ANRV334-ME59-26 ARI 7 December 2007 13:11
Herpes Simplex: Insights
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Annu. Rev. Med. 2008. 59:381–95
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on Pathogenesis and
Possible Vaccines
David M. Koelle1,2,3,4,5 and Lawrence Corey1,2,4
1
Department of Medicine, 2 Department of Laboratory Medicine, 3 Interdisciplinary
Graduate Program in Pathobiology, University of Washington, Seattle, Washington;
4
Program in Infectious Diseases, Fred Hutchinson Cancer Research Center, Seattle,
Washington; 5 Benaroya Research Institute, Seattle, Washington;
email: viralimm@u.washington.edu, lcorey@u.washington.edu
Key Words
herpes simplex virus, vaccine, lymphocyte, human
immunodeficiency virus
Abstract
Herpes simplex viruses are evolutionarily ancient and ubiquitous. In
the past 20 years, there has been increasing recognition of a world-
wide pandemic of HSV-2 infection. Moreover, HSV-2 prevalence
has increased despite fairly widespread use of antiviral drugs for HSV.
The success of HSV-1 and HSV-2 stems from latency within long-
lived neurons and frequent mucocutaneous shedding. The generally
mild medical consequences of HSV infection reflect a functional
equilibrium between host and microbe in most immunocompetent
persons. However, significant gaps in our knowledge of the correlates
of disease severity and HSV immune evasion are limiting rational ad-
vances in these areas. Human genetic studies are gradually outlining
important innate responses, while recent imaging and biopsy studies
have begun to show that the temporal and spatial anatomic inter-
play between virus reactivation and host immune response may be
important in reactivations and disease expression.
381
 ANRV334-ME59-26 ARI 7 December 2007 13:11
INTRODUCTION
Herpes simplex viruses types 1 and 2 (HSV-1,
HSV: herpes HSV-2) are ubiquitous human pathogens. A
simplex virus
balanced household survey (1) from 1999 to
Reactivation: HSV 2004 estimated that 57% of US adults are
DNA in sensory infected with HSV-1 and 17% with HSV-2.
ganglia neurons The accessibility of animal models and clinical
directs synthesis of
populations, the ease of virus propagation, the
mRNA molecules
that encode proteins medically serious aspects of infection, and fas-
required for HSV cination with the relapsing pattern of disease
DNA replication and have attracted the attention of many investi-
assembly of daughter gators. Every advanced technique in molec-
virions. Viral
ular medicine has been applied to HSV (2).
components move
Nevertheless, a vaccine has remained elusive
Annu. Rev. Med. 2008.59:381-395. Downloaded from www.annualreviews.org
anterograde toward
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epithelia, and because of the subtle and successful adapta-
infectious virus is tion of the HSV to its human hosts, as well
released without as our lack of understanding of the virologic
neuronal death
and innate and acquired immune correlates of
infection severity.
The recurrent mucocutaneous infections
associated with HSV are painful and socially
concerning (3), and account for the bulk of
health care utilization. However, they are not
the most serious manifestations of infection.
Primary HSV infections can be devastating
in newborns (4) or immune compromised
hosts (5). Because HSV infection is so preva-
lent, rare complications of recurrent HSV
have a considerable medical burden in both
immune competent and immune compro-
mised persons. These complications include
encephalitis, hepatitis, pneumonia, esophagi-
tis, and keratitis. In rare cases, summarized be-
low, specific or generalized immune deficien-
cies or dysregulation have been implicated in
these diseases. For most patients, however, the
host or viral factors associated with these un-
usual, severe infections remain unknown. The
use of sensitive diagnostic tests, particularly
sensitive PCR assays of cerebrospinal fluid
or serum, and safe, systemic antiviral therapy
may limit further damage. The licensure of
the nucleoside analog acyclovir in 1982 was a
landmark in the development of safe, effective
antiviral therapy (6).
Detailed discussions of diagnosis and treat-
ment (7, 8) are beyond the scope of this re-
view. Instead, we emphasize how molecular,
382 Koelle · Corey
cellular, animal model, and human research
can help explain the clinical manifestations of
HSV infection and disease and provide con-
text for current and future interventions.
INTERACTIONS BETWEEN HSV
AND HIV-1 INFECTIONS
Increasing evidence of significant interplay
between HSV and HIV-1 has renewed in-
terest in HSV-2 control. HSV-2 infection is
significantly related to HIV-1 transmission
(recently reviewed in References 9–11). Coin-
