Schistosomiasis and HIV co-infection in fishing communities along Lake Victoria, Uganda
description
Transcript of Schistosomiasis and HIV co-infection in fishing communities along Lake Victoria, Uganda
Schistosomiasis and HIV co-infection in fishing communities along Lake Victoria, Uganda
Pontiano KaleebuMedical Research Council (MRC UK)
Uganda Virus Research Institute (UVRI)ENTEBBE
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Introduction• A wide geographic overlap in occurrence NTDs and
HIV
• Infection with S.mansoni may be associated with increased susceptibility to HIV infection and disease progression (earlier studies inconclusive)
• Fishing communities in Uganda with high HIV infection rates and high S. mansoni prevalence (50%), suitable for investigation of interactions of HIV and worms 2
Division of labour in the fishing community
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Project goals
• Impact of S. mansoni on HIV acquisition and associated immune responses in co-infected individuals (Case control study)
• Impact of praziquantel treatment on HIV disease progression and immunological responses among individuals (Intervention study)
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Study areaIn 2009, 1000 HIV- at risk volunteers were enrolled from 5 fishing sites along lake Victoria to assess HIV incidence and study retention.- They were followed six monthly for 18
months- HIV prevalence 29%, incidence
5/100pyo) and high S. mansoni prevalence (50%)
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Case control study Objectives
• To determine the odds of S.mansoni infection among 50 HIV incident cases compared to 150 HIV negative controls identified from a fisher folk cohort
• To compare prevalence of S. mansoni infection status from stored blood samples at enrollment and at 18 months among 50 HIV incident cases and 150 HIV negative controls
• To investigate innate and adaptive immune responses among HIV incident cases with worm infections 6
Study design-nested case control
1 2 3 4 (5)
0 mo 6 mo 12 mo 18 mo
(Recalled volunteers for schistosomiasis Case-control study nested within the prospective cohort
50 HIV+ incident cases150 HIV- controls) were enrolled
Enrol
1000 HIV-1 negative 13-49 yrs at high risk of infection,
HIV VCTPlasmaSerum
HIV VCTPlasmaSerum
HIV VCTPlasmaSerum
HIV VCTPlasmaSerum
HIV VCTPlasmaSerum
Kato Katz on 3 consecutive stool samples to ascertain S.mansoni infection among cases and controls at study exit 35 ml blood :2.5 ml PAXgene tube~30 ml PBMC + plasma0.6 ml whole blood assay
Circulating Anodic Antigen (CAA) test (van Dam / Corstjens) on stored plasma (visits 1,2,3,4)
visit:
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Results
S. Mansoni + S. Mansoni - Total
HIV + cases 26 24 50
HIV - controls
76 74 150
102 98 200
OR 1.05 95%CI (0.53 – 2.10) No evidence of association between S. mansoni infection and HIV sero-conversion
CAA serum analysis is on-going to establish if S.mansoni infection occurred before HIV sero-conversion
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Innate signalling patterns in HIV – Schistosome co-infection
Whole blood:RPMI (1:1) + innate stimuli:
24h
sups
medium
LPS (100 ng/ml) TLR4
PAM3Cys (100 ng/ml) TLR1/2
FSL-1 (50 ng/ml) TLR2/6
Mannan (100 ug/ml)DC-SIGN, MR
LPS + Mannan
CL097 (1 ug/ml) TLR7/8
CpG (5 ug/ml) TLR9
SEA (10 ug/ml)DC-SIGN, MR, xx
LPS + SEA
Curdlan (100 ug/ml) Dectin-1
cytokines (Luminex) TNF-
α
IL-1
0
IL-1
3
IFN
-γ
IFN
-α
Fisher Folk HIV-1 incidence study – schistosomiasis substudy
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Fisher Folk HIV-1 incidence study – schistosomiasis substudyAcquired responses
HIV PTE pools GAG (~1 μg/ml, 24 h, costim + BFA from start) POL
ENVNEFNEG controlSEB
Schistosome antigens SEA(10 μg/ml, 24h*, BFA added AWAfor last 6 h) NEG control
If cells are sufficient:(2nd priority) pos/neg regulators panel[live CD3 CD4 CD8 CD160 LAG-3 PD-1 2B4 CTLA-4](3rd priority) Tregs panel[live CD3 CD4 CD25 CD45RO FOXP3 CD127](4th priority) differentiation panel[live CD3 CD4 CD8 CD27 CD45RA CD127 CCR7](5th priority) cytotoxic panel[live CD8 Grm A Grm B GrmK Pf CD 45RA CD127]
Flow cytometry
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Cytotoxicity genes and Treg associated genes: enhanced in HIV+SM+
Marielle Haks et al. unpublished
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0.2
.4.6
.81
% c
ells
CD4 - ENV
0.5
11.
52
% c
ells
CD8 - GAG
01
23
% c
ells
CD8 - ENV
0.5
11.
5%
cel
ls
CD4 - GAG
+ + +
+ +
+ +
+
+
+
+
+
SM+SM- SM+SM- SM+SM- SM+SM- SM+SM- SM+SM- SM+SM-
+ + +
+ +
+ +
+
+
+
+
+
SM+SM- SM+SM- SM+SM- SM+SM- SM+SM- SM+SM- SM+SM-
TNF-αIL-2IFN-γ
HIV+ S. m.-HIV+ S. m.+
S. mansoni & HIV co-infected individuals have higher Th1 type responses to HIV than HIV mono infected
Andrew Obuku 2012 (unpublished)
P=0.04
P=0.03
P=0.04
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Intervention studyObjectives• Compare HIV progression (viral loads, CD4
count, clinical) among HIV+/S.mansoni+ patients treated with intensive (quarterly) Vs standard (annual) treatment with praziquantel
• Compare immunological changes between the treatment arms over the study period
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Study design- RCT
360 HIV+
226 SM+
113 pzqannually
113 pzqquarterly
134 SM-
follow up 3 monthly
Participant recruitment starting this month and will be followed 3 monthly for 15 months
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Immunological and gene expression profile studies
Innate and adaptive assaysLuminex assaysFlow cytometryRNA expression profiling (RT-MLPA;
Illumina)
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Funders: EDCTP; IAVI; MRC-UK; IDEA (EU)Fisherfolk and Intervention study investigators: P. Kaleebu, A. Kamali, J.Seeley, A. Gershim; L. Nielsen; J Mpendo; A. Elliott; P. Pala ; J Levin; J Nakiyinji-Miiro; G Pantaleo; S. DingSchistosomiasis /HIV Immunology studies: P. Pala; A. Elliott; A. Obuku ; P Kaleebu; R Sekaly; M. Cameron; M. Haks; H. Smits; M. Perrau; A. Harari; S. Ding; G. Pantaleo
Acknowledgements
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