Bioactive Hydrogel Substrates : Probing Leukocyte Receptor -- Ligand Interactions in Parallel Plate Flow Chamber Studies The binding of activated integrins on the surface of leukocytes facilitates the adhesion of leukocytes to vascular endothelium during inflammation . Interactions between selectins and their ligands mediate rolling , and are believed to play an important role in leukocyte adhesion , though the minimal recognition motif required for physiologic interactions is not known . We have developed a novel system using poly -LRB- ethylene glycol -RRB- -LRB- PEG -RRB- hydrogels modified with either integrin-binding peptide sequences or the selectin ligand sialyl Lewis X -LRB- SLeX -RRB- within a parallel plate flow chamber to examine the dynamics of leukocyte adhesion to specific ligands . The adhesive peptide sequences arginine -- glycine -- aspartic acid -- serine -LRB- RGDS -RRB- and leucine -- aspartic acid -- valine -LRB- LDV -RRB- as well as sialyl Lewis X were bound to the surface of photopolymerized PEG diacrylate hydrogels . Leukocytes perfused over these gels in a parallel plate flow chamber at physiological shear rates demonstrate both rolling and firm adhesion , depending on the identity and concentration of ligand bound to the hydrogel substrate . This new system provides a unique polymer-based model for the study of interactions between leukocytes and endothelium as well as a platform to develop improved scaffolds for cardiovascular tissue engineering . Introduction Leukocyte adhesion to sites of inflammation is crucial to eliminate the cause of irritation and repair the surrounding tissue . After the initiation of inflammation by cytokines such as interleukin-1β -LRB- IL-1β -RRB- , tumor necrosis factor-α -LRB- TNF-α -RRB- , lipopolysaccharide , and interleukin-3 , -LRB- IL-3 -RRB- , leukocyte velocity slows dramatically due to leukocyte contact with the vascular wall .9,27,34 Rolling , the initial transient interaction , is mediated by selectin molecules present on the activated endothelial cell surface . E-selectin is an inducible surface glycoprotein that is known to bind the carbohydrate ligand sialyl Lewis X -LRB- SLeX -RRB- , which is present on various leukocytes10 ,11,13,35,41,43 and mediates stronger adhesions and slower rolling than P - or L-selectin.27 Following this primary contact , firm adhesion takes place via activated β2-integrins binding intracellular adhesion molecule-1 -LRB- ICAM-1 -RRB- expressed on the endothelium , and through the most important member of the β1 integrin subfamily , very late antigen-4 -LRB- VLA-4 ; α4β1 -RRB- . VLA-4 binds vascular cell adhesion molecule-1 -LRB- VCAM-1 -RRB- , and is responsible for lymphocyte adhesion to vascular endothelium and leukocyte recruitment to the inflamed area .1,10,11,27 Though well studied , the exact mechanism of adhesion to the vascular endothelium is not known . There are two suggested mechanisms of integrin activation ; one proposing that activation is a result of chemokine stimulation of leukocytes2 ,43 and another suggesting that selectin binding leads to integrin activation .12,42 Several systems have been developed to examine the dynamics of rolling and firm adhesion and to elucidate the exact mechanism of the binding cascade . Leukocytes isolated from human blood have been studied under static and flow conditions on activated endothelial cell monolayers as well as on cells engineered to express endothelial cell adhesion molecules .3,28,37,40 Polystyrene microspheres coated with adhesion ligands have also been shown to interact with stimulated cell monolayers17 and on substrates coated with selectins and other cell adhesion molecules .11 Yeast engineered to display E-selectin has been observed rolling on substrates coated with SLeX . 2 Recently , poly -LRB- ethylene glycol -RRB- -LRB- PEG -RRB- has been tethered to gold surfaces to create cell resistant surfaces and spatial gradients of PEG on gold surfaces have been used to study the kinetics of static cell adhesion .32,33 While each of these systems has revealed new insight into the dynamics of leukocyte interactions with endothelial cell adhesion molecules , the ultimate goal must be to establish a simple , cell-free system that more closely mimics the in vivo environment . PEG hydrogels are crosslinked hydrophilic networks that demonstrate excellent biocompatibility , being highly resistant to protein adsorption and cell adhesion , and causing minimal inflammatory responses .20,21,22,36 These highly swollen networks have similar water content and mechanical properties to soft tissues and may be engineered to contain cell adhesion peptides , growth factors , and therapeutics for localized drug delivery .5,6,26,29,30,39,44 PEG diacrylate hydrogels may be covalently modified with cell adhesive peptide sequences to encourage cell adhesion , spreading , and migration and the interactions of cells with these hydrogels has been extensively studied under static conditions .15,16,24,25,29,31,38 A key benefit of such materials is that the base material , PEG , is intrinsically resistant to protein adsorption , so the adhesive interactions with cells are limited to the factors that are specifically engineered into the hydrogel network . In this work we propose a novel system to study leukocyte adhesion under shear using photopolymerized PEG copolymer hydrogels . After forming thin flat PEG diacrylate base hydrogels , we are able to polymerize a layer of monoacrylate PEG-peptide -LRB- or SLeX -RRB- to the surface , and using a parallel plate flow chamber , we can observe cell adhesion using video microscopy . Materials And Methods All chemicals were purchased from Sigma -- Aldrich -LRB- St. Louis , MO -RRB- unless otherwise stated . Synthesis of Polyethylene Glycol Diacrylate Polyethylene glycol diacrylate -LRB- PEG-DA -RRB- was synthesized by dissolving 12 g dry PEG -LRB- MW : 6000 ; Fluka , Milwaukee , WI -RRB- in 16 ml anhydrous dichloromethane -LRB- DCM -RRB- with an equimolar amount of triethylamine and 0.72 g acryloyl chloride -LRB- Lancaster Synthesis , Windham , NH -RRB- added dropwise . The mixture was stirred under argon for 24 h , washed with 2 M K2CO3 , and separated into aqueous and DCM phases to remove HCl . The DCM phase was dried with anhydrous MgSO4 -LRB- Fisher Scientific , Pittsburgh , PA -RRB- , and the PEG diacrylate was then precipitated in diethyl ether , filtered , and dried under vacuum at room temperature overnight . The resulting polymer was dissolved in N,N-dimethylformamide-d7 and characterized via proton NMR -LRB- Avance 400 MHz ; Bruker , Billerica , MA -RRB- to determine the extent of acrylation . Synthesis of PEG Derivatives Containing Cell Adhesion Molecules The cell adhesive peptide sequence used in this study include arginine -- glycine -- asparagines -- serine -LRB- RGDS ; American Peptide Company , Inc. , Sunnyvale , CA -RRB- , and a peptide containing the cell adhesive leucine -- asparagines -- valine sequence -LRB- glycine -- proline -- glutamic acid -- isoleucine -- leucine -- asparagines -- valine -- serine -- threonine , GPEILDVST -RRB- , which was synthesized using standard fluorenylmethoxycarbonyl -LRB- Fmoc -RRB- chemistry on an Applied Biosystems 431A peptide synthesizer -LRB- Foster , CA -RRB- . The high affinity 4 - -LRB- -LRB- N ′ -2-methylphenyl -RRB- ureido -RRB- - phenylacetyl-leucine-aspartic acid-valine-proline -LRB- Bio1211 ; Commonwealth Biotechnologies , Inc. , Richmond , VA -RRB- 5,6 was also used as an alternate LDV-containing compound . The non-adhesive sequences used as negative controls were arginine -- glycine -- glutamic acid -- serine -LRB- RGES ; American Peptide Company , Inc. , Sunnyvale , CA -RRB- and glycine -- proline -- glutamic acid -- isoleucine -- leucine -- glutamic acid -- valine -- serine -- threonine -LRB- GPEILEVST -RRB- , also synthesized using Fmoc chemistry on a peptide synthesizer . Peptides were conjugated to PEG monoacrylate by reaction with acryloyl-PEG-N-hydroxysuccinimide -LRB- PEG-NHS ; MW 3400 ; Nektar Therapeutics , Huntsville , AL -RRB- in 50 mM sodium bicarbonate -LRB- pH 8.5 -RRB- at a 1:1 molar ratio for 2 h . The mixture was then dialyzed -LRB- MWCO 1000 -RRB- , lyophilized , and stored at − 20 °C . Gel permeation chromatography with UV and evaporative light scattering detectors -LRB- Polymer Laboratories , Amherst , MA -RRB- was used to determine the coupling efficiency . The selectin ligand sialyl Lewis X -LRB- SLeX -RRB- was conjugated to PEG using an avidin -- biotin bridge . PEG-NHS -LRB- 25 mg -RRB- was reacted with a lysine -- biotin conjugate -LRB- biocytin -RRB- at a 1:2 molar ratio in 50 mM sodium bicarbonate -LRB- pH 8.5 -RRB- for 2 h. SLeX-biotin -LRB- 500 μg ; Glycotech , Gaithersburg , Maryland -RRB- was reacted with avidin -LRB- 10 -- 15 units mg − 1 -RRB- at a ratio of 2 units avidin per mole of SLeX-biotin in 50 mM sodium bicarbonate -LRB- pH 8.5 -RRB- for 2 h . The reaction mixtures were then combined to allow further conjugation of avidin and biotin , thereby linking acryloyl -- PEG -- NHS -- lysine -- biotin to avidin -- biotin -- SLeX . Synthesis of Bilayered PEG Copolymer Hydrogels Hydrogels were formed by first dissolving 0.2 g ml − 1 PEG diacrylate in 10 mM HEPES buffered saline -LRB- HBS , pH 7.4 -RRB- ; the polymer solution was then filter sterilized using a 0.22 μm filter -LRB- Gelman Sciences , Ann Arbor , MI -RRB- . The photoinitiator 2,2-dimethoxy-2-phenyl acetophenone in N-vinylpyrrolidinone -LRB- 300 mg ml − 1 -RRB- was added at 10 μl ml − 1 polymer solution . This mixture was injected between rectangular glass plates separated by 0.5 mm spacers and polymerized under UV light -LRB- 365 nm , 10 mW cm − 2 -RRB- for 30 s . The top plate was removed and the hydrogel surface rinsed with sterile PBS . A second layer , consisting of 5 μmol ml − 1 of either acryloyl-PEG-peptide or acryloyl-PEG-SLeX in HBS and 10 μl ml − 1 2,2-dimethoxy-2-phenyl acetophenone in N-vinylpyrrolidinone was then layered on top of the PEG diacrylate base gel , the upper glass plate replaced , and the second layer photopolymerized by exposure to UV light -LRB- 365 nm , 10 mW cm − 2 -RRB- for 1 min . Cell Maintenance JURKAT cells -LRB- human T-lymphocytes ; ATCC , Manassas , VA -RRB- were maintained in RPMI-1640 prepared with 10 % fetal bovine serum -LRB- FBS ; BioWhitaker , Walkersville , MD -RRB- , 2 mM l-glutamine , 1 unit ml − 1 penicillin , and 100 mg l − 1 streptomycin -LRB- GPS -RRB- . 