fection with HSV-2 is very common in
HIV-1-infected persons worldwide. HSV-2 is
now appreciated as a major cause of geni-
tal ulcer disease worldwide (12–14). HSV-2
reactivation is associated with increasing
amounts of HIV-1 RNA and infectious virus
in the genital tract (15). In coinfected West
African women not receiving antiretroviral
therapy (ART), daily anti-HSV therapy re-
duced the frequency and amount of geni-
tal HIV-1 RNA shedding (9, 16). Among
coinfected women receiving efavarenz-based
highly active antiretroviral therapy (HAART)
who had residual cervicovaginal HIV-1 shed-
ding at baseline, daily suppressive anti-HSV
therapy further reduced the frequency and
titer of genital HIV-1 RNA shedding (17).
An interventional study (18) in which coin-
fected potential HIV-1 transmitters receive
anti-HSV therapy is under way to determine
if this reduced genital tract HIV-1 shedding
translates into reduced HIV-1 transmission to
susceptible partners. A recent study of East
African women showed that previously or re-
cently acquired HSV-2 infection was signifi-
cantly associated with HIV-1 acquisition (19).
A second interventional study (HPTN 039) is
evaluating the efficacy of daily anti-HSV ther-
apy in preventing acquisition of HIV-1 among
HSV-2 infected persons (18).
The within-person impact of HSV in-
fection on HIV-1 pathogenesis may vary
with HIV-1 disease status and treatment.
Untreated coinfected persons have somewhat
(0.3–1 log10 ) higher HIV-1 plasma viral loads
 ANRV334-ME59-26 ARI 7 December 2007 13:11
than do HSV-uninfected persons (10, 20).
Providing anti-HSV therapy for three months
to coinfected persons not on ART lowered the
mean plasma HIV-1 RNA level by 0.53 log10
(16). These HIV-1 viral load differences are
clinically meaningful (21). It is possible that
an inexpensive and safe intervention—daily
anti-HSV therapy, costing as little as $30 per
year in the developing world—could delay the
need for ART. Longer-term data and mea-
sures of CD4 T cells and immune activation
are needed to explore this possibility.
HSV-2 TRANSMISSION AND ITS
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PREVENTION
Classically, primary HSV infection in the
absence of pre-existing immunity is symp-
tomatic and prolonged. It has been sur-
prising, therefore, to learn that the ma-
jority of HSV-2 seroconversion events are
asymptomatic. These data come from the
placebo arms of prospective vaccine trials
(22). Some individuals experience typical re-
currences, but others remain permanently
asymptomatic. Prospective studies have also
shown that most horizontal HSV-2 trans-
mission events occur during asymptomatic
shedding (23). Patient education coupled
with intensive pathogen detection can move
the dividing line between symptomatic and
asymptomatic shedding (24, 25), but avoid-
ance of contact during obvious recurrences is
not enough. HSV-2 shedding is quite vari-
able between individuals, and no biomarker
for frequent reactivation exists. Among im-
munocompetent, HSV-2-seropositive per-
sons, PCR analysis of swabs of the anogen-
ital region, collected on a daily basis, show
that 95% of persons shed HSV-2. The me-
dian shedding rate averages 25% of days but
varies from 2% to 75%, with more than one
third of patients shedding on >40% of days.
This high frequency of reactivation is a major
factor in transmission to others.
Absent a vaccine, how can we limit trans-
mission? Retrospective analyses indicate that
regular condom use is associated with lower
sexual HSV-2 transmission (26). Unfortu-
nately, intensive safer-sex counseling did not
prevent HSV-2 acquisition in a prospective
Asymptomatic/
study of men who have sex with men (27). unrecognized
Daily antiviral therapy can reduce HSV-2 mu- shedding: HSV
cocutaneous shedding by 60%–80% depend- detection with no
ing on detection method, and titers are lower signs or symptoms of
infection
during residual sheds (28). During a one-year
observation period, transmission of HSV-2 GH: genital herpes
within a group of largely heterosexual cou-
ples was reduced by 48% if the potentially
transmitting partner took valacyclovir daily
(29). The US Food and Drug Administration
has approved valacyclovir for prevention of
HSV-2 transmission.
Natural history data suggest additional
measures to limit HSV infections, although
clinical trial data are lacking. For vertical
transmission, these include avoidance of un-
protected sex by HSV-seronegative pregnant
women, use of antiviral therapy for recur-
rences in late pregnancy, and possibly pro-
phylactic treatment of newborns known to
have been exposed during delivery. Patients
should be counseled to avoid sex when they
have lesions or prodromes. The higher rates
