dr penny moore
DESCRIPTION
C APRISA. CENTRE FOR THE AIDS PROGRAMME OF RESEARCH IN SOUTH AFRICA. CAPRISA is a UNAIDS Collaborating Centre for HIV Prevention Research. Characterization of acute infection in South Africa and its relevance to HIV vaccine discovery - focus on neutralizing antibodies. Dr Penny Moore. - PowerPoint PPT PresentationTRANSCRIPT
Characterization of acute infection in South Africa and its relevance to HIV vaccine
discovery - focus on neutralizing antibodies
Dr Penny Moore
CENTRE FOR THE AIDS PROGRAMME OF CENTRE FOR THE AIDS PROGRAMME OF RESEARCH IN SOUTH AFRICARESEARCH IN SOUTH AFRICACCAPRISAAPRISA CAPRISA is a UNAIDS CAPRISA is a UNAIDS
Collaborating Centre for HIV Collaborating Centre for HIV Prevention ResearchPrevention Research
AIDS Virus Research Unit, National Institute for Communicable Diseases, Johannesburg, South Africa
Salim Abdool Karim, PIKoleka MlisanaThumbi Ndung’u
Carolyn Williamson Joanne Passmore
Lynn MorrisClive Gray
Winston Hide
Registration Number: 2002/024027/08 http://www.caprisa.org
CENTRE FOR THE AIDS PROGRAMME OF RESEARCH IN SOUTH AFRICACAPRISA CAPRISA is a UNAIDS
Collaborating Centre for HIV Prevention Research
Western Cape
Eastern Cape
Northern Cape
North West
Free State
Northern Province
Gauteng
KwaZuluNatal
Mpumalanga
Durban
Vulindlela
Introduction – neutralizing antibodies
Neutralizing antibody (nAb) responses develop in most HIV-1 infected individuals within a few months of infection (Moog et al, 1997; Richman et al, 2003; Wei et al, 2004)
Much of the variation that occurs in Env during early infection may be due to nAb pressure (Frost, 2005)
Neutralization escape extensively documented in HIV-1 subtype B and SIV – substitutions, indels, glycan shifts (Richman et al, 2003; Wei et al, 2004)
Autologous nAb response in subtype C develop to higher titres and show greater type-specificity (Li et al, 2006; Gray et al, 2007)
CENTRE FOR THE AIDS PROGRAMME OF CENTRE FOR THE AIDS PROGRAMME OF RESEARCH IN SOUTH AFRICARESEARCH IN SOUTH AFRICACCAPRISAAPRISA CAPRISA is a UNAIDS CAPRISA is a UNAIDS
Collaborating Centre for HIV Collaborating Centre for HIV Prevention ResearchPrevention Research
CENTRE FOR THE AIDS PROGRAMME OF CENTRE FOR THE AIDS PROGRAMME OF RESEARCH IN SOUTH AFRICARESEARCH IN SOUTH AFRICACCAPRISAAPRISA CAPRISA is a UNAIDS CAPRISA is a UNAIDS
Collaborating Centre for HIV Collaborating Centre for HIV Prevention ResearchPrevention Research
Autologous neutralizing responses(n=14)
0 10 20 30 40 50 60 70 80 90 10010
100
1000
10000
Controllers (n=3)Rapid progressors (n=3)Intermediate progressors (n=8)
weeks post-infection
Ave
rag
e ac
cum
ula
ted
neu
tral
izat
ion
Median initial autologous response is 19 weeks post-infection
Development of the autologous neutralizing antibody response in early subtype C infection
CCAPRISAAPRISAGray ES, Moore PL et al., JV 2007
CCAPRISAAPRISA
CAP 8 CAP 45 CAP 61 CAP 63 CAP 84 CAP 85 CAP 88 CAP 206 CAP 210 CAP 228 CAP 239 CAP 244 CAP 255 CAP 256CAP 8 733 <20 40 <20 29 248 <20 37 <20 <20 <20 29 23 <20CAP 45 <20 6199 <20 <20 <20 <20 <20 <20 <20 <20 <20 <20 <20 <20CAP 61 <20 <20 54 <20 145 84 <20 <20 <20 <20 32 <20 <20 <20CAP 63 <20 <20 <20 5490 <20 <20 <20 <20 <20 <20 <20 <20 <20 <20CAP 84 <20 <20 <20 <20 2585 21 <20 <20 <20 <20 <20 <20 <20 <20CAP 85 29 <20 <20 113 <20 1697 <20 <20 <20 <20 <20 <20 <20 <20CAP 88 <20 <20 <20 <20 <20 33 1097 <20 <20 <20 <20 <20 <20 <20CAP 206 <20 <20 <20 <20 <20 236 <20 2425 <20 <20 <20 <20 <20 <20CAP 210 <20 <20 <20 <20 <20 <20 <20 <20 138 <20 <20 <20 <20 <20CAP 228 <20 36 <20 <20 27 41 <20 51 <20 405 <20 <20 <20 <20CAP 239 <20 <20 37 <20 28 <20 <20 <20 <20 <20 3841 <20 <20 <20CAP 244 <20 <20 <20 <20 <20 <20 <20 <20 <20 <20 <20 416 <20 <20CAP 255 <20 <20 96 <20 <20 78 <20 <20 <20 <20 67 <20 2163 <20CAP 256 <20 195 27 <20 <20 <20 <20 <20 <20 <20 85 <20 <20 188
12th months serum
Enrolment virus
<2020-5050-100100-500500-1000
>1000
Gray ES, Moore PL et al., JV 2007
The Early Neutralizing Antibody Response at 1 Year is Highly Type-specific
V1V2 C3-V4 C3 V4 V5CAP45 ++ ++ - - -CAP84 - +++ - - +/-CAP63 - +++ - +/- -CAP88 ++ +++ +++ - -
Moore PL, Gray ES et al., JV 2008 CCAPRISAAPRISA
The Major Target of the Early Autologous Neutralizing Antibody Response is the C3-V4 Region of the HIV-1
Subtype C Envelope
Numbers and kinetics of autologous nAbs in early infection is not known
0 25 50 75 100 12540
400
4000
40000 88.1m.c1788.6m.c1088.6m.c4488.12m.c288.12m.c1788.12m.c2388.12m.c4588.12m.c46
Weeks p.i.
