Mononuclear Phagocytes & HIV Infection Guido …Mononuclear Phagocytes & HIV Infection Guido Poli,...
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Mononuclear Phagocytes & HIV InfectionGuido Poli, M.D.
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Mononuclear Phagocytes & HIV Infection
Guido Poli, M.D.AIDS ImmunoPathogenesis Unit, San Raffaele
University & Scientific Institute, Milano
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No preventive vaccine is yet available
The HIV pandemic - 2010
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HIV structure
• Secondly discovered human pathogenic retrovirus (first: HTLV-1) in 1983 (Nobel Prize in 2008)
• Etiological agent of the Acquired Immunodeficiency Syndrome (AIDS)
Mononuclear Phagocytes & HIV InfectionGuido Poli, M.D.
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HIV targets cells express CD4 (primary receptor)and CCR5 or CXCR4 (co-receptors)
After: E.A. Berger et al., Nature 391: 240, 1998; P. Lusso, Virology, 273: 228, 2000
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The HIV life cycle
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Macrophages as “Trojan horses”of HIV virions
Mononuclear Phagocytes & HIV InfectionGuido Poli, M.D.
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CD4+ T lymphocytes• Both R5 and CXCR4-
using HIV
• Acute, cytopathic,depleted in vivo (AIDS)
• Latent infectionin “resting memory” cells
Macrophages• Mostly R5
• Low-absent cytopathicity, prolonged virus production, NOT depleted in vivo
• “Trojan horses”: accumulation of virions in i.c. vacuoles (debated origin)
Main distinctive features of HIV infection of T cells and macrophages
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Mononuclear phagocytes; differentiation & HIV infection
HIV
? ? ?
9 Science, 1988
HIV infects bone marrow MP precursors in vitro
?
Mononuclear Phagocytes & HIV InfectionGuido Poli, M.D.
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HIV infects bone marrow MP precursors in vivo
?
11 Clin. Exp. Immunol. 1985
HIV infection affects the function of circulating monocytes
?
HIV
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HIV infects circulating monocytes
?
HIV
Mononuclear Phagocytes & HIV InfectionGuido Poli, M.D.
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• HIV & the Brain
• HIV & Intestinal Macrophages
HIV & tissue macrophages: heterogeneous susceptibility to infection & viral reservoirs
?
14 JAMA, 1986
HIV & the brain: macrophages and microglia are the dominant infected cells
15 After: P. Smith et al., J. Leuk. Biol., 2003
• Intestinal macrophages are CD4+, but devoid of the expression of the virus entry co-receptors CXCR4 and CCR5
Intestinal (resident) macrophages do not express HIV entry Co-R...
Mononuclear Phagocytes & HIV InfectionGuido Poli, M.D.
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16 After: P. Smith et al., J. Leuk. Biol., 2003
...and are not infectible by HIV...
• Intestinal macrophages are resistant to both R5 and X4 virus infection, as exemplified by the BaL and IIIB isolates, that can efficiently propagate in intestinal lymphocytes, as measured by an ELISA assay specific for the presence of the p24 Gag antigen of HIV in culture supernatants
17 After: P. Smith et al., J. Leuk. Biol., 2003
Intestinal (resident) macrophages do not express HIV entry Co-R...
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HIV replication in myelo-monocytic cell lines; What can we learn?
Mononuclear Phagocytes & HIV InfectionGuido Poli, M.D.
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Promonocytic U937 & its chronically infected derivative U1 cell lines
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Promonocytic U937 & its chronically infected derivative U1 cell lines (2)
21 L. Cassetta et al., AIDS, 2009
HMGB1 selectively inhibits X4 HIV-1 replication in minus, but not plus U937 cell clones
Mononuclear Phagocytes & HIV InfectionGuido Poli, M.D.
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22 L. Cassetta et al., AIDS, 2009
Differential expression of HMGB1-Rin minus and plus U937 cell clones
23 Anna Kajaste-Runitski et al., J. Virol. 2011
Only minus U937 cell clones express TRIM22, an intracellular factor
inhibiting HIV transcription
24 After: T.M. Folks et al., Science, 1987; J. Immunol. 1988
Promonocytic U937 & its chronically infected derivative U1 cell lines
Mononuclear Phagocytes & HIV InfectionGuido Poli, M.D.
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25 After: G. Poli et al., Science 1989; P. Biswas et al., J. Exp. Med. 1992
Differential effect of IFN-a and IFN-gon HIV virion production from Mø
26After: *M. Alfano et al., P.N.A.S., 2002;
**L. Fantuzzi et al., Blood 2003; ***M. Alfano et al., Blood 2009
Differential effect of IFN-a and IFN-gon HIV virion production from Mø (2)
Urokinase-Type Plasminogen Activator
(uPA)*
CCL2/MCP1**
Mac1 Integrin***
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...and the cellular capacity of sustaining virus replication?
Does Mø polarization influencesusceptibility to HIV infection?...
Mononuclear Phagocytes & HIV InfectionGuido Poli, M.D.
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Human macrophages can be polarized...
Pro-InflammatoryAnti-Tumor
Anti-Microbial
Anti-InflammatoryTissue Repair
M1
M2
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R5 HIVInfection
E. Cassol et al., J Immunol 2009
MDM
7 days
D-MEM+FCS/HS
Monocytes
M1
18 h
CD16LOW
M2CD14LOW
Polarization of human monocyte-derived macrophages
30 E. Cassol et al., J Immunol 2009
Days post-infection
RT
activ
ity (c
pm/μ
l) Control
M1
M2a
Both M1 and M2a polarization of human MDM inhibits HIV-1 replication
Mononuclear Phagocytes & HIV InfectionGuido Poli, M.D.
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M1 and M2a differentially modulate CD4 expression…
…. and chemokine productionafter polarization
0
1,000
2,000
3,000
4,000
pg/m
l
E. Cassol et al., J Immunol 2009
0 3 705
1015202530354045
CTRM1M2
Days
%C
D4+
MD
M
Functional differences between M1 and M2 human MDM
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48 h post-infection
Control M1 M2aHIV
DNA
Cop
ies/
2.5x
104C
ells
p=0.006p=0.006
256
512
1,024
2,048
4,096
Actin
Control M1 M2a15010075
50
37
2520
250
7 days p.i.Western blot
for HIV-1 ProteinsE. Cassol et al., J Immunol 2009
Differential inhibitory effects of M1 vs. M2 inhibition of HIV-1 replication
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• In addition to CD4+ T lymphocytes, mononuclear phagocytes (MP) represent a strategic target for HIV infection
• Unlike CD4+ T cells, infected MP (including BM precursors, circulating monocytes and tissue Mø) remain viable, although dysfunctional, and represent pool of either latent or productive infection
• The MP unique feature of being “Trojan horses” of pre-formed mature virions render them one of the most important HIV reservoirs also in individuals receiving anti-retroviral therapy
• Modulation of Mø polarization regulates their susceptibility to infection by HIV-1 and its replicative capacity although these features are transient in vitro
Conclusions
Mononuclear Phagocytes & HIV InfectionGuido Poli, M.D.
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EdanaCassol
MassimoAlfano
LucaCassettaElisa
Vicenzi
AIDS immunopathogenesis & viral pathogens & biosafety units, HSR
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