VIROLOGY - MCB 5505

VIRUS FAMILY: HERPESVIRIDAE (HERPES = TO CREEP)

I. DISTINGUISHING CHARACTERISTICS
A. LARGE, ENVELOPED, ICOSAHEDRAL DNA VIRUS
B. DNA IS DS AND HAS TRs AT ENDS AND INTERNALLY-
>100 GENES.
C. GENES EXPRESSED IN THREE WAVES (α, β & γ)
D. THREE SUBFAMILIES OF HUMAN VIRUSES - DEFINED
CLINICALLY (NINE GENERA)
E. ALPHAHERPESVIRINAE KNOWN FOR LATENT/RECURRENT INFECTIONS
II. STRUCTURE - HERPES SIMPLES 1 (HHV-1)
A. SIZE: 125 nm DIAMETER
B. ENVELOPE: YES-A DOUBLE BILAYER (FROM NUCLEAR MEMBRANE)
1. GLYCOPROTEINS: > 10 GLYCOPROTEINS
2. OTHER PROTEINS:
3. MATRIX PROTEINS: > 15 TEGUMENT (MATRIX) PROTEINS
C. NUCLEOCAPSID (6 PROTEINS: HEXON, PENTON & 4 TRIPLEXES)
1. NUCLEIC ACID
a. TYPE: DNA BALTIMORE TYPE: I
b. STRANDED: DS WITH TRs (SEE BELOW)
c. POLARITY: +/-
d. MOL. WT.: 150 kbp, 90 Md

e. # GENES: >70, MOST HAVE NO INTRONS

2. GENETIC (PHYSICAL) MAP FOR HHV-1:

a b UL b a'a'c US c a

(THERE ARE 7 CONSERVED GENE BLOCKS)

(THREE TYPES OF PROMOTERS: α, β & γ)

FOUR DIFFERENT ORIENTATIONS ARE POSSIBLE

3. CAPSID
a. SYMMETRY: ICOSAHEDRAL, T=16
b. CAPSOMERS: 12 PENTONS, 150 HEXONS
c. SIZE: 150 nm IN DIAMETER
d. COMPOSITION
(1) PROTEINS: AT LEAST SIX PROTEINS
(2) OTHER PROTEINS: ?

D. TEGUMENT - IN OTHER VIRUSES CALLED MATRIX PROTEINS.

WITH HERPES VIRUS THE TEGUMENT (OR MATRIX) IS MUCH
MORE COMPLEX AND CONTAINS AT LEAST 15 DIFFERENT
PROTEINS. THEY PROBABLY HAVE FUNCTIONS SUCH AS NUCLEAR
TRANSPORT, AND AT LEAST ONE IS RESPONSIBLE FOR TURNING
ON EARLY GENE TRANSCRIPTION (αTIF).
VIRUS FAMILY: HERPESVIRIDAE

III. CLASSIFICATION AND CHARACTERISTIC MEMBERS (HUMAN)

SUBFAMILY GENERA PROPERTIES MEMBERS

ALPHAHERPESVIRINAE SIMPLEXVIRUS LATENT/RECURRENT HHV-1,2

VARICELLOVIRUS DISTINCT GP, L/R HHV-3

BETAHERPESVIRINAE CYTOMEGALOVIRUS DISTINCT, LG CELL HHV-5(CMV)

MUROMEGALOVIRUS
ROSEOLOVIRUS DSTNCT,T-CELL INF HHV-6,7

GAMMAHERPESVIRINAE LYMPHOCRYPTOVIRUS DSTNCT,B-CL INF HHV-4(EBV)

RHADINOVIRUS FIBRO.,B,T-CL INF HHV-8(KSAV)