of asymptomatic and total HSV-2 shedding
in the first year after primary genital herpes
(GH) infection (30) suggest that advising pa-
tients to reduce exposures during this time
is also rational. Up to 50% of first-episode
GH is due to HSV-1 in some clinical settings
(31). Given the much lower rate of HSV-1
reactivation in the genital tract compared to
HSV-2, typing of genital isolates (HSV-1 ver-
sus HSV-2) can rank GH patients for their
risk of transmitting HSV genitally and allow
individualized, stratified counseling.
INNATE IMMUNE RESPONSE
TO HSV
Herpesviruses are evolutionarily ancient and
infect hosts as simple as mollusks. In-
nate virus sensor and effector mechanisms,
predating the acquisition of rearranging anti-
gen receptors on T and B lymphocytes, re-
main important in initiating and modulating
www.annualreviews.org • Herpes Simplex 383
 ANRV334-ME59-26
DC: dendritic cell
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ARI 7 December 2007 13:11
“classical” immune responses. We have
known for several decades that interferon
(IFN)-α and -β, secreted by blood cells and fi-
broblasts, respectively, have potent anti-HSV
activity. Siegal and colleagues characterized
the “natural” IFN-α producing cells in blood
as plasmacytoid dendritic cells (pDCs) (32).
pDC numbers decline significantly in un-
treated HIV-1 infection (33), and even if
present, pDCs can be nonresponsive to HSV
(34). More recently, non-HIV-infected sub-
jects with defective pDCs and severe HSV in-
fection have been described (34, 35). pDCs
seem to function mainly as viral sensors. They
are known to express toll-like receptors 7 and
9, and HSV DNA can trigger responses via
TLR9 (36). Mouse studies of HSV-1 skin
infection and HSV-2 vaginal infection indi-
cate that pDCs are not the proximal antigen-
presenting cells (APCs) for T cell priming (37,
38) but are more involved in innate resistance
(39). While DCs typically influence Th1/Th2
balance via IL-12/IL-10, the role of the pDC
subset at this innate/acquired interface is
controversial.
The importance of IFN-α and -β (type 1
IFN) in the host response to HSV is high-
lighted by the enhanced virulence of HSV in
IFN-receptor-deficient mice, and by the spe-
cific type 1 IFN evasion functions mediated
by several HSV-encoded proteins (40). The
HSV γ34.5 protein allows HSV to evade type
I IFN activity by activating a cellular phos-
phatase that activates eukaryotic translational
initiation factor 2 alpha (EIF2α). This negates
the IFN-induced effect of protein kinase R, an
IFN-stimulated gene (ISG), and permits re-
sumption of viral protein synthesis. An impor-
tant early event after innate sensing of viruses
is the translocation of interferon response fac-
tor (IRF)-3 to the nucleus, where it upreg-
ulates IFN-β expression. An HSV protein,
ICP0, blocks the type 1 IFN response up-
stream of IFN-β by inhibiting IRF-3 nuclear
translocation (41). Yet another HSV protein,
US11, counteracts the antiviral function of
another ISG, 2 –5 oligoadenylate synthetase
(42). Candidate live attenuated HSV vaccine
384 Koelle · Corey
strains typically contain deletions of these and
other virulence factors that act by evading the
host innate or acquired immune system.
IFN-γ, also known as type 2 or immune in-
terferon, is secreted both by antigen-specific
Tc1 CD8 and Th1 CD4 T cells in response
to peptide/major histocompatibility complex
(peptide-MHC), and by innate and border-
line lymphocytes such as NK, NKT, and γδ T
cells. A further blurring of the innate/acquired
divide occurs at the level of target cells: Al-
though type 1 and 2 IFNs bind to separate
receptors, both trigger transcription factors,
termed signal transducers of activated T cells
(STAT)-1 and -2, to be phosphorylated, move
to the nucleus with or without IRF cofactors,
and stimulate expression of ISG mRNAs. The
consequences of lesions in the STAT path-
way can be severe. For persons with a rare
homozygous mutation at an amino acid in
STAT-1, HSV infection can be fatal (5). In-
nate lymphocytes such as NK and γδ T cells
accumulate at sites of HSV infection (43, 44)
and can lyse HSV-infected cells (45, 46), but
as yet, little is known about positive signal-
ing to these cells that might result in IFN-γ
release or cell-mediated cytotoxicity.
NFκB is another mobile transcription fac-
tor that is a convergence point for signal-
ing after pathogen detection by TLR2 and
other sensors. HSV signals through TLR2
and causes brisk activation of the NFκB path-
way (47, 48). Clinical and laboratory strains
of HSV have unexplained differences in their
ability to activate cells via TLR2 (48). NFκB
movement to the nucleus triggers expres-
sion of anti-HSV effectors such as TNF-α.
