Can GBVC interfere with HIV infection

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Can GBV-C interfere with HIV infection?

• or Can 2 viruses be better than one?

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GBV-C Background

• Closely related to HCV
• Capable of Persistent infection
• Doe not appear to cause disease
• Replicates in CD4, CD8 T cells and B cells
• High replicative rate (av. VL 6.3 x 107 GE/mL)
• Common 3 US blood donors 5-20 in
  developing countries 20-40 of
  HIV-infected viremic
• Viremia assoc. with survival in HIV-infected

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Complicated epidemiology. Persistent GBV-C
viremia associated with prolonged survival in
every study prior to HAART,
HR (95 CI) 0.52 (0.32, 0.85) model 1 0.69 (0.40,
1.18) 0.36 (0.17, 0.75) 0.29 (0.20, 0.41) 0.15
(0.05, 0.40) 0.58 (0.15, 2.21) 0.41 (0.23, 0.69)
n 1294
Zhang et al.,. HIV Med, 2006
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GBV-C effect gt CCR5D32
MACS Seroconvertors
1.0 0.8 0.6 0.4 0.2
0.6
Hazard Ratio
0.47
0.41
GBV-C Pos CCR5D32
CD4 gt 500 vs.
vs.
vs. GBV-C Neg
CCR5 200
- 350
Stapleton et al., J Clin Micro 2004
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GBV-C and HIV transmission
Maternal GBV-C RNA RH 0.3 CI
0.08-1.05 (p0.06)
Relative Risk of HIV MTCT
0 0.1 0.2
0.3
Infant GBV-C RH 0.13 CI 0.03-0.54 Plt0.001
HIV Med 8561, 2007 J.Infect. Dis. 1971369,
2008 Handelsman et al. Supapol, W. et al.
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Summary of Clinical Studies

• Prevalence high (regardless of CD4 count)
• Prolonged Survival with persistent GBV-C
• Reduced Vertical Transmission Definitely with
  GBV-C in infant
• Data not shown
• Associated with lower HIV VL
• Delayed CD4 depletion
• Improved response to HIV ART

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How might GBV-C interfere with HIV infection?
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Interfere with HIV replication
HIV Infection
X4 HIV Infection
Mock
Mock
GBV moi 0.5
GBV moi 0.5
p24 Ag (pg/ml)
p24 Ag (pg/ml)
GBV moi 1
GBV moi 1
GBV moi 2
GBV moi 2
0 3 7
Days post-infection
0 2 4
Days post-infection
Jung et al. AIDS 1912567, 2005
Xiang et al. Lancet 3632040, 2004

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RANTES Expression
GBV-C Decreases CCR5
Mock-IC GBV-C IC Mock
CCR5 GBV-C- CCR5
RANTES (pg/mL)
Day 0 Day 6
SDF-1 Expression
GBV-C CCR5 Mock-
CCR5
SDF-1 (pg/mL)
Xiang et al. Lancet 3632040, 2004
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GBV-C and CCR5 in vivo
CCR5 significantly decreased on cells (activation
marker) Natterman et al. T cell activation
markers CD38 and HLA-DR were significantly
decreased in GBV-C Pos CD4 T cells.
(Maidana-Giret, et al IAS 2007) GBV-C viremia
polarized Th cytokine profile towards Th1
(decreased Th2) Nunnari et al, Ann. Int. Med.
13926, 2003.
CCR5 expression Effect of E2 protein
CD3 expression Effect of E2 protein
Natterman et al., AIDS, 2003
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Is GBV-C replication required?
E2 alone inhibits HIV and intracellular
expression downregulates CCR5, induces
RANTES. E2 present on virions. GBV-C average
titer 6.2 x 107 GE/mL serum
Jung et al., AIDS 191267, 2005
Jung et al., AIDS 21645, 2007
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NS5A - productively infected cells HIV
NS5A downregulated CXCR4 mRNA and protein, and
induced SDF-1 release by CD4 cells
Xiang et al. PLoS One 3e250, 2008
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GBV-C NS5A peptides inhibit HIV when added to
CD4 cells
HIV p24Ag (pg/mL)
Xiang et al. PLoS One 3e250, 2008
Days post HIV Infection
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Dengue virus in HIV-positive individuals
during acute dengue fever
6 control subjects without dengue infection
CID 361067, 2003
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Are GBV-C effects shared?
DEN
YFV
TBEV
WNV
GBV-B
GBV-A
CSFV
HGV
BVDV
GBV-C
2a
3a
HCV
2b
1b
1a
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GBV-C NS5A (1-414 aa)
EMC IRES
GFP
152-167
Scr
126 - 236 FS
EMC IRES
HCV NS5A (1-447)
GFP
HCV DI (1-215)
DV NS5 (1 - 898 aa)
EMC IRES
GFP
EMC IRES
WNV NS5 (1 - 904 aa)
GFP
EMC IRES
YFV NS5 (1 - 905 aa)
GFP
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Flavivirus NS5 proteins Inhibit HIV Replication







Control Cell Lines
HIV p24 antigen (pg/mL)
NS5 Cell Lines
Days post-infection
Submitted
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NS5 protein effects reproduced during YFV
replication in vitro
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YFV (17D) inhibits HIV replication in CD4 cells
A.
B.
0
0.01
0.1
1
0
0.1
1
(R5 HIV)
HIV p24 Ag (pg/mL)
HIV p24 Ag (pg/mL)
3 4 5 6
Days post HIV infection
3 4 5 6
Days post HIV infection
D.
C.
(X4 HIV)
HIV p24 Ag (pg/mL)
HIV p24 Ag (pg/mL)
3 4 5 6
Days post HIV infection
0 3 4 5 6
Days post HIV infection
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GBV-C NS5 Inhibits Apoptosis
Percent cells with activated caspase
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How can GBV-C interfere with HIV infection?

• Let me count the ways

• Interfere with HIV replication
• Modulate HIV entry receptors
• Induce HIV-inhibitory chemokines
• Diminish CD4 activation and proliferation
• Promotes a Th1 cytokine profile
• Decrease CD4 programmed cell death

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GBV in vitro and in vivo correlate

• Effects HIV transmission progression
• Effects require viremia
• Virus modifies host cell (decreases risk of
  resistance)
• Need
• Characterize mechanisms, identify virus-host
  cell interactions, determine structures for
  mimetics
• Should we infect everyone with GBV-C?

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UI Groups and Collaborators

• Stapleton Lab Group HIV/HCV Clinics
  Collaborators
  
• Jinhua Xiang Kris Davis Georg Hess
• Jim McLinden Jeff Meier Alfred Engel
• Donna Klinzman All HIV Clnic
  Staff Carolyn Williams
• Qing Chang Jungsuh Kim
• Tom Kaufman Lou Katz
• Emma Jordan Mohr
• Jamie Christianson
• Eli Katz Grant support
• Inara Souza DAIDS RO1
• VA MR jts, jx
  

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