The impact of endogenous

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The impact of endogenous retroviruses on HIV
infection
Christian Willberg University of California, San
Francisco
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Outline

• Introduction to Endogenous Retroviruses
• Reconstitution of an Infectious Human Endogenous
  Retrovirus
• HERV expression in HIV infection
• HERV specific CD8 T cell responses
• The impact of HERV expression on HIV immune
  responses

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Infections limited to somatic cells only allow
horizontal transmission
Examples include HIV and HTLV
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Infection of the germ lines cells, results in
offspring that will carry the now endogenous
retrovirus (ERV) within their genome.
Providing the ERV does not result in a strong
disadvantage to the host, the ERV will become
fixed within the population.
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From Mice to Man Retroviruses that integrated
into our ancestors genomes are still fixed in
our genomes today
ERV - L
HERV-K (6 million years ago)
HERV-L
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26 distinct HERV lineages within the human
genome. All HERVs are replication incompetent
due to mutations introduced by random mutations
introduced during cell division, as well as
cellular proteins.
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Reconstitution of an Infectious Human Endogenous
Retrovirus Young Nam Lee, Paul D. Bieniasz, PLoS
Pathog 3(1) e10.
Used 10 recent (6 million years ago) HERVs to
reconstitute a complete infection virus.
HERV-K113 HERV-K104 HERV-K115 HERV-K101 HERV-K102
HERV-K108 HERV-K107 HERV-K12q14 HERV-K109 HERV-K11
q22
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Reconstitution of an Infectious Human Endogenous
Retrovirus Young Nam Lee, Paul D. Bieniasz, PLoS
Pathog 3(1) e10.
Used 10 recent (6 million years ago) HERVs to
reconstitute a complete infection virus.
HERV-K113 HERV-K104 HERV-K115 HERV-K101 HERV-K102
HERV-K108 HERV-K107 HERV-K12q14 HERV-K109 HERV-K11
q22
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Reconstitution of an Infectious Human Endogenous
Retrovirus Young Nam Lee, Paul D. Bieniasz, PLoS
Pathog 3(1) e10.
Used 10 recent (6 million years ago) HERVs to
reconstitute a complete infection virus.
HERV-K113 HERV-K104 HERV-K115 HERV-K101 HERV-K102
HERV-K108 HERV-K107 HERV-K12q14 HERV-K109 HERV-K11
q22
HERV-KCON
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Reconstitution of an Infectious Human Endogenous
Retrovirus Young Nam Lee, Paul D. Bieniasz, PLoS
Pathog 3(1) e10.
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Reconstitution of an Infectious Human Endogenous
Retrovirus Young Nam Lee, Paul D. Bieniasz, PLoS
Pathog 3(1) e10.
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KEY POINTS

• 8 of the human genome is derived from
  endogenous retroviruses

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KEY POINTS

• 8 of the human genome is derived from
  endogenous retroviruses

• HERVs have very limited expression within the
  body and do not produce functional viruses

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KEY POINTS

• 8 of the human genome is derived from
  endogenous retroviruses

• HERVs have very limited expression within the
  body and do not produce functional viruses

• But, every cell has the capacity to express HERV
  proteins

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Esnault, Nature 2005 NAR 2006
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HIV-Rev
Esnault, Nature 2005 NAR 2006
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Can we detect HERV expression in HIV infected
individuals?
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Searching for Increased HERV Expression within
the plasma

• RT-PCR for HERV specific RNA Transcripts.
• Designed Primers for HERV Insertions.
• Compared HIV Positive to HIV Negative Subjects.

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Summary

• Genome contains ancient endogenous retrovirus,
  that can be re-assembled in vitro to form
  functional viruses.

• HIV integration occurs into a genome full of
  other retro-viruses.

• HIV suppression of Apobec allows HERV expression.

• HERV transcripts are found at significantly
  higher levels in the plasma of HIV individuals.