NEMO/IKK-γ is a molecule that regulates
NFκB, and hemizygous mutation in NEMO
is associated with fatal HSV (49).
Another interesting mutation in an in-
nate immunity pathway has recently been as-
sociated with fatal HSV encephalitis (HSE)
in children. Up to 13% of HSE cases oc-
cur in consanguineous families, and HSE
patients typically have no evidence of overt
immune deficiency to other infectious agents.
Casanova and colleagues studied whole blood
 ANRV334-ME59-26 ARI 7 December 2007 13:11
from HSE patients in consanguineous fam-
ilies and reported that IFN-α responses to
HSV and TLR7 and TLR9 agonists were low
to absent (49a). Unique, homozygous, non-
synonymous mutations in the UNC-93B gene
were detected in two patients. UNC-93B en-
codes an endoplasmic reticulum transmem-
brane involved in TLR signaling. Mutations
in other proteins at the innate-acquired cross-
roads have also been associated with severe
HSV infection. These include CD16, an Fc
receptor expressed by NK cells and involved
in antibody-dependent cellular cytotoxicity,
and CD40L, which is required for the licens-
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ing of DCs as well as B cell class switch-
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ing (50, 51). With the exception of a recent
study of TLR2 (52), little research has inves-
tigated more subtle variations in these innate
or crossover immune molecules and the non-
morbid spectrum of HSV severity.
The TLR7 and -8 agonist resiquimod is a
powerful inducer of IFN-α. Recent phase III
trials showed that topical application of re-
siquimod to GH lesions decreased the sub-
sequent rate of HSV-2 shedding (53). Al-
though clinically apparent recurrences were
not delayed at the dose studied, the au-
thors consider the induction of IFN-α via
TLRs a promising therapeutic approach for
treating mucosal HSV infection in humans.
Topical TLR9 agonists are powerful induc-
ers of a local anti-HSV state in the gen-
ital tract and have strong adjuvant activity
for local vaccines (54). pDCs and their type
I IFN product also have favorable effects
on the skin-homing characteristics of mem-
ory, HSV-specific T cells (55) (Figure 1),
further supporting a role for manipulations
of innate immunity in future efforts to reduce
the spread and health impact of HSV.
ACQUIRED IMMUNE RESPONSE
TO HSV
The acquired immune response to HSV in-
cludes CD4 and CD8 T cells and antibodies.
CD4 T cells are probably important in both
antibody and CD8 responses. HSV-specific
CD8 T cells develop poorly in the absence
of CD4 T cell help, and HSV-specific CD4
T cells “license” DCs to prime HSV-specific
CD8 T cells. The same DCs that present HSV
antigen to CD4 T cells, and are licensed in
the process, are necessary and sufficient to
prime naive CD8 T cells (56). The impor-
tance of CD4 cells as pure effector cells re-
mains controversial. In the immune mouse in-
travaginal HSV-2 rechallenge model, CD4 T
cells and IFN-γ are clearly important mucosal
effectors (57). In our cross-sectional human
study of non-HAART-treated HIV-1/HSV-
2 coinfected men, low HSV-2-specific CD8,
but not CD4, T cell number correlated with
GH lesion severity (58). In these subjects,
CD4 T cells may have been available to as-
sist CD8 priming if HSV-infection predated
HIV-1 infection. CD4 T cell loss clearly cor-
relates with HSV-2 shedding in non-HAART-
treated HIV-1-infected persons (59). When
HAART is administered, GH lesion severity
improves while HSV-2 shedding remains high
(60). HSV-2-specific CD4 T cells certainly lo-
calize to GH lesions (61) and can interact with
infected skin keratinocytes that have been ac-
tivated by IFN-γ, as has been shown to occur
in lesions (62). These data are consistent with
a model in which HSV-2-specific CD4 T cells
participate in lesion resolution.
CD8 T cells may be important for con-
trolling HSV replication and shedding in the
ganglia and skin/mucosa. Vaccines stimulat-
ing CD8 responses alone can be protective
in animal models (63). During primary in-
fection, infiltration of CD8 T cells is asso-
ciated with control of acute ganglionic infec-
tion. In the chronic stage, HSV-specific CD8
T cells that recognize a structural HSV glyco-
protein persistently infiltrate the dorsal root
ganglia of latently infected mice (64). This
implies some level of lytic protein expression
sufficient to drive local immune monitoring.
These cells have cytolytic and IFN-γ effector
functions, and explant studies show the lat-
ter are functionally important for HSV sup-
pression. Human autopsy studies (65) show
that HSV-1-specific CD8 T cells with these
www.annualreviews.org • Herpes Simplex 385
 ANRV334-ME59-26 ARI 7 December 2007 13:11