300.19 / E cells -LRB- mouse pre-B lymphoblast ; ATCC , Manassas , VA -RRB- were sustained in RPMI-1640 prepared with 10 % FBS , 1 % GPS , and 0.1 mM 2-mercaptoethanol . Cells were maintained at 37 °C in a 5 % CO2 environment . Cell Adhesion and Rolling on Adhesive PEG Gels Flow assays were performed using a circular parallel plate flow chamber -LRB- Glycotech , Gaithersburg , MD -RRB- mounted on the stage of a Zeiss Axiovert 135 microscope -LRB- Carl Zeiss Inc. , Thornwood , NY -RRB- . The chamber was placed on top of photopolymerized PEG copolymer hydrogels and vacuum sealed to the surface using a portable vacuum pump -LRB- Fisher Scientific , Pittsburgh , PA -RRB- as shown in Fig. 1 . Cell suspensions were drawn through the flow field -LRB- 1 cm path width , 0.01 in thickness -RRB- using a programmable syringe pump -LRB- BS-8000 Multi-Phaser ™ Programmable Syringe Pump , Braintree Scientific Inc. , Braintree , MA -RRB- at varying flow rates corresponding to a shear stress range of 3.5 -- 35 dynes cm − 2 , which is comparable to in vivo shear rates . Cellular interactions with the hydrogels were monitored using a Nikon CoolPix 5000 camera -LRB- Nikon Inc. , Melville , NY -RRB- and transferred to videotape for further analysis . Figure 1 . Schematic of parallel plate flow chamber system . A small pump is used to create a vacuum , sealing the chamber on the surface of the gel . Cells are then perfused over the gel surface using a programmable syringe pump . Cation Dependent Binding JURKAT cells were treated with 2 mM magnesium -LRB- Mg2 + -RRB- , calcium -LRB- Ca2 + -RRB- , or manganese -LRB- Mn2 + -RRB- or with 10 mM EDTA and then perfused through the flow chamber and allowed to settle on the gel for 5 min . Controls were exposed to standard formulations of RPMI-1640 containing 0.4 mM Ca2 + and 0.4 mM Mg2 + . Ten fields of view were scanned to get an average number of cells per field of view . Flow rates corresponding to shear stresses of 0.5 , 1.0 , and 10 dynes cm − 2 were used to wash away unbound cells . The number of cells remaining for each shear stress was counted and averaged over several fields of view . LDV Specificity JURKAT cells treated with 2 mM Mg2 + were allowed to settle on the LDV gel for 5 min and an average number of cells per field of view was determined . Specificity was demonstrated by the addition 7 μg ml − 1 of either a mouse anti-human monoclonal antibody that blocks VLA-4 binding to VCAM-1 -LRB- anti-CD49d , clone BU49 ; Ancell Corporation , Bayport , MN -RRB- or an IgG1 isotype control -LRB- purified mouse myeloma IgG1 ; Invitrogen Corporation , Carlsbad , CA -RRB- at a shear stress of 0.5 dynes cm − 2 . The average number of cells bound per field of view was again counted to determine the amount of cells remaining bound to the surface . Specificity was also demonstrated by the addition of a solution of either 10 mM EDTA or 150 μM Bio1211 introduced into the flow chamber under a shear stress of 0.5 dynes cm − 2 . An average number of cells bound to the gel under flow was determined every minute for 13 min . Video Analysis Cells were allowed to settle on each gel for 5 min . An average of 10 fields of view was scanned and the number of cells settled on the peptide gel was counted . After flow began , fields of view were scanned again and the number of cells remaining -LRB- bound to the gel -RRB- was counted . After flow was established on the SLeX gels , video was paused and the number of interacting cells was counted . The numbers were averaged over 10 fields of view for each shear stress . Statistical Analysis Data were compared with two-tailed , unpaired t-tests ; p-values less than 0.05 were considered to be significant . Results Synthesis of PEG Hydrogels PEG hydrogels were formed under UV light in the presence of a photoinitiator between two glass plates . Hydrogels 0.5 mm thick were formed after 30 s of exposure . The addition of an acryloyl-PEG-peptide derivative mixed with the photoinitiator to the surface of the hydrogels resulted in a covalently bound layer of cell adhesive moiety on the surface -LRB- Fig. 1 -RRB- . Quantification of Cell Adhesion and Rolling Cell rolling on SLeX hydrogels was quantified over a range of shear stresses , and 86.8 ± 11.6 cells per field of view rolled on the gel surface at 3.5 dynes cm − 2 with an average rolling velocity of 141.3 μm s − 1 -LRB- Fig. 2 -RRB- . Rolling decreased with increasing shear stress -LRB- 7.0 dynes cm − 2 : 15.2 ± 3.8 cells , average rolling velocity 232.7 μm s − 1 ; 14 dynes cm − 2 : 8.2 ± 1.9 cells , average rolling velocity 486.8 μm s − 1 ; 21 dynes cm − 2 : no rolling observed -RRB- . Figure 2.300.19 / E cells rolling on SLeX modified gel . 300.19 cells transfected with human E-selectin was perfused over a SLeX modified gel . The number of rolling cells were counted per field of view . SLeX ability to support rolling decreased as shear stress increased -LRB- * p < 0.02 as compared to shear rate of 3.5 dyne cm − 2 -RRB- . Approximately 98.5 ± 18.6 % of cells contacting hydrogel surfaces modified with Bio1211 adhered to the gel surface . In comparison , 41.5 ± 13.4 % of cells in contact with the surface of PEG-LDV , an interaction specific for the α4β1 integrin expressed on JURKAT cells , adhered to the hydrogels and 23 ± 8.5 % of cells contacting PEG-RGDS hydrogels adhered to the gel surface -LRB- Fig. 3 -RRB- . No cells adhesion to PEG-DA or PEG-RGES hydrogels was observed ; however the control LEV peptide-modified gels had 1.6 ± 1.2 % of cells contacting the surface adhere . Figure 3 . Peptide ability to bind VLA-4 . JURKAT cells were allowed to settle on PEG-DA gels conjugated with different peptides at similar densities . After 5 min , cells were subjected to a shear stress of 0.5 dynes cm − 2 to remove unbound cells and the remaining cells were counted -LRB- * p < 0.02 compared to Bio1211 -RRB- . Cation Dependant Binding Cation sensitivity was assessed by the addition of cations or EDTA to cell cultures prior to their exposure to PEG-LDV hydrogels . The presence of 10 mM EDTA had the greatest inhibitory effect on binding , followed by 2 mM Ca2 + . Mg2 + and Mn2 + had little effect on the ability of JURKAT cells to bind LDV , and a higher number of cells exposed to both calcium and magnesium were able to bind to the gel surface than those exposed to calcium alone -LRB- Fig. 4 -RRB- . Figure 4 . Cation dependent binding of VLA-4 to LDV peptide . JURKAT cells were incubated with 2 mM cations or 10 mM EDTA prior to settling on the LDV gel ; controls were exposed to standard formulations of RPMI-1640 containing 0.4 mM Ca2 + and 0.4 mM Mg2 + . The percentage of cells on the gel was determined based on the total number of cells before initiating a shear stress of 0.5 dynes cm − 2 -LRB- * p < 0.05 compared to Control -RRB- . LDV Specificity JURKAT cell binding to PEG-LDV hydrogels was reversed upon the addition of a monoclonal anti-VLA-4 -LRB- 3.4 ± 2.1 % bound -RRB- . Cells exposed to an isotype-matched control antibody were still able to adhere to the hydrogel surface -LRB- 88.8 ± 33.4 % bound -RRB- , demonstrating specificity of LDV for the VLA-4 integrin . The higher affinity of Bio1211 compared to the LDV peptide was also observed by the addition of unbound Bio1211 after cells were allowed to settle on PEG-LDV hydrogels -LRB- Fig. 5 -RRB- . Bio1211 was able to remove cells from the gel surface better than EDTA through competitive binding of VLA-4 . Figure 5 . LDV Specificity for VLA-4 . 10 mM EDTA or 1.5 uM Bio1211 was introduced into the flow chamber at a wall shear stress of 0.5 dynes cm − 2 after JURKAT cells were allowed to settle on the LDV gel for 5 min . Bio1211 , which has a higher affinity for VLA-4 was able to compete the cells off the LDV modified gel surface . EDTA was not as effective as Bio1211 as cells detached more slowly and not completely . The dashed line represents the uninhibited controls , in which 40 ± 15.2 % of the cells initially exposed to the hydrogel remained bound through the duration of the experiment . Each data point represents the average percent of bound cells per 10 fields of view and error bars represent the standard deviation of the percent of bound cells within those 10 fields of view . The influence of peptide concentration on cell adhesion was determined by varying the amounts of LDV bound to the hydrogel surface -LRB- Fig. 6 -RRB- . The number of cells bound to the gel increased with LDV concentration , and LDV was better able to support adhesion at lower shear stresses for all concentrations when compared to higher rates of shear . Figure 6 . Dilution effect of LDV . The number of JURKAT cells bound to the gel decreased as the LDV peptide concentration was lowered . LDV was better able to support adhesion at lower shear stresses for all concentrations -LRB- * p < 0.05 comparing shear rates at each concentration -RRB- . Discussion The system of hydrophilic hydrogels modified with cell adhesion peptides implemented in this study exhibits the ability to mimic the cell adhesion cascade that occurs during the onset of inflammation in the vascular system . The capacity to modify hydrogels with cell adhesion molecules for the study of cellular interactions with biomaterials for drug delivery and tissue engineering is well documented .4,7,15,16,18,24 -- 26,29 -- 31,38,39,44 This study implements the use of these materials under physiological flow conditions to examine the mechanisms of leukocyte rolling and firm adhesion . The formation of thin flat PEG diacrylate hydrogels for use with a parallel plate flow chamber improves upon earlier systems that utilize hydrophobic surfaces with adsorbed cell adhesion molecules . The highly crosslinked structure of swollen PEG networks have water content similar to native vessels , and covalent incorporation of cell adhesive peptides guarantees control of concentration and allows for patterning of one or more adhesion sequences on the gel surface .23 This system is based on a flexible substrate with tunable stiffness , the properties of which can be exploited to examine the responses of different cell types in microenvironments that mimic native tissues in various states of development , remodeling , regeneration , and disease . It has been suggested that the differentiation of cellular function and response could depend significantly on matrix elasticity ,8,14,45 and varying the polymer composition or concentration in the hydrogel can alter the permeability and mechanical properties ,36 simulating a range of biologically relevant conditions . In addition , the local mobility of adhesive ligands in the solvated hydrogel system should be considerably better than on solid substrates , allowing more variable orientations which could contribute to a greater fraction of accessible ligands available to receptors on the cell surface . Leukocyte cell adhesion to the surfaces of modified PEG-DA hydrogels was highly specific , reversible , and sensitive to ligand site density and affinity , demonstrating the efficacy of the system to mimic the events leading to the firm adhesion of immune cells on activated endothelium . The slow rolling of 300.19 / E cells on the surfaces of PEG-SLeX hydrogels confirms the integration of SLeX into the system through the use of an avidin -- biotin linkage , which did not disrupt the active binding site of the carbohydrate . Incorporation of the RGD and LDV peptides encouraged firm cell adhesion to the materials surface under shear in a concentration dependant manner , and cells remained adherent throughout the duration of the flow experiment . These results illustrate that this method of studying leukocyte adhesion succeeds in mimicking the interactions seen on the in vivo vascular wall under shear . With further optimization , such as incorporation of signaling molecules , this system using of PEG gels can improve insight into the mechanisms of rolling and firm cell adhesion at sites of active vascular disease . Conclusions The covalent modification of PEG hydrogel surfaces with cell adhesive peptides was accomplished in continuous layers of adhesive regions . These materials encouraged vascular cell adhesion through both transient interactions with selectin molecules and firm binding via integrins . The system presented here to expose adhesive hydrogels to cells under flow conditions represents a method to study cell -- material interactions in environments that closely mimic in vivo environments .

