semen -...
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Presented at the 6th Int. Workshop on HIV Transmission, 14 – 15 July 2011, Rome, Italy
HIV-1 and Reactivated Coinfecting Herpesviruses Rearrange the Cytokine Network in Semen
of Infected Individuals
Andrea Introini,
National Institute of Child Health and Human Development
NIH
Bethesda, MD, U.S.A.
Presented at the 6th Int. Workshop on HIV Transmission, 14 – 15 July 2011, Rome, Italy
SEMEN
• Is a complex fluid that contains spermatozoa and
soluble factors, including cytokines
• Natural carrier of many pathogens
• Pathogens replication is affected by cytokines and
also affect cytokine expression
Do HIV-1 infection and coinfecting herpesviruses
affect cytokine profile in semen?
Presented at the 6th Int. Workshop on HIV Transmission, 14 – 15 July 2011, Rome, Italy
OUR STUDY
• Viral load of:
HIV-1
Herpes Simplex Virus-2 (HHV-2)
Epstein Barr Virus (HHV-4)
Cytomegalovirus (HHV-5)
HHV-6 A and B
HHV-7
HHV-8
Blood and seminal plasma from:
• 74 HIV-1-infected individuals therapy naïve
• 33 uninfected individuals
• Cytokines
Presented at the 6th Int. Workshop on HIV Transmission, 14 – 15 July 2011, Rome, Italy
HIV-1 LOAD L
og
10 (
co
pie
s/m
l)
Blood Semen
100%
positive
94%
positive
HIV-1 blood load Log10 (copies/ml)
HIV
-1 s
em
en load
Log
10 (
co
pie
s/m
l)
R=0.64 p<0.0001
4.5 4.0
Presented at the 6th Int. Workshop on HIV Transmission, 14 – 15 July 2011, Rome, Italy
0
20
40
60
80
HERPESVIRUSES REACTIVATION
p<0.001
HIV-1-infected HIV-1-uninfected
Semen
Blood
po
sitiv
e s
am
ple
s (
%)
CMV ML vs log10(copies/ml)
* *
positiv
e s
am
ple
s (
%)
EBV ML vs log10(copies/ml)
0
5
10
Presented at the 6th Int. Workshop on HIV Transmission, 14 – 15 July 2011, Rome, Italy
1
2
3
4
5
6
7
8
9
CMV
Vira
l lo
ad
Log
10
(copie
s/m
l)
Blood Semen
HIV-1-CMV coinfected
77% semen only
19% both semen and blood
3% blood only
CMV REACTIVATION IS COMPARTMENTALIZED
Presented at the 6th Int. Workshop on HIV Transmission, 14 – 15 July 2011, Rome, Italy
CONCURRENT EBV AND CMV INFECTION IS ASSOCIATED WITH AN
HIGHER HIV-1 SHEDDING IN SEMEN
p<0.05 V
ira
l lo
ad
Log
10 (
copie
s/m
l)
HIV-1 *
Presented at the 6th Int. Workshop on HIV Transmission, 14 – 15 July 2011, Rome, Italy
CYTOKINE PANEL
• Pro-inflammatory cytokines: IL-1α, IL-1β, IL-6,
IFN-γ, TNF-α
• Anti-inflammatory cytokines: TGF-β
• CCR5 ligands: RANTES, MIP-1α, MIP-1β, Eotaxin
• CXCR4 ligands: SDF-1β
• Chemokines: MCP-1, MIP-3α, IP-10, MIG, IL-8
• Growth factors: IL-2, IL-7, IL-15, IL-16, GM-CSF
Presented at the 6th Int. Workshop on HIV Transmission, 14 – 15 July 2011, Rome, Italy
SEMEN AND BLOOD ARE SEPARATE IMMUNE COMPARTMENTS (UNINFECTED MEN)
Semen/Blood MEDIAN RATIO
Enriched
in semen
Enriched
in blood
*
* *
* *
* * *
*
*
* *
*
= p<0.05 *
Presented at the 6th Int. Workshop on HIV Transmission, 14 – 15 July 2011, Rome, Italy
HIV-1 UPREGULATES FEW CYTOKINES IN BLOOD
N-f
old
0
2
4
6
8
HIV-1+/HIV-1- RATIO
0.1
= p<0.05
1
* * *
* *
*
*
*
Presented at the 6th Int. Workshop on HIV Transmission, 14 – 15 July 2011, Rome, Italy
1
3
5
7
N-f
old
= p<0.05
HIV-1 UPREGULATES MANY CYTOKINES IN SEMEN
HIV-1+/HIV-1- RATIO
* *
*
*
* * *
*
*
*
* * * *
*
*
*
Presented at the 6th Int. Workshop on HIV Transmission, 14 – 15 July 2011, Rome, Italy
HIV-1 INFECTION REARRANGES THE CYTOKINE NETWORK IN SEMEN
HIV-1-infected
HIV-1-noninfected
Spearman’s rank
correlation coefficient
Presented at the 6th Int. Workshop on HIV Transmission, 14 – 15 July 2011, Rome, Italy
CONCLUSIONS
• EBV and CMV reactivate in the course of HIV-1 infection
predominantly in semen
• HIV-1 infection increases the number and the strength of
correlations between cytokines in semen
• Concurrent shedding of CMV and EBV in semen is
associated with higher HIV-1 seminal load
• HIV-1 infection upregulates more cytokines in semen than
in blood
• Blood and semen are two separate immunological
compartments with different cytokine profiles
Presented at the 6th Int. Workshop on HIV Transmission, 14 – 15 July 2011, Rome, Italy
CONCLUSION
HIV-1 together with its copathogens significantly change the
immunological landscape of semen, probably affecting HIV-1
evolution in this compartment and selecting for transmissible
HIV-1 variants.
Presented at the 6th Int. Workshop on HIV Transmission, 14 – 15 July 2011, Rome, Italy
Leonid Margolis
Andrea Lisco
Christophe Vanpouille
Jean-Charles Grivel
Wendy Fitzgerald
Anush Arakelyan
Sarman Singh
Arshi Munawwar