effector functions also localize to trigeminal
ganglia in the natural host. Neuron dropout
or death is not observed clinically or histolog-
ically. Inhibitory molecules capable of modu-
lating T cell activation have been detected in
infected ganglia (66). T cells’ effector func-
tions are probably also reduced by the sup-
pressive environment, including the presence
of regulatory T cells, in the anterior cham-
ber during ocular infections (67). It will be

a CD8 IFN-γ
H
H H H H
H H
LESION NK
H
KERATOCYTES
H EPIDERMIS
H
CD4 CD4
++HLA
Annu. Rev. Med. 2008.59:381-395. Downloaded from www.annualreviews.org

CD8 class I CLA

by Brigham Young University - Idaho on 06/01/13. For personal use only.

IL-2
IP-10, Mig, IP-9 CD4

IL-12
CD8 IFN-α DC
H

CD4
E-selectin+

CLA+ DERMAL CD4

CD8 CXCR3+ VENULE

EC

b 104
Events

0.61% of total CD8s

103 specific for this
HSV peptide
HSV-2 tetramer

100 101 102 103 104

CLA
102
Events

101

100 101 102 103 104

CLA
100
100 101 102 103 104
CD8

386 Koelle · Corey

 ANRV334-ME59-26 ARI 7 December 2007 13:11

important in future studies to determine how
inflammation and immune privilege interact
in these important sites of infection.
In the periphery, HSV-2-specific CD8 T
cells are attracted to GH lesions, where the
infiltration of local cytotoxic T cells corre-
lates with viral clearance (43). These cells can
be detected at low levels in peripheral blood
mononuclear cells by ELISPOT or peptide-
MHC oligomers but are greatly enriched in
herpetic skin. Stable, specific, and high ex-
pression of a skin-specific lymphocyte vascu-
lar adressin, cutaneous lymphocyte-associated
antigen (CLA), by circulating HSV-2-specific
Annu. Rev. Med. 2008.59:381-395. Downloaded from www.annualreviews.org
search in this area is just beginning. A screen
of about half the HSV-2 proteome using syn-
thetic peptides revealed surprising diversity
Peptide-MHC
for CD8 target antigens, with some HLA oligomer: a
dependence and a median of 11 open read- fluorescent probe
ing frames recognized per subject (71). The with multiple
functional properties and within-epitope di- functional groups of
major
versity of the CD8 response are also impor-
histocompatibility
tant. Mouse experiments show that CD8 T complex (MHC)
cell avidity and clonotypic complexity are as- molecule loaded with
sociated with mild disease (72). These newer an antigenic viral
anatomic data and, by implication, the failure peptide. The
oligomer binds
of antibody and CD4-stimulating vaccines to
specifically to T
significantly impact HSV in preventative or lymphocytes that

CD8 T cells may participate in their rapid therapeutic modalities argue for a renewed recognize the viral
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homing to a site of skin infection (68). Re- effort to design and test vaccines that can peptide. Oligomers
cently, the spatial and temporal relationships maximally stimulate this arm of the immune of human leukocyte
antigen (HLA) class I
between infiltrating HSV-2-specific CD8 T response, while carefully monitoring for ex-
molecules bind
cells and HSV-2 replication were studied in cessive immune activation in the ganglia. human virus-specific
human genital skin biopsies using peptide- Antibodies are functionally relevant in the CD8+ T
MHC oligomers (69). When lesions are ac- prevention of neonatal transmission of HSV-1 lymphocoytes; class
tive, these cells are abundant in the dermis, or HSV-2 in the setting of chronic infection, II oligomers bind
CD4+ cells. Murine
and they also penetrate the epidermal layer a mature IgG response that can cross the pla-
homologs contain
where HSV-2 is replicating. After clinical centa, and recurrent cervicovaginal shedding MHC rather than
healing, HSV-2-specific CD8 T cells persist at delivery. The per-delivery risk of neonatal HLA molecules
for up to eight weeks, often adjacent to the infection is quite low, in contrast to maternal
sensory nerve endings that are believed to be primary infection in which IgG antibody is
sites of HSV egress from neurons (Figure 2). lacking. This disparity implies that passively
These studies were performed with CD8 transferred antibody is protective (73). Iso-
T cells specific for proteins in the tegument lated antibody deficiency is rarely associated
layer of the HSV virion. Unbiased library with severe primary or recurrent HSV infec-
screens and clonal dominance studies (70) in- tion, and elicitation of neutralizing antibodies
dicate that tegument-specific CD8 T cells alone, to levels seen during natural infection,
may be somewhat immunodominant, but re- has thus far not correlated with preventative
←−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−
Figure 1
Model for selected events in a recurrent cutaneous HSV-2 lesion. Top: Dermal venule and infected
epidermal keratinocytes. Circulating HSV-2-specific CD8 T cells express cutaneous
lymphocyte-associated antigen (CLA), allowing them to adhere to E-selectin, which is upregulated on
endothelial cells in HSV-2 lesions. Unpublished data and animal gene knockout models support possible
roles for CXCR3 and its ligands, IP-10, Mig, and IP-9, in attracting HSV-specific T cells.
HSV-2-specific CD4 T cell expression of CLA may be assisted by innate plasmacytoid dendritic cell
(pDC) secretion of IFN-α and/or IL-12 in response to HSV (H in red hexagons). In the skin,
HSV-2-specific CD8 T cells kill HSV-2-infected keratinocytes (yellow arrows). Expression of human
leukocyte antigen (HLA) class I, necessary for this recognition, may be assisted by IFN-γ secreted by
HSV-2-specific CD4 and NK cells. CD4 cells secrete IL-2, supporting CD8 cells. Bottom: Circulating
HSV-2-specific CD8+ T cells, identified by staining with a specific fluorescent tetramer reagent (right
upper quadrant of left panel ), overexpress the skin-homing marker CLA (upper right) compared to
bystander CD8+ T cells (lower right). Data from References 55 and 68.