Tit
er
Neutralization escape in HIV-1 subtype C – CAP88
SGA derived clones from 1 month, 6 months and 12 months p.i. were tested against plasma spanning 2 years p.i. to assess neutralization escape.
12 months p.i.
6 months p.i.
1 month p.i.
Peak 1 Peak 2
Moore et al., PLoS Pathogens, in press
0 25 50 75 100 12540
400
4000
40000 88.1m.c17
63/88/63-C3
CAP6363/88/63-V1V2
Weeks p.i.
Tit
erAnti-C3 Anti-V1V2
Temporal variations in neutralization titers correspond to waves of evolving specificities – CAP88
Use of heterologous chimeric envelopes suggest:
• initial anti-C3 response develops, peaking at 26 weeks p.i., then waning.
• second anti-V1V2 response peaking at 81 weeks p.i.
Moore et al., PLoS Pathogens, in press
α2helix __________________ [ V1 V2 ] [ C3 ] ____________________________ _______________________________________ __________________________________________________ 88.1mo.6A CTNVTVVNATHTNKSMNGEIDMKEEMKNCSFKTTTGIRGKKQTEYALFYRPDIVPLSKESSEYILISC KDRWIATLEKVKKKLEEHFPNKTKIKFAPSSGGDLEVTTHSFNCGGEFFY 88.1mo.17 .................................................................... .................................................. 88.1mo.6B ...................T................................................ .................................................. 88.1mo.9 .................................................................... .................................................. 88.1mo.15 .................................................................... .................................................. 88.6mo.29 ................D................................................... ....N............................................. 88.6mo.5 .............T............................................G......... ....N...K......................................... 88.6mo.2 .................E.................................................. ....N...K......................................... 88.6mo.25 .................................................................... ....N...K......................................... 88.6mo.48 .................................................................... ....N...K......................................... 88.6mo.44 ...............R.................................................... ....N..........K.................................. 88.6mo.10 .................E.................................................. ....N..........K.................................. 88.6mo.21 .................E.................................................. ....N..........K.................................. 88.12mo.15 ................T.........................................D--....... ....N..........A.................................. 88.12mo.23 ...............R.........................................NS--....... ....N................N............................ 88.12mo.17 .................V.T......................................D--....... ....N..........K.......-.......................... 88.12mo.35 ................T.........................................D--....... ....N...K..............-.......................... 88.12mo.47 .................V.T......................................D--....... ....N...K..............-.......................... 88.12mo.1 .............R.....T..............P.....E................N.......... ....S..................-.......................... 88.12mo.2 ..................--..............P.....E................N.......... ....N..........K.......-.......................... 88.12mo.46 ..................--....................EK...............N.......... ....N..................-.......................... 88.12mo.16 ..................--..............P.....E................N.......... ....N..................-.......................... 88.12mo.45 ...I..............--.................I..................NN.......... ....N...........K......-.......................... 88.12mo.25 .............R....................-......................N.......... ....N..................-.......................... 88.12mo.21 .............R.....T..............-......................N.......... ....N..................-.......................... 88.12mo.31 ..................--...........Q..P.....................GN.......... ....N..................-..........................
