Immunology of HPV Infection

1
Immunology of HPV Infection
Craig Woodworth Department of Biology Clarkson
University Potsdam, NY
2
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

3
The Papillomavirus Life Cycle hasEvolved to
Evade the Immune Response
capsid assembly and virus release
expression of late genes
E6/E7 expression DNA replication
persistence of HPV and malignant progression
low level episomal replication
4
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
5
Type I Interferons Exert DirectAntiviral Effects

• Interferons a and b are produced by HPV-infected
  keratinocytes
• Inhibit cell proliferation and immortalization of
  HPV-expressing 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.

6
HPV-16 E6 and E7 Proteins Directly Inhibit
Interferon Signaling
IFN
interferon a R2
interferon a R1
TYK2
cytoplasm
E6
STAT2
STAT1
nucleus
ISGF3
E7
E6
inhibits IRF-3 and IRF-1
p48
E7
ISRE
7
Inflammation is Important for Innate and Adaptive
Immunity
IL1
IL18
TLRs
TNF
cell lysis release of bioactive IL1-a
NF-kB
cytokines (IL1, TNF-a) IL-12, IFN-g, chemokines,
danger signals
8
Imiquimod Activates theToll-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
9
HPV-16 E6 and E7 Proteins Interfere with
Proinflammatory Signaling
E6/E7
IL1
TLRs
TNF
cell lysis release of bioactive IL1-a
E6
NF-kB
E6
cytokines (IL1, TNF-a) IL-12, IFN-g, chemokines,
danger signals
10
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

11
HPV Early Proteins Alter Expressionof MHC Class
I Genes
E5/E7
TAP-1
HPV antigens
E5
proteasome
class I HLA
E5/E7
HLA class I transcription
ER
12
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
  HPV-linked carcinogenesis

13
Adaptive Immune Response to HPV
activated macrophages Th1 helper T
cells secretion of IgG memory T cells
stimulation of a Th1 type cell mediated immune
response
HPV-infected keratinocytes
Langerhans cells mature and migrate to lymph
nodes where they cross present HPV antigens
14
Langerhans Cells Cross Present HPV Antigens to
the Immune System
HPV antigens danger signal
IL-10 TGF-b1
HPV-infected keratinocyte
Langerhans cell
lymphocyte
15
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
16
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

17
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
  long-lasting (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

18
Summary

• Most HPV infections are not apparent or regress,
  suggesting that the hosts immune response is
  effective
• The HPV life cycle has evolved to evade the
  hosts 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

19
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?