www.annualreviews.org • Herpes Simplex 387

 ANRV334-ME59-26 ARI 7 December 2007 13:11

H and E H and E CD8+HSV-2

Normal skin Herpes lesion Lesion

B7/RPR
CD8 CD8
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CD8

DAPI

Figure 2
Histologic features of recurrent human genital HSV-2 lesions. Top left and center: Hematoxylin and
eosin-stained frozen sections of normal and buttock genital HSV-2 lesional skin, showing dermal
infiltrate and loss of epidermis. Top right: two-color confocal image of CD8+ cells (green, mostly in dermis)
and HSV-2 antigen (red, confined to superficial skin). Bottom left: transverse frozen section of HSV-2 lesion
showing occasional CD8+ cells ( green) in epidermis. Nuclei are stained blue with DAPI. Center: Three
color stains including visualization of HSV-2-specific CD8 T cells (red ) using HLA-peptide multimers
conjugated to quantum dots. HLA–peptide–quantum dot multimers stain HSV-2-specific CD8 T cells
red. At right is a section parallel to the skin surface, showing CD8 T cells in the dermal rete ridges. Skin
was obtained four weeks after resolution of clinical lesions. From Reference 69.

vaccine efficacy in humans (74). Functional
roles for antibody are implied by the fact that
HSV encodes a potent Fc receptor that con-
tributes to pathogenesis in appropriate mouse
models (75). The recent elucidation of struc-
tures for HSV envelope proteins involved in
receptor binding and fusion (76, 77) may al-
low rational vaccine design to further boost
neutralizing antibody levels and revitalize this
area of vaccine research.
Because HSV in genital lesions and vagi-
nal/cervical secretions appears to exist as “free
gD2: glycoprotein
virus,” it is likely that an optimal vaccine will
D of HSV-2
need to provide high levels of neutralizing
gB2: glycoprotein B
antibodies. Prior subunit vaccines contain-
of HSV-2
ing the major neutralizing proteins gD2 and
gB2 have not effectively blocked infection,
suggesting that neutralizing antibodies may
provide a necessary but insufficient immune
response to prevent infection in humans. A
vaccine containing truncated gD2 in a novel
lipid adjuvant was recently shown to prevent
HSV-2 disease in phase III clinical trials (77a).
This vaccine elicits antibody and CD4 T cell
responses. Clinical activity was observed only
in women who were both HSV-1- and HSV-
2-uninfected. A confirmatory trial is under
way in this population. Vaccine regimens that
elicit both effector antibodies and adaptive
T cell responses appear to offer the great-
est hope for developing an effective immuno-
gen. Some of the approaches currently being

388 Koelle · Corey

 ANRV334-ME59-26 ARI 7 December 2007 13:11

developed in the HIV-1 vaccine field, such as tack. Antiapoptotic HSV miRNA expressed
the inclusion of fusion intermediates as tar- during latency (79) and inhibitory T cell
gets for antibodies and the use of potent viral receptor/ligand pairings in the ganglia (66)
Latency: HSV
vectors to elicit CD8 T cell responses, may be may modulate the destructive potential of DNA exists
applicable to HSV vaccine development. the T cell infiltrate, but further research is extrachromosomally
needed. in nuclei of sensory
The factors responsible for variation in ganglia neurons.
UNANSWERED QUESTIONS HSV-2 severity in apparently immunocom-
Specific
latency-associated
Many of the most important questions in the petent persons, including severe loss of con- RNA transcripts, not
immunobiology of HSV infections remain trol of HSV replication in persons with en- proven to encode
unanswered or unaddressed. As discussed cephalitis or hepatitis, remain unknown. The proteins, accumulate
above, there are few data on the correlates host polymorphisms described to date (men- in these neurons.
Newer shedding data
of protection in humans and few clear asso- tioned above) provide a few clues, but most of
indicate latency may
ciations between adaptive or innate immune the spectrum remains mysterious. The role be less tight than
Annu. Rev. Med. 2008.59:381-395. Downloaded from www.annualreviews.org

responses and frequencies of reactivation of of viral polymorphisms in disease severity previously believed
by Brigham Young University - Idaho on 06/01/13. For personal use only.