IV. VIRAL MULTIPLICATION (FOR HHV-1)

A. ABSORPTION: Adsorption of HHV requires a cell receptor

called HIgR, "herpesvirus Ig-like receptor" a member of
CD155 family of the immunoglobulin superfamily of membrane
proteins. At least two other related receptors also may be
used by herpesviruses. Entry is by membrane fusion.
C. UNCOATING: The nucleocapsid is transported to a
nuclear pore and the viral DNA enters the nucleus leaving
the capsid behind.
D. GENE EXPRESSION: Host RNAP II produces At least 80 different
mRNAs. Three waves of transcription are seen, and are directed
by promoters α (immediate early transcription), β (early
transcription) and γ (late transcription). Immediate early or
α promoters are recognized with a virion tegument protein
called αTIF. Proteins made in the previous wave activate the
β and γ promoters. The α proteins are regulatory and some
interfere with splicing (only 4 of the 80 herpes mRNAs are
spiced). The β proteins are involved in DNA synthesis and even
nucleotide metabolism enzymes are made (e.g., THYMIDINE
KINASE, see below). The γ proteins are mostly virion proteins
(core, tegument and membrane proteins). The latter all return to
the nucleus for virus assembly.
E. GENOME REPLICATION: The TR ends ("a" region) of the linear
DNA are used to circularize the genome. Late DNA replication is
by rolling circle. Unit length genomes are cut and the TR "a"
region is "repaired" using the internal "a" region as a template
in a complicated recombinational event. As a result four
orientations of genomic DNA are produced.
F. ASSEMBLY: The core and tegument assemble in the nucleus
and bud through the nuclear membrane. There may be other
"budding-like events" in the cytoplasm.
G. BUDDING AND/OR RELEASE: Mechanism of release is obscure. It
may require a packaging process in the Golgi apparatus and
vesicle fusion with the plasma membrane.
V. CLINICAL CORRELATIONS

All herpesviruses are extremely opportunistic. In immune

suppressed individuals primary and recurrent (or chronic)
infections can become severe and even life threatening.

A. The Alphaherpesvirinae are known for their latent and

recurrent infections. These include HHV1, HHV2 (herpes simplex 1
and 2) and HHV3 (varicella-zoster virus) The primary infections
are usually the most severe (like chicken pox) and recurrent
infections less severe (shingles, cold sores). All establish
latent infections of sensory nerve cells and when activated
travel down nerve fibers (sensory nerve axons) to the nerve
endings where epithelial cells are infected with sometimes
painful, inflammatory reactions.

B. The Betaherpesvirinae cause chronic infections of immune

cells and other visceral cells (kidney cells with CMV). They
often cause subclinical infections, but in individuals who are
immune suppressed, more serious infections occur. CMV (HHV5)
causes birth defects because the fetus can be infected with
serious consequences (kidney failure). HHV6 is associated with
roseola(sixth disease)in infants, a rash-fever of short duration.
C. The Gammaherpesvirinae represented by HHV4 (Epstein-Barr
virus, EBV) and HHV8 (Kaposi's sarcoma-associated virus, KSAV)
cause chronic or latent infections of B-lymphocytes. EBV cause
infectious mononucleosis in young adults and has been strongly
implicated in two types of cancer that occur in two geographical
areas. Burkitt's lymphoma is found in central Africa associated
with malaria, and is a leading causes of death in children. EBV
is also associated with nasopharyngeal carcinoma found mainly in
parts of China. EBV proliferation and its ability to cause
serious disease are dramatically enhanced with reduced immune
responses in the host.
HHV8 has been found to be strongly associated with Kaposi's
sarcoma in individuals with AIDS. Even though they primarily
infects B cells, the cancer is of endothelial cell origin and is
multifocal. This cancer is usually not aggressive, but in immune
suppressed individuals, especially those with AIDS, it becomes a
serious cancer. Like HHV2 this virus is transmitted sexually.

One very popular drug for the herpesviruses is acyclovir (and its
derivatives, e.g., Valtrex & Cytovene). The drug, a nucleoside
analog of guanosine, is activated by the herpes enzyme, thymidine
kinase, which phosphorylates the drug at a position analogous to
the 5'-hydroxyl group of guanosine. Host enzymes convert the
drug to the triphosphate, and the triphosphorylated acyclovir
inhibits DNA synthesis. Therefore, THE DRUG IS ONLY ACTIVE IN
HERPES VIRUS INFECTED CELLS UNDERGOING DNA SYNTHESIS.