Optimal temp. for rhinovirus (common

cold) replication is 33º C Restricts replication to respiratory

epithelium (e.g. lining of the nose and throat)

Acid/Protease lability Enteric (gut) viruses must be able to survive low pH (acidic)

of stomach, high pH of intestine and actions of digestive enzymes

Some viruses exploit presence of digestive enzymes to “activate” viral envelope protein

Reovirus

LTRTranscription

(tat)

Transcriptional Control--retroviruses

DNA Binding Motifs for various transcription factors

Pappilomavirus Replication in Epidermis

Primary Infection,Permissive for genome replication, but transcription of late structural genes is blocked

Transcription of late Structural genes, virion assembly

Mature virions and viral shedding

Tropism, Viral Variation andPathogenesis/Virulence

Avian Influenza Virus H5N2 serotype circulates in domesic fowl Virulent serotype occurred in domestic poultry

(1983 in Penn., 1995 in Mexico) Virulence is due to single amino acid change

in envelope--deleted a glycosylation site close to Env cleavage site

Fusion Competent

Plasma membrane

proteasecleavage

Mutant Virus--replicate to higher titers, in wider range of tissues--mild disease becomes rapidly fatal

CD4+CD4+MacrophagesT cell LinePrimary T cells CD4+M-tropic T-tropicCCR5+CXCR4+CCR5+CXCR4+

0 6 12 18 24 30 36 42 48

VIR

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6

7

3

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WEEKS AFTER INFECTION

0 6 12 18 24 30 36 42 48

CD

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TIO

0.0

0.5

1.0

1.5

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MACROPHAGE-TROPICSHIV SF162PLPL DEPLETED

LYMPHOCYTE-TROPICSF33ALN DEPLETED

HIV tropism and Pathogenesis