HIV-1 TRANSMISSION FROM SEMEN TO CERVICO-VAGINAL TISSUE EX VIVO Andrea Introini 1, Christophe Vanpouille 1, Andrea Lisco 1, Jean-Charles Grivel, Arshi.
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HIV-1 TRANSMISSION FROM SEMEN TO CERVICO-VAGINAL
TISSUE EX VIVO
Andrea Introini1, Christophe Vanpouille1, Andrea Lisco1, Jean-Charles Grivel,
Arshi Munawwar2, Sarman Singh2, and Leonid Margolis1
1National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United States, 2All India
Institute of Medical Sciences, New Delhi, India
Vaginal intercourse is the main route of HIV-1 sexual
transmission
HIV- infection of human cervico-vaginal tissue ex vivo
rectosigmoid
tonsillar
exocervicalHIV-1 in seminal fluid
Semen and blood from 50 HIV-1-
infected and 33 HIV-uninfected
men
SEMEN AND BLOOD ARE SEPARATE IMMUNOLOGICAL COMPARTMENTS
IL-1α
IL-1β
IL-6
IL-7
IL-8
IL-1
5
IL-2
Eota
xin
IFN
-γ
IL-1
6
MIG
IP-1
0
MC
P-1
MIP
-1α
MIP
-3α
MIP
-1β
SDF-
1βTN
F-α
TGF-β
GM
-CSF
SemenBlood
Sem
en:
Blo
od
pla
sma
rati
o
(S:B
ra
tio
)
HIV-1-UNINFECTED INDIVIDUALS
(HIV-1-uninfected)
seminal plasma blood plasma
The 2-way hierarchical cluster analysis confirms that blood and semen have 2 distinct cytokine profiles
Cytokine levels: high; low
IL-1aIL1-aIL-7
MCP-1IP-10IL-8MIG
MIP-3aSDF-1b
IL-6TGF-bIL-15IL-1b
MIP-1aGM-CSF
IL-2IGN-gIL-16
EotaxinMIP-1bTNF-a
20 c
orre
lati
ons
Correlations between cytokine levels in seminal plasma
HIV+-0.25 ≤ ≤ -0.5
+0.5 ≤ ≤ +0.7 ≥ +0.7
+0.25 ≤ ≤ +0.5No correlation
-0.5 ≤ ≤ -0.7 ≥ -0.7
HIV
¯71 correlations
HERPESVIRUSES REACTIVATION IN SEMINAL PLASMA
0%
2000%
4000%
6000%
8000%
HIV-1-infected%
of p
osi
tive
sa
mp
les
40
20
0
60
80
1
2
3
4
5
6
7
8
9
CMV
1
2
3
4
5
6EBV
Vir
al lo
ad
[lo
g 10 c
opie
s/m
L]
Vir
al lo
ad
[l
og10
cop
ies/
mL
]
blood semen blood semen
CMV and EBV seminal shedding occurs in absence of plasma viremia in 75 and 54% of the patients, respectively
EBV and CMV reactivation is compartmentalized
IL-7 is increased in semen ofchronically HIV-1-infected individuals
IL-7
(pg
/ml)
IL-7
(pg
/ml)
Blood Semen
IL-7
IL-7 role in HIV-1 transmission
to cervico-vaginal tissue?
IL-7
IL-7IL-7
Thymus
Naïve T-cell
Memory T-cell
Stromal cell
Survival Proliferation
HIV-1 infection of human tissue ex vivo
HIV-1IL-7
Collagen raft
3 6 9 121
2
3
Days
IL-7 enhances HIV-1 replication in cervico-vaginal tissue ex vivo
HIV
-1 p
24ga
g (
ng/m
l)
3 6 9 120
1
2
3
4
Days
HIV-1BaL
HIV-1BaL + IL-7
[BaL
+IL
-7]
[BaL
]
HIV-1BaL HIV-1BaL+ IL-7
CD4
HIV-1 p24gag
Day 6
IL-7 increases the number of HIV-1-infected CD4 T-cells
0.0
10.0
20.0
30.0
40.0
50.0
CD
4+ d
eple
tion
(%)
p=0.0005
IL-7 decreases HIV-1-induced CD4 T-cells depletion
Day 9
- +IL-7
HIV-1LAI.04
0.00
4.00
8.00
12.00
IL-7 decreases apoptosis ofHIV-1-infected CD4 T-cells
IL-7
- +
Day 6 p=0.0049
HIV-1LAI.04
p24 g
ag+ A
PO
2.7+
(% o
f C
D4+
)
IL-7 decreases apoptosis ofHIV-1-infected CD4 T-cells
Day 9
Bcl-2
HIV-1LAI.04
HIV-1LAI.04 + IL-7C
um
ula
tive
dis
trib
uti
on
fun
ctio
n
Conclusions
• Semen and blood are immunologically separate compartment which differ in their cytokine spectra.
• HIV-1 infection enhances this difference changing the entire pattern of cytokine networks.
• IL-7 is one of the seminal cytokines greatly upregulated in HIV-1 infected men
• Upon deposition on cervico-vaginal tissue IL-7 enhances HIV-1 transmission
• Enhancement of HIV-1 infection is associated with IL-7-mediated prevention of death of HIV-1-infected CD4 T-cells, due to suppression of apoptosis
• Cervico-vaginal tissue contains much less CD4 T cells than lymph nodes or other lymphoid organs, which may be one of the reasons for a relatively low probability of male-to-female HIV-1 sexual transmission. By preventing the death of the small initial pool of infected cells, IL-7 gives HIV more time to find and infect target cells in cervix/vagina and to start dissemination
• Concentration of IL-7 in the semen of an HIV-1 infected man may be a determinant of infectiousness for his uninfected female partner.
Speculations
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