Download The HPV life cycle has implications for the immune response

Immunology of HPV Infection
Craig Woodworth
Department of Biology
Clarkson University
Potsdam, NY
The Natural History of HPV Infection
Suggests that Immunity is Effective
• Most HPV infections are cleared without clinical
disease. When lesions develop, they regress after
several months
• Individuals who have decreased cell mediated
immunity (transplant recipients and patients with
HIV) have an increased prevalence and
persistence of HPV infections
• The humoral immune response accompanies
papilloma regression, and is effective in
preventing reinfection
• Immunity to HPV is effective but often delayed
The Papillomavirus Life Cycle has
Evolved to Evade the Immune Response
capsid assembly
and virus release
expression of
late genes
E6/E7 expression
DNA replication
low level episomal
replication
persistence of
HPV and
malignant
progression
The Innate Immune System is the First
Line of Defense Against HPV
epithelial barrier
type I interferons
toll-like receptors
HPV-infected keratinocytes
macrophages
proinflammatory
cytokines
NK cells
Type I Interferons Exert Direct
Antiviral Effects
• Interferons a and b are produced by HPV-infected
keratinocytes
• Inhibit cell proliferation and immortalization of HPVexpressing keratinocytes
• Down regulate expression of the HPV-16 E6 and E7
proteins in immortal keratinocytes
• Stimulate expression of HLA class I proteins
• However, therapy using type I interferons has had
variable success….
HPV-16 E6 and E7 Proteins Directly
Inhibit Interferon Signaling
IFN
interferon a R2
interferon a R1
TYK2
E6
STAT2
STAT1
cytoplasm
nucleus
ISGF3
E7
p48
ISRE
E6
E7
inhibits IRF-3
and IRF-1
Inflammation is Important for Innate
and Adaptive Immunity
IL1
cell lysis & release
of bioactive IL1-a
IL18 TLRs TNF
NF-kB
cytokines (IL1, TNF-a)
IL-12, IFN-g, chemokines,
& ‘danger’ signals
Imiquimod Activates the
Toll-Like Receptor 7
imiquimod
TLR-7
cell lysis & release
of bioactive IL1-a
NF-kB
cytokines (IL1, TNF-a)
IL-12, IFN-g, chemokines,
& ‘danger’ signals
HPV-16 E6 and E7 Proteins Interfere
with Proinflammatory Signaling
E6/E7
IL1
cell lysis & release
of bioactive IL1-a
E6
E6
TLRs TNF
NF-kB
cytokines (IL1, TNF-a)
IL-12, IFN-g, chemokines,
& ‘danger’ signals
HLA Class I and II Proteins
• HLA class I proteins are expressed on the surface
of keratinocytes and contribute to immune
recognition
• HLA class II proteins are expressed by Langerhans
cells and are required for cross presentation of
antigens
• Specific HLA haplotypes are associated with
protection from cervical cancer (HLA DRBI * 13 /
DBQI * 0603)
• Cervical cancers show down regulation of HLA
class I and up regulation of class II proteins
HPV Early Proteins Alter Expression
of MHC Class I Genes
E5/E7
TAP-1
HPV
antigens
E5
proteasome
class I
HLA
E5/E7
HLA class I
transcription
ER
NK Cells and Macrophages
• NK cells target HPV-infected keratinocytes that
express low levels of class I protein
• HPV-infected keratinocytes are relatively resistant
to NK mediated lysis, but sensitive to LAK cells
• NK activity is decreased in patients with
precancerous or malignant anogenital disease
• Macrophages are present in regressing papillomas,
they produce 1L-12, and they contribute to
elimination of HPV-infected cells
• Dysregulation of MCP-1 gene expression and lack
of macrophage infiltration may contribute to HPVlinked carcinogenesis
Adaptive Immune Response to HPV
activated macrophages
Th1 helper T cells
secretion of IgG
memory T cells
HPV-infected
keratinocytes
stimulation of a
Th1 type cell mediated
immune response
Langerhans cells
mature and migrate to
lymph nodes where
they cross present
HPV antigens
Langerhans Cells Cross Present HPV
Antigens to the Immune System
HPV antigens +
‘danger signal’
IL-10
TGF-b1
HPV-infected
keratinocyte
Langerhans
cell
lymphocyte
A Th1 Helper T Cell Response is
Associated with Papilloma Regression
Th1 helper T cell response
regressing HPV infections
IFN-g, IL-2, TNF-a
IL-12
IFN-g
Th1
Th2 helper T cell response
progressing HPV infections
IL-4, IL-5, IL-10
IL-4
TGF-b
Th2
Immune Events in Regressing Papillomas
• Non-regressing papillomas contain few immune cells
and no inflammation
• Regression is associated with a Th1 type cell
mediated immune response and increased
expression of IFN-g, IL-12, and TNF-a
• There is a large infiltration of mononuclear cells in
the epithelium and stroma. This consists of CD4+
cells, macrophages, and CD8+ cells
• Infected keratinocytes express HLA class II proteins
and ICAM-1
The Humoral Immune Response
Protects Against Reinfection
• An antibody response to the L1 protein occurs
commonly after HPV infection. Seroconversion is
delayed for several months
• Both IgG and IgA are secreted. The IgG response to
the L1 capsid protein is type-specific and longlasting (over 10 years). The IgA response may be as
long lived
• Antibodies are neutralizing and are directed to
conformational epitopes on L1.
• The humoral immune response protects against
reinfection, but does not cause regression of
existing papillomas
Summary
• Most HPV infections are not apparent or regress,
suggesting that the host’s immune response is
effective
• The HPV life cycle has evolved to evade the host’s
immune response, and HPV early proteins directly
inhibit specific components of immunity
• Papilloma regression is mediated by a Th1 type
cell mediated immune response with infiltration of
macrophages and CD4+ cells
• Humoral immunity is protective and is mediated by
neutralizing antibodies to conformation specific
epitopes of the L1 protein
Questions
• How do HPV-16 early genes alter the ability of
infected keratinocytes to contribute to the innate
and adaptive immune responses?
• What is the most effective method for preventing
tolerance or stimulating a strong Th1 helper T
cell response?
• Do the innate and adaptive immune responses
differ in the cervical transformation zone where
most carcinomas develop?