infection. There are documented, though in-
frequent, examples of recovery of multiple
strains on more than one occasion each, con-
sistent with reinfection of immune hosts (78).
It is likely that wild-type infection is partially
protective against second-strain infection and
disease. Knowledge of the strength of this ef-
fect would provide a rational target for vaccine
research.
We do not know how local HSV-specific
T cells in dorsal root ganglia interact with
infected neurons. Secretion of IFN-γ ap-
pears to be crucial to limiting viral reactiva-
tion (64), implicating T cell activation; but
clinically and histologically, infected neurons
appear to be protected from cytotoxic at-
remains largely unexplored. Epidemiologic (see text)
studies suggest a poor correlation between the
severity of GH in transmitting and receiving
persons (80). However, many HSV genetic
markers have been associated with dramatic
pathogenesis effects in animal models (81),
and little sequencing has been performed on
clinical isolates. The tools for such a project
are now available.
The long coevolution of host and
pathogen may limit the power of animal mod-
els to address some of these issues. The only
certainties are that human behavior guaran-
tees ongoing opportunities for HSV-2 trans-
mission and research, and that HSV is as-
suredly wilier than we are clever.

SUMMARY POINTS
1. HSV-2 infection is a significant cofactor for HIV-1 transmission.
2. Clinical trials of anti-HSV drugs to prevent HIV-1 acquisition and transmission are
nearing completion. Results, if positive, will provide further impetus for medical
approaches in prevention as well as vaccine initiatives.
3. HSV-2-specific CD8 T cells have surveillance functions to limit HSV-2 reactivation
in ganglia and skin.
4. A HSV-2 vaccine eliciting antibody and CD4 T cell responses with partial clinical
activity in HSV-uninfected women only is being investigated in a confirmatory phase
III clinical trial.
5. Asymptomatic shedding accounts for the majority of HSV-2 transmission.

www.annualreviews.org • Herpes Simplex 389

 ANRV334-ME59-26 ARI 7 December 2007 13:11

6. Suppression of viral shedding in the source partner using nucleoside analog drugs
decreases HSV-2 transmission. This raises the possibility that immunotherapy could
also reduce shedding and transmission, as well as alleviate symptoms.
7. The frequency of asymptomatic genital HSV-2 shedding, averaging 25% of days using
multiple samples and sensitive methods, indicates that persistent lytic infection, rather
than latency with intermittent reactivation, may more accurately describe HSV-2 in
the human sacral ganglia.
8. Innate immunity defects have emerged as correlates of severe HSV infections. Innate
immunity stimulators have powerful anti-HSV effects in animals but have not reached
clinical licensure.
Annu. Rev. Med. 2008.59:381-395. Downloaded from www.annualreviews.org
by Brigham Young University - Idaho on 06/01/13. For personal use only.

FUTURE ISSUES
1. What are the innate and acquired immune correlates of disease severity?
2. Will anti-HSV interventions prevent HIV-1 transmission or acquisition?
3. Will efficacy of the gD2/alum/ASO4 vaccine in HSV-seronegative women be con-
firmed?
4. Will CD8-directed vaccines ameliorate severity and shedding when used prophylac-
tically? Will they have therapeutic benefit?

DISCLOSURE STATEMENT
Dr. Koelle has received grant support from Antigenics, Inc.; 3M, Inc.; and GlaxoSmithKline.
He is a coinventor on patents related to HSV-2 vaccines. Dr. Corey is director of the University
of Washington Virology Division, which has received grant support from GlaxoSmithKline
and Novartis, two companies that make antiviral drugs for the treatment of HSV-2. However,
he receives no salary support from these studies. In the past he has received consulting fees
from Antigenics, which is developing an HSV-2 vaccine.