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O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O

hydrogel
leukocyte adhesion
flow chamber


How

Uganda

Reversed

Its

HIV

Epidemic

Uganda

is

one

of

only

two

countries

in

the

world

that

has

successfully

reversed

the

course

of

its

HIV

epidemic

There

remains

much

controversy

about

how

Uganda

's

HIV

prevalence

declined

in

the

This

article

describes

the

prevention

programs

and

activities

that

were

implemented

in

Uganda

during

critical

years

in

its

HIV

epidemic

to

Multiple

resources

were

aggregated

to

fuel

HV

prevention

campaigns

at

multiple

levels

to

a

far

greater

degree

than

in

neighboring

countries

We

conclude

that

the

reversed

direction

of

the

HIV

epidemic

in

Uganda

was

the

direct

result

of

these

interventions

and

that

other

countries

in

the

developing

world

could

similarly

prevent

or

reverse

the

escalation

of

HIV

epidemics

with

greater

availability

of

HIV

prevention

resources

and

well

designed

programs

that

take

efforts

to

a

critical

breadth

and

depth

of

effort

Introduction

Since

the

beginning

of

the

World

Health

Organization

's

collaboration

with

developing

countries

Uganda

was

for

many

years

the

only

country

in

Africa

and

only

one

of

two

countries

-LRB-

the

other

Thailand

-RRB-

in

the

developing

world

to

have

clearly

reversed

its

HIV

epidemic

-LRB-

Asiimwe-Okiror

et

al.

Mason

Markovitz

Kitsiripornchai

UNAIDS

USAID

US

House

of

Representatives

Hearing

on

the

Global

AIDS

crisis

and

pandemic

in

Africa

-RRB-

although

more

recently

other

reports

indicate

additional

countries

are

showing

possible

reductions

-LRB-

Gregson

Garnett

Nyamukapa

Hallet

Kibian

USAID

-RRB-

Uganda

's

changes

remain

the

first

most

extensive

and

of

largest

scale

of

decline

-LRB-

USAID

-RRB-

but

are

still

subject

to

controversy

as

to

how

these

changes

occurred

-LRB-

Parkhurst

Stoneburner

Low-Beer

-RRB-

With

regard

to

the

changes

in

Uganda

much

has

been

written

describing

which

sexual

behaviors

changed

in

the

Uganda

population

-LRB-

Asiimwe-Okiror

et

al.