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Can HIV-specific CD8 T cells recognise
HERV-epitopes?
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MHC Class I antigen presentation pathway.
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MHC Class I antigen presentation pathway.
HERV protein expression from within the host cell
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Infectious Retrovirus Phylogeny
HIV
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HIV epitopes similar to HERV epitopes
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Methods for analyzing the T cell response

• Panels of peptides containing HIV/HERV similar
  epitopes, HERV unique epitopes, HIV unique
  epitopes.
• Subjects from the UCSF OPTIONS primary HIV-1
  infection cohort.
• ELISPOT analysis of Interferon-g production.
• Spot Forming Units (SFU) per 106 PBMC

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T Cell Responses to HERV and HIV Antigens
gt4 identical amino acids
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OP581 Responds to HERV and HIV peptides
SFU/106 PBMC
HERV-specific responses
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OP581 Responds to HERV and HIV peptides
SFU/106 PBMC
HERV-specific responses
HERV/HIV -specific response
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OP581 Responds to HERV and HIV peptides
SFU/106 PBMC
HERV-specific responses
HERV/HIV -specific response
HIV-specific response
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OP581 Responds to HERV and HIV peptides
SFU/106 PBMC
HERV-specific responses
HERV/HIV -specific response
HIV-specific response
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Responses Timecourse With HIV-1 Viral Load
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Inverse Correlation between anti-HERV T Cell
Response and HIV-1 Plasma Viral Load
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HERV-Specific CD8 T Cell Phenotype
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CD8 T Cell functional subsets
Memory status
Phenotype
?Function?
Perforin
Low
Naive
high
CD28
high
CD27
high
CCR7
CD45RA
Perforin

-
CD28
HIV
Intermediate
CD27

-
CCR7
CD45RA-/
Antigen experienced cell high cytotoxic
capacity IFNg IL-2-
Perforin
high
CD28 -
CMV
Late
CD27
-
CCR7 -
CD45RA-/
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HERV-specific CD8 T cells are cytotoxic
HERV epitopes
Irrelevant epitope
No epitopes
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Summary

• HIV and HERVs share similar epitopes, and able
  potentially be recognised by cross reactive CD8
  T cells.

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Summary

• HIV and HERVs share similar epitopes, and able
  potentially be recognised by cross reactive CD8
  T cells.
• HERV unique epitopes are capable of generating a
  specific CD8 T cell response.

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Summary

• HIV and HERVs share similar epitopes, and able
  potentially be recognised by cross reactive CD8
  T cells.
• HERV unique epitopes are capable of generating a
  specific CD8 T cell response.
• HERV CD8 T cells have a late memory phenotype.

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Summary

• HIV and HERVs share similar epitopes, and able
  potentially be recognised by cross reactive CD8
  T cells.
• HERV unique epitopes are capable of generating a
  specific CD8 T cell response.
• HERV CD8 T cells have a late memory phenotype.
• HERV-specific CD8 T cells are capable of
  killing HERV epitope presenting target cells.

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Hypothesis for HERV expression impact in HIV
infection
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Hypothesis for HERV expression impact in HIV
infection
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Hypothesis for HERV expression impact in HIV
infection
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Hypothesis for HERV expression impact in HIV
infection
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Hypothesis for HERV expression impact in HIV
infection

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Hypothesis for HERV expression impact in HIV
infection

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Hypothesis for HERV expression impact in HIV
infection

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Conclusion

• Genome contains ancient endogenous retrovirus,
  that can be re-assembled in vitro to form
  functional viruses.

• HERV transcripts are found at significantly
  higher levels in the plasma of HIV individuals.

• HERV unique epitopes are capable of generating a
  specific CD8 T cell response.
• HERV CD8 T cells are cytotoxic and have a late
  memory phenotype.

• Stimulation of HERV specific T cell responses
  could be used as part of an immunotherapeutic
  vaccine

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Further Reading
Garrison KE .et al.PLoS Pathog. 2007
Nov3(11)e165
Young Nam Lee, Paul D. Bieniasz, PLoS Pathog
3(1) e10.
Contreras-Galindo R, et al., AIDS Res Hum
Retroviruses. 2006 Oct22(10)979-84
Contreras-Galindo R, et al., AIDS Res Hum
Retroviruses. 2007 Sep23(9)1083-6.
Gifford R Tristem M. Virus Genes. 2003
May26(3)291-315
Any Questions, please email me
Christian.Willberg_at_UCSF.edu