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Annual Review of
Medicine

Contents Volume 59, 2008

The FDA Critical Path Initiative and Its Influence on New Drug
Development
Janet Woodcock and Raymond Woosley p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p1
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Reversing Advanced Heart Failure by Targeting Ca2+ Cycling

David M. Kaye, Masahiko Hoshijima, and Kenneth R. Chien p p p p p p p p p p p p p p p p p p p p p p p p 13
Tissue Factor and Factor VIIa as Therapeutic Targets in
Disorders of Hemostasis
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Therapy of Marfan Syndrome
Daniel P. Judge and Harry C. Dietz p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 43
Preeclampsia and Angiogenic Imbalance
Sharon Maynard, Franklin H. Epstein, and S. Ananth Karumanchi p p p p p p p p p p p p p p p p p 61
Management of Lipids in the Prevention of Cardiovascular Events
Helene Glassberg and Daniel J. Rader p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 79
Genetic Susceptibility to Type 2 Diabetes and Implications for
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Allan F. Moore and Jose C. Florez p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 95
Array-Based DNA Diagnostics: Let the Revolution Begin
Arthur L. Beaudet and John W. Belmont p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p113
Inherited Mitochondrial Diseases of DNA Replication
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Childhood Obesity: Adrift in the “Limbic Triangle”
Michele L. Mietus-Snyder and Robert H. Lustig p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p147
Expanded Newborn Screening: Implications for Genomic Medicine
Linda L. McCabe and Edward R.B. McCabe p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p163
Is Human Hibernation Possible?
Cheng Chi Lee p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p177
Advance Directives
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v
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Genetic Determinants of Aggressive Breast Cancer

Alejandra C. Ventura and Sofia D. Merajver p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p199
A Role for JAK2 Mutations in Myeloproliferative Diseases
Kelly J. Morgan and D. Gary Gilliland p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p213
Appropriate Use of Cervical Cancer Vaccine
Gregory D. Zimet, Marcia L. Shew, and Jessica A. Kahn p p p p p p p p p p p p p p p p p p p p p p p p p p p p p223
A Decade of Rituximab: Improving Survival Outcomes in
Non-Hodgkin’s Lymphoma
Arturo Molina p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p237
Nanotechnology and Cancer
James R. Heath and Mark E. Davis p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p251
Annu. Rev. Med. 2008.59:381-395. Downloaded from www.annualreviews.org
by Brigham Young University - Idaho on 06/01/13. For personal use only.

Cancer Epigenetics: Modifications, Screening, and Therapy

Einav Nili Gal-Yam, Yoshimasa Saito, Gerda Egger, and Peter A. Jones p p p p p p p p p p p p267
T Cells and NKT Cells in the Pathogenesis of Asthma
Everett H. Meyer, Rosemarie H. DeKruyff, and Dale T. Umetsu p p p p p p p p p p p p p p p p p p p p281
Complement Regulatory Genes and Hemolytic Uremic Syndromes
David Kavanagh, Anna Richards, and John Atkinson p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p293
Mesenchymal Stem Cells in Acute Kidney Injury
Benjamin D. Humphreys and Joseph V. Bonventre p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p311
Asthma Genetics: From Linear to Multifactorial Approaches
Stefano Guerra and Fernando D. Martinez p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p327
The Effect of Toll-Like Receptors and Toll-Like Receptor Genetics in
Human Disease
Stavros Garantziotis, John W. Hollingsworth, Aimee K. Zaas,
and David A. Schwartz p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p343
Advances in Antifungal Therapy
Carole A. Sable, Kim M. Strohmaier, and Jeffrey A. Chodakewitz p p p p p p p p p p p p p p p p p p361
Herpes Simplex: Insights on Pathogenesis and Possible Vaccines
David M. Koelle and Lawrence Corey p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p381
Medical Management of Influenza Infection
Anne Moscona p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p397
Bacterial and Fungal Biofilm Infections
A. Simon Lynch and Gregory T. Robertson p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p415
EGFR Tyrosine Kinase Inhibitors in Lung Cancer: An Evolving Story
Lecia V. Sequist and Thomas J. Lynch p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p429
Adaptive Treatment Strategies in Chronic Disease
Philip W. Lavori and Ree Dawson p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p443

vi Contents
 AR334-FM ARI 18 December 2007 17:20

Antiretroviral Drug–Based Microbicides to Prevent HIV-1 Sexual

Transmission
Per Johan Klasse, Robin Shattock, and John P. Moore p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p455
The Challenge of Hepatitis C in the HIV-Infected Person
David L. Thomas p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p473
Hide-and-Seek: The Challenge of Viral Persistence in HIV-1 Infection
Luc Geeraert, Günter Kraus, and Roger J. Pomerantz p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p487
Advancements in the Treatment of Epilepsy
B.A. Leeman and A.J. Cole p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p503

Indexes
Annu. Rev. Med. 2008.59:381-395. Downloaded from www.annualreviews.org
by Brigham Young University - Idaho on 06/01/13. For personal use only.

Cumulative Index of Contributing Authors, Volumes 55–59 p p p p p p p p p p p p p p p p p p p p p p p p525

Cumulative Index of Chapter Titles, Volumes 55–59 p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p529

Errata

An online log of corrections to Annual Review of Medicine articles may be found at

http://med.annualreviews.org/errata.shtml

Contents vii