Stoneburner

Carballo

Stoneburner

Low-beer

Barnett

Whiteside

UNAIDS

-RRB-

but

there

has

still

been

little

written

about

the

strategies

activities

and

program

elements

that

took

place

that

affected

these

changes

In

other

words

the

changes

in

sexual

behaviors

in

Uganda

that

occurred

during

that

time

period

are

known

and

the

effects

on

the

HIV

epidemic

are

known

yet

the

continuously

missing

part

of

the

discussion

has

been

why

did

these

behavior

changes

occur

Similarly

why

did

these

changes

occur

in

Uganda

and

seemingly

not

in

the

neighboring

countries

at

the

time

or

to

that

degree

still

anywhere

in

the

developing

world

This

article

attempts

to

fill

this

gap

We

offer

our

description

of

these

activities

as

persons

who

were

involved

in

Uganda

's

AIDS

program

's

inception

and

the

first

seven

years

-LRB-

-RRB-

of

the

program

when

its

effects

occurred

Simplistic

explanations

such

as

leadership

migration

or

awareness

of

the

deaths

of

others

seem

unlikely

to

be

responsible

on

their

own

since

country

leadership

principally

defines

the

will

for

programs

and

the

willingness

to

ensure

activities

occur

but

does

not

explain

what

actual

activities

did

occurred

Regarding

migration

changes

in

HIV

prevalence

occurred

in

at

least

seven

and

possibly

nine

towns

and

villages

simultaneously

in

Uganda

-LRB-

Stoneburner

et

al.

-RRB-

making

migration

an

unlikely

explanation

Also

since

similarly

high

rates

of

infection

-LRB-

-RRB-

were

seen

in

the

major

cities

of

at

least

four

neighboring

countries

-LRB-

i.e.

