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 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
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)
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
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
EM
IA (R
NA
CO
PIE
S P
ER
ML
) 3
4
5
6
7
3
4
5
6
7
WEEKS AFTER INFECTION
0 6 12 18 24 30 36 42 48
CD
4:CD
8 RA
TIO
0.0
0.5
1.0
1.5
2.0
0.0
0.5
1.0
1.5
2.0
MACROPHAGE-TROPICSHIV SF162PLPL DEPLETED
LYMPHOCYTE-TROPICSF33ALN DEPLETED
HIV tropism and Pathogenesis