CXCR4Utilizing HIV1 Strains Activate Innate Immunity Via CD14 and TollLike Receptor 2

1
CXCR4-Utilizing HIV-1 Strains Activate Innate
Immunity Via CD14 and Toll-Like Receptor 2
Hongxia Zhu,1 Richard C. Huard,1,4 Marcelo
Nociari,1 Tian He,2 Khaled Zerria,1 Zhiwei Chen,2
Douglas T. Golenbock,3 John L. Ho1
1Division of International Medicine and
Infectious Diseases, Weill Medical College of
Cornell University, New York, NY 10021, USA.
2Aaron Diamond AIDS Research Center, The
Rockefeller University, New York, NY 10016, USA.
3Department of Medicine, University of
Massachusetts Medical School, Worcester, MA
01605, USA. 4Clinical Microbiology Service,
Department of Pathology, NewYork-Presbyterian
Hospital, New York, NY 10032.
Acknowledgements The work was supported in part
by grants RO1 HL61960 and RO1 AI39606 (JLH), and
KO1 HL70438-01 (MN) from the National Institutes
of Health, DHHS. The authors thank Drs. Yuxian
He and Kyu Rhee for their input and Drs. David D.
Ho, Linqi Zhang, and Warren D. Johnson Jr. for
support - HZ and KZ were funded by a Fogarty
International Center Training grant (D43-TW00018,
WDJ).
XVI International AIDS Meeting, Toronto,
Canada--August 17, 2006
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HIV-1 Infection, AIDS, and Innate Immunity

• How HIV causes AIDS remains a fundamental
  unanswered scientific question.
• Rising serum pro- and anti-inflammatory cytokine
  levels and generalized immune hyperactivation
  predict HIV-1 disease progression to AIDS and has
  been postulated as the alternate pathway leading
  to CD4 T cell depletion and immune cell
  dysfunction.
• However, whether and how HIV-1 stimulates, and
  what host receptor(s) promote inflammatory
  cytokine production, remain a mystery.
• Toll-like receptors (TLRs) of innate immune cells
  link the immune inflammatory response to microbes
  and the acquisition of antigen-specific adaptive
  immunity.
• Systemic activation of innate immune cells via
  TLR4 by lipopolysaccharide (LPS) from
  gram-negative bacteria causes sepsis, a syndrome
  with features similar to those of patients at
  AIDS onset.

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HIV-1 Triggers CHO CD25 Reporter Cells Via TLR2
4
Signaling Through TLR2 is Associated with HIV-1
Co-receptor Tropism
5
X4 HIV-1 Activation of Human Monocytes and
Myeloid Cell Lines is Independent of CD4 and
CXCR4 Chemokine Receptor
6
Activation of Human Monocytes and Myeloid Cells
by X4 HIV-1 Requires CD14 and TLR2
7
X4 HIV-1 Particles Activate Innate Immunity But
Not Through gp120 Env
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Summary

• Late-stage X4 HIV-1 strains transduced
  intracellular signals via human TLR2 but not
  TLR4.
• Both laboratory and clinical X4 HIV-1 stimulated
  the production of pro- and anti-inflammatory
  cytokines that are observed during patients
  disease progression to AIDS.
• In contrast, R5 HIV-1 strains lacked this
  activity.
• Innate immune response to X4 HIV-1 was CD14- and
  TLR2-dependent.
• These effects were mediated by intact HIV-1
  particles
• Chimeric HIV-1 molecular constructs suggested
  that the ligand is a protein other than gp120.

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Conclusion

• Overall, we have uncovered a new mechanism, and
  potentially the missing link, through which
  late-stage HIV-1 via sustained TLR2 signaling may
  disturb normal immune function and prompt the
  immune collapse and associated clinical
  pathologies of AIDS.
• TLR2 is central as an inducer of antimicrobial
  immunity.
• Many AIDS-defining OIs are sensed by TLR2 - Mtb,
  MAC, CMV, Candida, Pneumocystis, Toxoplasma.
• Could sustained activation by X4 HIV lead to a
  selective desensitization thereby allowing these
  microbes a foothold?
• Subversion of TLR function by HIV unifies many
  phenomena observed in AIDS- clinical,
  immuonolgical and virological.
• Could AIDS by a TLR2 disease?