Rwanda

Burundi

Zambia

and

Malawi

-RRB-

during

the

same

years

-LRB-

Stoneburner

Carballo

USAID

-RRB-

and

without

the

same

declines

we

must

look

at

what

was

the

Uganda

program

itself

As

will

be

seen

the

program

itself

differed

both

in

substance

and

in

intensity

from

all

neighboring

programs

in

Africa

This

article

focuses

on

the

years

when

the

HIV/AIDS

program

in

Uganda

was

first

formed

through

the

time

when

serologically

measured

changes

in

HIV

prevalence

occurred

Our

analysis

is

based

on

the

country

documents

national

program

plans

and

reports

of

that

period

and

our

experiences

as

part

of

that

program

An

attempt

is

also

made

to

provide

comparisons

with

other

national

AIDS

programs

in

Africa

that

occurred

in

the

same

years

and

to

describe

the

major

differences

between

Uganda

's

program

and

other

programs

in

the

region

at

the

time

First

we

describe

our

sources

of

information

followed

by

our

description

of

the

Uganda

AIDS

prevention

activities

and

their

implementation

Information

sources

This

paper

focuses

principally

on

program

strategies

processes

and

activities

of

the

Uganda

National

AIDS

Control

Program

-LRB-

NACP

-RRB-

for

the

years

Although

noted

here

we

do

not

provide

an

in

depth

analysis

of

the

trends

in

sexual

behavior

or

HIV

changes

themselves

which

have

been

analyzed

elsewhere

and

repeatedly

This

article

draws

on

sources

from

Ugandan

Ministry

of

Health

records

and

reports

World

Health

Organization

-LRB-

WHO

-RRB-

records

and

reports

on

the

country

program

and

programs

of

neighboring

countries

Uganda

country

assignment

reports

the

Uganda

National

Program

Review

and

plans

and

country

assessments

by

WHO

and

USAID

written

at

the

time

We

also

rely

on

data

from

specialized

studies

performed

at

the

time

and

reports

of

those

of

us

who

were

engaged

directly

in

the

program

reviews

planning

and

implementation

of

the

Uganda

AIDS

program

during

those

years

some

of

whom

were

also

involved

in

implementation

or

assistance

to

implementation

of

neighboring

African

countries

at

the

same

time

Brief

history

of

the

Uganda

National

AIDS

Control

Program

-LRB-

NACP

-RRB-

AIDS

cases

were

first

recognized

in

Uganda

in

with

the

first

cases

reported

by

rising

to

cases

by

-LRB-

Uganda

AIDS

Control

Programme

-RRB-

By

of

sex

workers

and

of

lorry

drivers

studied

were

HIV

positive

and

of

blood

donors

and

of

antenatal

clinic

attendees

in

major

urban

centers

were

also

HIV

positive

In

in

response

to

these

findings

the

national

government

of

Uganda

formed

the

National

Committee

for

the

Prevention

of

AIDS

-LRB-

NCPA

-RRB-

and

the

NACP

The

WHO

assisted

the

government

of

Uganda

in

both

of

these

endeavors

beginning

in

January

of

when

the

first

emergency

national

plan

was

written

Subsequently

a

short

term

plan

-LRB-

STP

-RRB-

and

the

year

medium

term

plan

-LRB-

MTP

-RRB-

were

written

in

A

program

review

was

performed

in

December

of

-LRB-

the

first

of

its

kind

in

Africa

and

in

the

world

-RRB-

and

the

next

MTP

was

drawn

up

immediately

following

the

findings

and

recommendations

of

the

first

program

review

All

of

these

rapid

and

intense

WHO

assisted

steps

were

set

in

motion

for

all

countries

in

Africa

and

subsequently

for

almost

all

countries

in

the

world

during

this

time

During

the

years

countries

developed

NAPs

developed

MTPs

and

had

program

reviews

before

WHO

all

but

disbanded

in

its

prior

formulation

and

became

less

involved

with

direct

country

support

-LRB-

SIDA/AIDS

WHO

Slutkin

Tarantola

US

House

of

Representatives

WHO

Global

Programme

on

AIDS

-RRB-

During

the

years

although

almost

all

AIDS

control

programs

especially

those

in

East

and

Central

Africa

were

progressing

Uganda

was

the

first

country

in

which

the

WHO

worked

with

the

concept

of

a

single

national

plan

and

budget

which

all

donors

would

agree

to

use

and

fund

to

focus

their

respective

aid

and

with

a

local

multi-donor

round

table

aimed

at

meeting

the

targeted

budget

Uganda

was

the

first

country

to

progress

through

all

of

the

STP

MTP

joint

donor

meeting

program

review

and

reprogramming

processes

Uganda

was

then

set

up

to

lead

the

way

among

all

countries

in

the

extent

of

programming

the

amount

of

on

the

ground

national

staffing

WHO

staffing

support

and

global

financial

support

-LRB-

Mann

WHO

-RRB-

Emergency

assistance

first

plan

in

Africa

The

strategies

of

Uganda

's

first

national

AIDS

control

plan

of

were

described

as

to

mount

an

educational

campaign

to

inform

the

public

on

the

modes

of

transmission

and

ways

to

avoid

infection

to

reduce

transmission

through

blood

transfusion

by

setting

up

laboratories

to

test

all

blood

before

transfusion

and

to

reduce

transfusion

to

a

minimum

to

advocate

careful

sterilization

of

instruments

and

contaminated

hospital

areas

to

assure

patient

and

health

worker

safety

and

to

measure

the

extent

of

the

outbreak

and

possible

co-factors

by

case

surveillance

seroprevalence

studies

and

operational

research

projects

-LRB-

Uganda

-RRB-

These

were

the

usual

strategies

for

all

early

AIDS

programs

-LRB-

WHO

Global

Programme

on

AIDS

-RRB-

This

initial

plan

was

supported

by

a

WHO

grant

of

made

available

within

weeks

of

the

signature

of

the

STP

and

then

million

more

was

provided

in

emergency

assistance

Blood

was

largely

screened

in

the

major

urban

areas

a

health

education

program

started

and

the

sentinel

surveillance

program

initiated

-LRB-

Slutkin

Chin

Tarantola

Mann

Uganda

-RRB-

For

the

later

two

strategies

activities

moved

far

in

advance

of

other

country

programs

at

the

time

This

plan

also

laid

the

groundwork

for

the

five-year

plan

which

was

to

be

developed

in

The

program

review

of

summarized

the

accomplishments

of

the

NACP

of

Uganda

in

its

first

and

half

years

The

first

Uganda

program

review

The

program

review

of

December

-LRB-

Ministry

of

Health

Uganda

-RRB-

was

performed

for

the

stated

purpose

of

reviewing

accomplishments

adequacy

relevance

progress

and

effectiveness

of

stated

activities

and

to

make

recommendations

for

the

next

phase

in

this

case

for

the

five

year

plan

that

was

to

be

written

in

the

following

month

It

should

be

noted

that

WHO

Global

Program

on

AIDS

-LRB-

GPA

-RRB-

at

this

time

and

the

Ugandan

government

were

both

in

an

emergency

mode

of

accelerated

program

development

cooperation

and

assistance

The

main

findings

of

the

Uganda

NACP

program

review

led

to

a

series

of

recommendations

Program

strengths

highlighted

by

the

review

included

continued

and

increased

political

commitment

of

the

Government

of

Uganda

and

especially

the

President

vital

contribution

-LRB-

s

-RRB-

of

non

governmental

organizations

and

a

strong

leadership

role

by

ACP

and

an

emerging

coordinating

role

by

-LRB-

the

national

-RRB-

AIDS

Control

Program

-LRB-

NACP

-RRB-

widely

accepted

by

Government

non

government

agencies

and

donors

Over

critical

recommendations

were

made

commenting

on

the

first

two

years

of

activities

that

were

to

instruct

the

next

five

years

of

work

Of

these

recommendations

the

following

were

thought

important

enough

to

be

highlighted

in

the

executive

summary

the

intensity

of

the

AIDS

control

activities

must

be

accelerated

especially

at

the

district

and

community

level

-LRB-

the

national

level

-RRB-

ACP

should

take

on

a

stronger

-LRB-

coordinating

-RRB-

role

prevention

should

remain

the

primary

objective

that

-LRB-

there

is

a

-RRB-

lack

of

adequate

renumeration

for

national

staff

and

that

Uganda

and

WHO

explore

all

possible

ways

of

overcoming

this

serious

problem

and

-LRB-

the

-RRB-

NACP

office

needs

to

have

more

expertise

in

planning

manpower

development

research

direction

coordination

and

administration

-LRB-

Uganda

-RRB-

The

first

recommendations

of

the

Uganda

Program

Review

-LRB-

Uganda

-RRB-

provided

insight

into

what

was

in

process

and

what

was

thought

to

be

needed

by

the

combined

international

and

national

expert

review

team

These

recommendations

were

then

within

weeks

integrated

into

the

plan

The

main

recommendations

quoted

from

the

report

were

the

need

for

stepwise

application

of

well-conceived

and

integrated

KAP/IEC

strategies

make

these

methods

available

to

all

groups

more

widespread

dissemination

of

factual

information

increased

emphasis

for

illiterate

people

materials

designed

for

groups

at

high

risk

and

for

families

with

AIDS

information

that

can

be

used

by

resistance

committees

-LRB-

village

level

political

structure

through

which

the

Musevini

government

operationalized

new

policies

-RRB-

to

raise

local

awareness

effective

channels

for

distributing

written

and

pictorial

information

training

communication

skills

teaching

training

skills

at

district

level

training

packages

distributing

training

packages

financial

support

to

enable

district

community

and

other

training

groups

to

run

training

courses

and

health

educators

to

-LRB-

be

-RRB-

fully

equipped

and

functional

within

weeks

rather

than

several

months

-LRB-

to

perform

this

education

in

the

districts

-RRB-

Regarding

condoms

the

NACP

was

advised

by

the

co-sponsored

review

only

to

review

the

use

of

condoms

as

part

of

the

strategy

particularly

where

transmission

rates

are

high

The

Ministry

of

Health

the

lead

ministry

for

the

Uganda

program

at

the

time

and

for

the

next

several

years

was

not

eager

to

embrace

condoms

for

a

number

of

reasons

that

included

availability

-LRB-

dependence

-RRB-

acceptability

and

disposal

and

the

fact

that

putting

trust

in

one

measure

was

not

strategic

These

reasons

were

constantly

cited

by

the

program

and

President

Musevini

The

review

repeatedly

noted

the

need

for

an

urgent

push

toward

the

rapid

expansion

of

the

information

education

communication

and

training

The

Uganda

medium

term

plan

-LRB-

MTP

-RRB-

The

Five

Year

plan

and

First

Year

Project

Plan

and

Budget

directed

the

immediate

acceleration

of

the

program

as

outlined

in

the

program

review

-LRB-

Ministry

of

Health

Uganda

Amana

Moodie

et

al.

Uganda

-RRB-

This

plan

's

priority

strategies

and

budget

allocations

are

shown

in

Table

The

sources

of

funds

for

the

year

were

as

follows

WHO

Trust

Fund

million

Bilateral

funds

-LRB-

e.g.

from

USAID

ODA

etc

-RRB-

million

and

national

-LRB-

Ugandan

-RRB-

million

Therefore

the

Uganda

program

grew

from

annual

expenditures

of

mil

to

mil

to

million

in

its

first

three

years

Dozens

of

organizations

were

involved

in

the

management

planning

and

implementation

of

the

Five

Year

Plan

including

local

and

international

non-governmental

organizations

-LRB-

NGOs

-RRB-

and

all

segments

of

Ugandan

society

The

management

concerns

discussed

in

the

program

review

were

addressed

in

part

by

assuring

that

the

Ugandan

NACP

remain

the

central

coordinating

body

and

its

staffing

was

enhanced

to

Ministry

of

Health

staff

supplemented

by

WHO

staff

Each

of

these

levels

of

staffing

was

substantially

larger

than

any

other

program

on

the

continent

We

do

not

recall

any

other

country

having

a

program

of

more

than

local

staff

or

WHO

staff

at

the

time

Table

national

AIDS

control

program

budget

-LRB-

mill

USD

-RRB-

Health

Surveillance

and

Lab

Source

Uganda

Aids

Control

Program

Ministry

of

Health

Government

of

Uganda

Entebbe

Uganda

As

can

be

seen

in

Table

the

Ugandan

health

education

-LRB-

IEC

-RRB-

budget

was

greatly

prioritized

among

all

strategies

implemented

The

IEC

program

is

discussed

in

more

detail

below

as

it

is

thought

essential

As

was

the

case

at

the

time

for

all

programs

in

central

and

east

Africa

it

was

essentially

demanded

of

WHO

by

the

country

's

government

that

enough

funds

be

made

available

to

ensure

a

safe

blood

supply

and

have

the

laboratory

supplies

and

facilities

to

perform

this

function

The

Ugandan

program

also

became

the

first

country

to

both

field

test

HIV

sentinel

surveillance

at

antenatal

clinics

and

other

settings

-LRB-

Nsambya

Uganda

being

the

first

sentinel

surveillance

site

in

Africa

and

is

still

operational

-RRB-

and

then

the

first

country

to

expand

this

system

initially

to

six

sites

and

then

country

wide

-LRB-

Slutkin

et

al.

Slutkin

Chin

Tarantola

Mann

-RRB-

However

with

this

infrastructure

in

place

including

management

lab

support

blood

screening

and

HIV

monitoring

it

was

then

completely

unique

on

the

continent

to

have

funds

remaining

for

a

national

AIDS

health

education

budget

to

be

supported

at

the

level

noted

Full

country

AIDS

program

budgets

for

the

six

neighboring

countries

were

all

in

the

range

of

million

total

-LRB-

cf.

million

for

Uganda

-RRB-

As

was

to

be

seen

the

Uganda

program

was

then

free

to

prioritize

and

implement

throughout

the

country

the

most

widespread

extensive

and

well

thought

out

information

education

and

communication

program

for

AIDS

prevention

-LRB-

and

care

-RRB-

of

any

country

in

Africa

As

can

be

also

seen

in

Table

-LRB-

shown

for

both

and

-RRB-

the

Uganda

Health

Education

budget

itself

was

to

specifically

prioritize

local

and

decentralized

programming

local

rather

than

international

expenses

and

to

ensure

local

staff

salaries

and

perdiems

Table

AIDS

health

education

budget

and

-LRB-

USD

-RRB-

Program

support

Source

Uganda

Aids

Control

Program

Ministry

of

Health

Government

of

Uganda

Entebbe

Uganda

In

the

first

year

in

which

financial

information

is

available

million

of

the

million

available

for

health

education

activities

were

made

available

from

the

WHO

Trust

Fund

The

additional

million

were

made

available

from

bilateral

sources

e.g.

UNICEF

USAID

U.S.

Red

Cross

MSF

and

U.S.

and

other

University

projects

Of

the

million

million

was

made

available

for

local

costs

Similarly

million

of

the

million

spent

from

the

WHO

Trust

fund

IEC

budget

was

used

for

local

costs

The

Evaluation

of

the

Uganda

IEC

activities

stated

that

the

DAMP

and

the

ACP

Mass

Media

activities

were

two

of

the

most

visible

of

the

NACP

's

projects

and

together

utilize

more

than

half

of

the

IEC

budget

The

health

education

campaign

The

Health

Education

-LRB-

Information

education

and

communication

IEC

-RRB-

Campaign

was

to

be

the

center

of

the

Uganda

program

-LRB-

Amana

Moodie

et

al.

Uganda

-RRB-

The

main

goals

of

the

Ugandan

IEC

program

were

three

fold

-RRB-

mobilization

of

all

formal

and

informal

sectors

of

Ugandan

society

-RRB-

providing

IEC

materials

to

all

districts

and

-RRB-

district

level

decentralized

information

and

training

The

principal

activities

were

as

proposed

by

the

program

review

and

plan

the

development

of

training

packages

and

a

training

of

trainers

program

for

all

sectors

public

education

materials

development

and

dissemination

and

district

level

mass

mobilization

with

cross

fertilization

from

one

district

to

another

training

educators

from

one

district

to

be

used

in

the

next

district

This

IEC

campaign

was

led

by

the

Ugandan

Ministry

of

Health

with

technical

and

implementing

assistance

from

WHO

and

had

very

active

support

and

involvement

from

UNICEF

and

from

several

critically

important

NGOs

The

specific

program

elements

are

described

below

Table

AIDS

information

education

and

communication

-LRB-

IEC

-RRB-

campaign

sectors

trained

-LRB-

partial

listing

-RRB-

Resistance

committeesAgricultural

workersPoliceSocial

mobilizationTraditional

healersPrisonsSchoolsUniversitiesYouthMediaMidwivesArmyPerformance

artistsWomen

's

groupsReligious

organizationsFamily

planning

workersRefugeesSource

Uganda

Aids

Control

Program

Ministry

of

Health

Government

of

Uganda

Entebbe

Uganda

Fig.

mobilization

implementation

model

-LRB-

DAMP

-RRB-

Source

Moodie

et

al.

ACP/MOH

Uganda

and

WHO/GPA

Training

of

trainers

A

partial

listing

of

the

specific

sectors

trained

by

the

program

are

listed

in

Table

The

main

focus

points

of

this

multi-sector

training

were

correct

information

on

how

HIV/AIDs

is

and

is

n't

transmitted

destigmatization

care

and

compassion

and

condoms

-LRB-

Moodie

et

al.

Uganda

-RRB-

Each

of

these

sectors

had

specific

training

activities

that

began

centrally

with

workshops

for

Ministries

or

other

central

level

personnel

e.g.

for

permanent

secretaries

ministries

parliamentarians

police

teachers

family

planning

association

workers

resistance

committee

members

etc

and

then

proceeded

with

a

top

down

or

center

out

cascade

of

information

dissemination

and

training

These

training

activities

were

meant

mostly

to

simply

convey

the

correct

information

about

how

HIV/AIDS

is

and

is

not

transmitted

and

that

persons

with

AIDS

were

to

be

treated

humanely

District

mobilization

The

District

AIDS

Mobilization

Project

-LRB-

DAMP

-RRB-

model

implemented

by

the

Ugandan

IEC

program

is

shown

in

Fig.

Resources

used

for

the

DAMP

included

paid

health

educators

of

the

Ministry

of

Health

local

graphic

designers

and

international

consultants

-LRB-

including

from

WHO

and

from

UNICEF

-RRB-

Seven

vehicles

for

the

central

pool

vehicles

for

the

district

health

educators

and

motorcycles

were

provided

by

the

international

community

and

by

the

government

for

this

campaign

Two

film

vans

for

mass

addresses

and

a

number

of

hand

held

megaphones

and

other

public

address

systems

were

also

purchased

or

made

available

for

this

campaign

The

District

course

content

as

noted

in

a

WHO

funded

special

IEC

review

stressed

topics

including

scientific

overview

basic

prevention

messages

common

questions

and

misconceptions

communicating

with

high

risk

groups

cultural

practices

special

concerns

of

women

effective

communication

skills

care

and

counseling

District

level

activities

used

to

convey

this

content

included

public

gatherings

plays

songs

contests

and

the

distribution

and

discussion

of

posters

leaflets

fliers

comic

books

documentaries

and

videos

The

basic

content

of

these

district

village

and

community

sessions

were

of

a

type

of

allowing

the

correct

information

to

be

discussed

to

give

it

time

to

allow

everyone

to

be

involved

and

to

disseminate

accurate

information

for

the

population

in

order

for

their

to

be

an

adequate

opportunity

to

mull

over

discuss

between

each

other

understand

and

facilitate

a

critical

mass

of

persons

who

knew

the

facts

Norm

change

was

intended

to

follow

facilitated

group

decision-making

IEC

materials

on

AIDS

such

as

posters

pamphlets

and

booklets

were

developed

and

translated

into

local

languages

and

distributed

to

District

Councilors

Resistance

Councilors

and

to

members

of

NGOs

at

training

workshops

Three

day

seminars

were

held

for

health

workers

followed

by

two

day

seminars

for

Resistance

Councilors

and

district

department

heads

and

sub-county

chiefs

The

general

public

was

to

get

their

materials

through

the

Resistance

Councilors

system

and

other

key

people

such

as

mass

mobilizers

and

community

development

workers

Resistance

committees

were

political

administrative

units

that

graduated

into

each

other

from

the

Resistance

Councilors

that

was

made

up

of

households

Resistance

committees

were

later

to

be

called

local

councils

or

local

area

councils

but

they

maintained

the

same

function

These

training

activities

were

followed

by

a

one

week

health

education

campaign

conducted

by

Resistance

Councilors

in

collaboration

with

assistant

health

educators

other

health

educators

community

development

workers

and

NGOs

The

DAMP

activities

and

the

training

of

trainers

through

multiple

formal

and

informal

natural

and

other

infrastructures

would

serve

to

cross

fertilize

in

other

words

allow

multiple

messengers

to

come

at

individuals

and

groups

through

multiple

channels

but

with

the

same

message

Although

DAMP

was

the

big

concept

UNICEF

funded

health

education

activities

included

a

community

Health

Education

Network

-LRB-

HEN

-RRB-

with

community

based

health

educators

imbedded

in

the

community

meant

to

sustain

DAMP

and

SHAPE

-LRB-

School

Health

Education

Project

-RRB-

Both

of

these

activities

cross

fertilized

with

and

were

thought

to

have

augmented

the

DAMP

Parents

and

the

community

were

to

get

information

from

HEN

and

their

children

got

information

from

the

schools

so

there

would

be

multiple

channels

alongside

the

district

level

work

and

specific

synergy

at

the

household

level

Country

wide

messaging

The

dominant

message

of

the

Ugandan

program

as

is

well

known

and

which

was

well

known

at

the

time

both

throughout

Uganda

and

throughout

Africa

-LRB-

as

the

Uganda

message

-RRB-

was

Zero

Grazing

alluding

to

the

traditional

way

cattle

were

fenced

in

or

tied

to

a

stick

to

limit

grazing

outside

their

own

pasture

This

clearly

meant

stick

to

one

partner

which

was

what

was

frequently

said

following

the

message

or

by

way

of

explanation

This

was

a

message

of

fidelity

although

that

word

was

rarely

used

at

the

time

as

it

not

only

pertained

to

during

marriage

but

to

during

dating

as

well

One

study

supported

by

WHO/GPA

reported

higher

village

recall

of

the

saying

or

having

seen

the

posters

Love

Faithfully

-LRB-

-RRB-

and

Love

Carefully

-LRB-

-RRB-

than

Zero

Grazing

Over

of

those

aware

of

Love

faithfully

interpreted

this

to

mean

stick

to

one

partner

over

of

those

who

heard

or

saw

Love

carefully

understood

it

to

meant

choose

your

partner

carefully

-LRB-

which

became

a

large

confusion

in

Uganda

-RRB-

and

over

half

of

those

who

saw

or

heard

zero

grazing

thought

it

to

mean

stick

to

one

partner

All

options

including

delaying

sex

not

engaging

in

sex

sticking

to

one

partner

and

to

a

lesser

extent

using

condoms

were

also

described

in

the

materials

and

discussions

in

trainings

and

in

the

district

level

courses

and

discussions

The

posters

at

the

time

emphasized

a

cow

in

a

pasture

surrounded

by

a

fence

and

many

Thank

God

I

said

no

posters

as

well

as

messages

of

care

and

compassion

The

word

abstinence

per

se

was

rarely

if

ever

heard

in

Ministry

conversations

although

delaying

onset

of

sex

was

part

of

usual

information

Although

all

means

of

transmission

noted

here

were

provided

as

information

we

believe

the

actual

ABC

phrase

came

out

of

the

USAID

in

the

mid

or

late

s

and

was

not

seen

in

any

of

the

country

plans

or

program

documents

or

known

at

the

time

of

the

first

years

of

the

Uganda

program

Materials

development

and

dissemination

There

was

an

enormous

emphasis

in

Uganda

on

material

development

production

and

reproduction

and

active

dissemination

out

of

the

capital

to

the

districts

Local

graphic

artists

held

subsidized

workshops

with

local

residents

to

design

materials

and

information

packets

for

use

in

the

trainings

and

DAMP

activities

A

full

time

printing

press

was

paid

for

by

WHO

and

put

into

the

Ministry

of

Health

along

with

other

equipment

and

staffing

support

to

intentionally

enhance

the

capacity

of

the

Ugandan

Ministry

of

Health

Health

Education

Unit

A

full

time

U.N.

Volunteer

-LRB-

UNV

-RRB-

funded

by

WHO/GPA

was

additionally

supported

for

the

Uganda

program

to

run

the

printing

press

The

instructions

to

the

UNV

were

to

continue

to

print

produce

and

disseminate

materials

no

matter

what

else

was

occurring

regarding

the

national

program

Posters

leaflets

fliers

and

comic

books

were

produced

by

this

and

other

means

Materials

for

persons

with

poor

literacy

skills

were

also

developed

and

actively

disseminated

Mass

media

Representatives

from

Ugandan

radio

and

television

were

included

in

the

program

and

planning

process

and

both

radio

-LRB-

thought

to

reach

over

of

the

population

-RRB-

and

television

were

widely

used

Short

jingles

were

designed

by

NACP

for

radio

to

convey

information

on

AIDS

The

Ugandan

daily

paper

MUNNO

ran

daily

articles

on

AIDS

The

weekly

Topic

and

daily

New

Vision

ran

a

combined

articles

on

AIDS

in

The

New

Vision

ran

the

AIDS

Corner

on

the

last

page

of

every

issue

that

posed

a

question

and

provided

an

answer

This

campaign

ran

daily

for

three

consecutive

years

The

Q

and

A

's

were

later

compiled

into

booklets

used

in

other

countries

Ugandan

TV

-LRB-

UTV

-RRB-

ran

regular

spots

discussion

programs

and

documentaries

Theater

was

used

to

convey

messages

and

almost

all

theater

groups

developed

plays

incorporating

HIV/AIDS

messages

President

Musevini

Dr.

Okware

then

National

AIDS

Program

Director

and

other

Ministry

officials

were

regular

spokespersons

in

the

media

and

the

program

appeared

to

speak

with

one

voice

so

there

was

little

opportunity

for

confusion

Church

leaders

and

imams

were

a

major

sources

of

information

for

about

of

the

population

but

between

and

of

three

villages

reported

having

received

messages

on

AIDS

from

the

church

Fidelity

and

monogamy

were

emphasized

in

addition

to

abstinence

Eighty-five

percent

of

respondents

in

the

NACP

study

felt

that

abstinence

was

not

a

practical

prevention

strategy

or

behavioral

option

for

any

or

all

members

in

their

community

similarly

felt

that

monogamy

was

not

practical

or

possible

at

that

time

Changes

in

social

norms

At

the

time

there

were

several

anecdotal

reports

of

villages

changing

norms

of

the

acceptability

of

sexual

contacts

between

teachers

police

and

the

military

in

terms

of

their

relations

with

young

women

These

decisions

were

arrived

at

by

group

decision

making

and

these

changes

in

enforced

norms

toward

total

unacceptability

were

also

supported

by

Presidential

directive

at

the

time

The

results

reported

were

that

teachers

or

police

who

did

engage

in

sexual

relations

with

young

women

and

girls

were

removed

from

their

assignments

and

likewise

forced

to

leave

the

towns

or

villages

The

full

extent

of

these

specific

changes

in

norms

and

practices

is

unknown

Changes

in

sexual

behavior

Between

and

changes

occurred

for

the

spectrum

of

relevant

sexual

behaviors

-LRB-

Asiimwe-Okiror

et

al.

Atkinson

Singh

Darroch

Bankole

Stoneburner

Carballo

USAID

US

House

of

Representatives

Hearing

on

the

Global

AIDS

crisis

and

pandemic

in

Africa

-RRB-

including

toward

delay

in

age

of

first

intercourse

-LRB-

fewer

initiated

at

young

ages

-RRB-

lesser

frequency

of

multiple

partners

fewer

non-regular

partners

a

narrowing

of

the

age

gap

between

girls

and

their

male

partners

-LRB-

USAID

-RRB-

and

toward

more

condom

use

The

proportion

of

male

and

female

youth

aged

years

old

who

reported

that

they

have

never

had

sex

increased

from

and

in

to

and

in

respectively

-LRB-

Assimwe-Okror

-RRB-

It

is

reported

that

there

was

no

general

pattern

of

increased

abstinence

among

those

who

had

ever

had

sex

-LRB-

Singh

et

al.

-RRB-

however

overall

sexual

activity

decreased

among

year

old

men

and

women

and

for

most

ages

Condom

use

was

unusual

prior

to

and

increased

from

to

over

among

unmarried

women

and

men

who

had

sex

in

the

prior

weeks

from

the

to

period

with

larger

increases

for

younger

ages

up

to

in

last

intercourse

for

sexually

active

year

olds

-LRB-

Singh

et

al.

-RRB-

In

the

NACP

study

between

and

of

persons

in

the

three

districts

studied

reported

having

made

some

changes

in

their

sexual

behavior

the

overwhelmingly

greatest

change

made

was

in

the

reduction

in

the

number

of

partners

-LRB-

Moodie

et

al.

-RRB-

Which

changes

occurred

may

or

may

not

correspond

directly

to

what

was

promoted

by

the

program

Changes

in

HIV

prevalence

Uganda

's

sentinel

surveillance

system

was

the

earliest

and

most

elaborate

system

of

HIV

monitoring

in

Africa

at

the

time

allowing

for

continuous

monitoring

of

the

epidemic

and

help

in

planning

in

order

to

ensure

strong

enough

efforts

at

sites

-LRB-

Asiimwe-Okiror

et

al.

Moodie

et

al.

Slutkin

et

al.

Slutkin

et

al.

Stoneburner

Carballo

UNAIDS

-RRB-

These

surveillance

studies

were

supplemented

by

other

studies

The

effects

of

such

an

extensive

and

strong

surveillance

system

itself

is

unknown

but

its

use

by

the

program

as

a

monitoring

tool

to

strengthen

and

help

target

implementation

was

highly

emphasized

within

the

Uganda

program

Changes

in

HIV

seroprevalence

occurred

during

the

period

between

and

with

continued

reductions

in

and

An

analysis

past

this

period

is

beyond

the

scope

of

this

article

The

changes

in

sexual

behavior

and

in

HIV

occurred

during

and

within

two

to

three

years

of

Uganda

's

planned

and

extensively

implemented

AIDS

education

effort

U.S.

Census

and

UNAIDS

estimates

are

of

a

drop

in

Ugandan

national

prevalence

between

and

-LRB-

Singh

et

al.

US

House

of

Representatives

Hearing

on

the

Global

AIDS

crisis

and

pandemic

in

Africa

-RRB-

For

six

sentinel

surveillance

sites

measuring

changes

among

year

old

antenatal

women

reductions

occurred

from

HIV

prevalence

rates

of

in

to

to

in

-LRB-

see

Table

-RRB-

Table

prevalence

-LRB-

-RRB-

changes

in

Uganda

for

years

old

and

sentinelsurveillance

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

NS

Summary

and

conclusions

Uganda

developed

the

first

and

what

was

soon

to

become

the

strongest

planned

and

best

supported

National

AIDS

program

with

the

largest

national

and

international

staffing

and

most

intensive

broadly

inclusive

decentralized

and

community

based

public

education

program

in

Africa

When

Uganda

was

receiving

million

in

support

other

countries

in

the

region

were

receiving

between

million

to

million

External

and

national

financial

support

to

the

Uganda

program

was

to

times

the

amount

provided

to

any

other

national

program

outside

of

the

industrialized

world

at

the

time

-LRB-

Mann

Tarantola

UNAIDS

-RRB-

The

messaging

emphasized

faithfulness

and

fidelity

although

the

IEC

program

at

both

national

and

district

level

provided

information

on

all

forms

of

HIV

transmission

and

all

forms

of

protection

Information

on

delaying

age

of

onset

of

sexual

activity

and

the

protective

value

of

condoms

were

included

in

the

program

Counseling

and

testing

and

condom

promotion

were

very

small

elements

in

the

early

years

in

which

the

changes

in

seroprevalence

were

first

seen

-LRB-

Moodie

et

al.

Uganda

-RRB-

Although

condom

knowledge

was

high

and

use

increased

substantially

overall

condom

distribution

was

of

the

order

of

million

condoms/year

an

amount

of

condoms

that

could

not

have

influenced

overall

reductions

in

HIV

prevalence

as

substantial

as

observed

-LRB-

Moodie

et

al.

USAID

-RRB-

The

ABC

phrase

was

not

known

during

these

years

and

it

is

estimated

that

it

began

to

be

used

in

the

mid

after

the

changes

in

Uganda

had

already

taken

place

-LRB-

USAID

Hardee

-RRB-

This

does

not

take

away

from

the

fact

that

the

full

range

of

information

was

provided

Openness

about

AIDS

destigmatization

and

promotion

of

care

and

compassion

were

also

important

components

of

the

Ugandan

program

Abstinence

itself

was

not

specifically

promoted

on

any

posters

billboards

or

leaflets

of

the

national

program

as

far

as

we

remember

or

as

noted

in

any

of

the

reports

of

the

time

Delaying

onset

among

young

persons

was

promoted

It

was

already

known

to

WHO

at

the

time

that

providing

full

information

about

all

means

of

transmission

and

ways

of

protection

had

been

demonstrated

to

be

the

most

effective

approach

to

sexual

behavior

change

in

particular

for

non-AIDS

programs

such

as

STD

control

family

planning

and

other

programs

and

therefore

comprehensive

education

was

the

standard

guidance

of

WHO/GPA

health

education

guiding

materials

at

the

time

-LRB-

Grunsheit

UNAIDS

-RRB-

Probably

most

importantly

the

intensity

of

messaging

of

the

Uganda

program

was

far

above

any

other

program

at

the

time

We

recall

returning

from

usual

mission

travel

to

multiple

countries

in

the

region

including

Rwanda

Burundi

Kenya

Tanzania

and

sometimes

Malawi

or

Zambia

and

noting

that

there

was

no

comparison

between

what

was

going

on

in

Uganda

and

the

other

countries

This

usually

referred

to

the

amount

of

visibility

of

the

program

by

way

of

billboards

and

other

public

education

materials

and

the

amount

of

decentralized

program

activity

Nevertheless

it

was

not

our

impression

at

that

time

that

this

would

necessarily

translate

into

effective

change

The

thinking

at

the

time

was

that

there

needed

to

be

a

still

more

professionally

designed

IEC

program

with

more

of

a

strategic

basis

findings

and

criticisms

that

were

noted

in

the

program

review

and

common

among

many

of

the

review

participants

at

the

time

and

a

problem

thought

common

to

all

programs

in

the

region

It

was

a

few

years

later

that

Hornik

-LRB-

-RRB-

would

reveal

the

close

relationship

between

intensity

of

messaging

and

behavior

change

and

the

large

importance

of

intensity

for

several

other

public

health/behavior

change

issues

as

well

President

Musevini

's

commitment

and

personal

leadership

and

the

involvement

of

the

whole

government

was

well

known

to

all

staff

at

WHO

at

the

time

and

throughout

the

continent

This

allowed

open

discussion

throughout

the

country

and

even

more

so

encouraged

it

The

President

guided

all

ministers

and

other

senior

level

government

officials

to

mention

and

speak

about

AIDS

at

all

public

functions

As

a

matter

of

policy

President

Musevini

's

speeches

were

to

end

with

a

note

on

HIV/AIDS

As

far

as

we

know

no

single

speech

local

or

international

ended

without

talking

about

HIV/AIDS

A

note

was

always

left

to

himself

to

use

his

knowledge

and

imagination

to

convey

the

message

There

is

nothing

intrinsically

different

about

the

Ugandan

people

problem

or

program

although

the

Resistance

Council

structure

did

facilitate

some

aspects

of

the

decentralization

performed

and

the

post-revolutionary

nature

of

the

society

at

the

time

probably

helped

ensure

an

appropriate

amount

of

zeal

for

the

effort

However

the

implementation

of

the

program

itself

was

notably

different

as

compared

to

all

of

the

neighboring

countries

at

the

time

We

believe

that

the

principal

difference

between

the

Uganda

's

HIV/AIDS

prevention

and

education

campaign

and

that

of

neighboring

countries

relates

mostly

to

the

intensity

depth

breadth

and

extensiveness

of

programming

of

its

behavior

change

campaign

the

level

of

involvement

of

all

sectors

the

pragmatism

and

extension

of

the

district

level

work

deep

into

communities

including

the

involvement

of

local

churches

and

mosques

and

the

high

level

of

financial

support

that

allowed

this

to

occur

Although

there

are

several

matters

different

about

the

HIV/AIDS

situation

now

most

notably

the

increased

availability

of

drug

treatment

it

is

still

believed

that

given

the

full

support

proper

planning

and

strength

of

implementation

serious

HIV/AIDS

prevention

and

public

education

campaigns

of

this

nature

still

largely

missing

in

Africa

could

and

should

be

implemented

in

almost

any

country

with

this

degree

of

problem

or

risk

of

problem

For

the

most

part

in

the

late

and

early

the

other

countries

in

Africa

were

thought

to

be

simply

behind

Uganda

in

planning

implementation

and

in

their

own

movement

toward

enhanced

support

The

Uganda

program

was

the

first

program

and

for

this

reason

as

well

as

reasons

of

high

donor

concern

obtained

very

strong

financial

and

other

support

Uganda

also

had

the

commitment

and

the

ability

to

mobilize

and

decentralize

the

program

and

to

develop

the

management

capacity

to

implement

the

IEC

program

at

this

broad

and

high

level

of

effort

Beginning

in

the

early

and

mid

serious

interruptions

in

programming

in

neighboring

countries

began

to

occur

as

the

WHO/GPA

global

effort

began

to

be

less

globally

coordinated

more

bilaterally

fragmented

and

less

prevention

focused

for

various

reasons

partially

explained

elsewhere

but

which

include

the

change

in

leadership

at

WHO

the

international

preference

for

bilateral

support

and

a

move

toward

UN/WHO

coordination

and

consolidation

without

sufficient

attention

at

the

time

to

ensuring

preservation

of

all

relevant

functions

and

priority

to

prevention

-LRB-

Slutkin

-RRB-

Some

barriers

to

implementation

and

support

may

still

exist

in

some

countries

but

there

is

no

technical

or

program

reason

that

the

authors

see

today

as

to

why

all

or

most

other

countries

could

not

perform

similar

reversals

today

with

appropriate

planning

implementation

and

intensity

of

effort

and

support

to

reverse

their

HIV/AIDS

epidemics

With

million

people

being

newly

infected

each

year

and

treatment

lagging

further

and

further

behind

programs

with

this

leadership

programming

and

intensity

of

effort

need

to

be

common

rather

than

rare

Authors

Biography

Dr.

Slutkin

was

the

WHO/SPA

and

then

WHO/GPA

epidemiologist

assigned

to

support

the

Uganda

program

from

He

also

co-developed

-LRB-

along

with

Drs.

Chin

and

Tarantola

-RRB-

the

serosurveillance

methods

used

to

monitor

trends

in

HIV

within

and

among

all

countries

-LRB-

global

-RRB-

and

supported

the

other

countries

of

Central

and

East

Africa

during

the

same

years

Dr.

Sam

Okware

was

the

director

of

the

National

AIDS

Programme

of

Uganda

Dr.

Warren

Naamara

was

the

epidemiologist

responsible

for

the

serosurveillance

system

of

Uganda

and

director

of

the

Uganda

ACP

from

Dr.

Don

Sutherland

was

the

WHO

Team

Leader

and

epidemiologist

assigned

to

Uganda

following

the

work

of

Dr.

Ros

Widi-Wirski

now

deceased

whose

trip

reports

were

consulted

Donna

Flanagan

was

the

health

educator

assigned

to

Uganda

from

Dr.

Erik

Blas

provided

the

logistic

managerial

and

financial

back-up

support

to

the

Uganda

program

as

well

as

dozens

of

other

programs

around

the

world

from

WHO/GPA

Dr.

Paul

Delay

was

the

epidemiologist

of

the

Malawi

AIDS

program

and

then

the

global

USAID

program

director

for

AIDS

and

subsequently

Chief

of

Monitoring

and

Evalution

for

UNAIDS

Dr.

Michel

Carael

worked

in

the

social

and

behavioral

research

unit

of

WHO/GPA

Dr.

Daniel

Tarantola

the

Chief

National

Programme

Support

was

responsible

for

all

national

programs

globally

for

WHO/GPA

During

this

time

frame

Dr.

Tarantola

supervised

the

development

of

over

national

programs

The

authors

would

also

like

to

acknowledge

Adjoa

Amana

the

driving

force

for

the

IEC

training

and

messaging

in

the

period

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