Escape mutations in CAP88
CENTRE FOR THE AIDS PROGRAMME OF CENTRE FOR THE AIDS PROGRAMME OF RESEARCH IN SOUTH AFRICARESEARCH IN SOUTH AFRICACCAPRISAAPRISA CAPRISA is a UNAIDS CAPRISA is a UNAIDS
Collaborating Centre for HIV Collaborating Centre for HIV Prevention ResearchPrevention Research
CENTRE FOR THE AIDS PROGRAMME OF CENTRE FOR THE AIDS PROGRAMME OF RESEARCH IN SOUTH AFRICARESEARCH IN SOUTH AFRICACCAPRISAAPRISA CAPRISA is a UNAIDS CAPRISA is a UNAIDS
Collaborating Centre for HIV Collaborating Centre for HIV Prevention ResearchPrevention Research
0 25 50 75 100 12540
400
4000
4000088.1m.c17
88.12m.c2
88.12m.c2-V1V2s
88.12m.c2-V1V2s,C3s
88.6m.c10
Weeks p.i.
Tit
er0 25 50 75 100 125
40
400
4000
40000 88.1m.c1788.6m.c1088.6m.c10-C3s
weeks p.i.
Tit
re
Escape at 6 months p.i. is mediated by 2 amino acid changes in C3
Escape at 12 months p.i. is mediated by changes in V1V2 (and C3)
Limited nAb specificities drive sequential escape mutations – CAP88 cont
CENTRE FOR THE AIDS PROGRAMME OF CENTRE FOR THE AIDS PROGRAMME OF RESEARCH IN SOUTH AFRICARESEARCH IN SOUTH AFRICACCAPRISAAPRISA CAPRISA is a UNAIDS CAPRISA is a UNAIDS
Collaborating Centre for HIV Collaborating Centre for HIV Prevention ResearchPrevention Research
CENTRE FOR THE AIDS PROGRAMME OF CENTRE FOR THE AIDS PROGRAMME OF RESEARCH IN SOUTH AFRICARESEARCH IN SOUTH AFRICACCAPRISAAPRISA CAPRISA is a UNAIDS CAPRISA is a UNAIDS
Collaborating Centre for HIV Collaborating Centre for HIV Prevention ResearchPrevention Research
Limited and sequential nAb specificities drive sequential escape mutations – CAP177
Escape at 6 months p.i. is mediated by changes in C3
Escape at 12 months p.i. is mediated by changes in V1V2
In CAP88 and CAP177, nAbs first target the C3 region, then the V1V2 loop
The V1V2 region is a target of autologous nAbs and changes within V1V2 mediate escape – CAP210
V1V2 is the nAb target in CAP210 (heterologous chimera data)
Escape at 12 months p.i. is mediated by changes in V1V2
CENTRE FOR THE AIDS PROGRAMME OF CENTRE FOR THE AIDS PROGRAMME OF RESEARCH IN SOUTH AFRICARESEARCH IN SOUTH AFRICACCAPRISAAPRISA CAPRISA is a UNAIDS CAPRISA is a UNAIDS
Collaborating Centre for HIV Collaborating Centre for HIV Prevention ResearchPrevention Research
CENTRE FOR THE AIDS PROGRAMME OF CENTRE FOR THE AIDS PROGRAMME OF RESEARCH IN SOUTH AFRICARESEARCH IN SOUTH AFRICACCAPRISAAPRISA CAPRISA is a UNAIDS CAPRISA is a UNAIDS
Collaborating Centre for HIV Collaborating Centre for HIV Prevention ResearchPrevention Research
A single specificity mediates neutralization of CAP45
0 25 50 75 100 12540
400
4000
4000045.2wk.c945.12m.c7
45.12m.c7 E460K/G462D
Weeks p.i.
Tit
er
CENTRE FOR THE AIDS PROGRAMME OF CENTRE FOR THE AIDS PROGRAMME OF RESEARCH IN SOUTH AFRICARESEARCH IN SOUTH AFRICACCAPRISAAPRISA CAPRISA is a UNAIDS CAPRISA is a UNAIDS
Collaborating Centre for HIV Collaborating Centre for HIV Prevention ResearchPrevention Research
CENTRE FOR THE AIDS PROGRAMME OF CENTRE FOR THE AIDS PROGRAMME OF RESEARCH IN SOUTH AFRICARESEARCH IN SOUTH AFRICACCAPRISAAPRISA CAPRISA is a UNAIDS CAPRISA is a UNAIDS
Collaborating Centre for HIV Collaborating Centre for HIV Prevention ResearchPrevention Research
K460E,D462G/K460E [ (V5) ] __________________ 45.2wks.9 TRDGGKTDRNDTEIFRPG 45.2wks.8 .................. 45.2wks.A5 .................. 45.2wks.A2 .................. 45.2wks.A4 .................. 45.2wks.B12 .................. 45.2wks.B9 .................. 45.2wks.B1 .................. 45.2wks.B8 .................. 45.2wks.B10 .................. 45.2wks.TA1 .................. 45.2wks.B4 .................. 45.4mo.14 .......G.......... 45.4mo.19 .....---.......... 45.4mo.20 .......G.......... 45.4mo.23 .......G.......... 45.4mo.26 .......G.......... 45.4mo.3 .......G.......... 45.4mo.7 .......G.......... 45.8mo.40 .....E............ 45.8mo.9 .......G.......... 45.8mo.15 .......G.......... 45.8mo.18 .......G...A...... 45.8mo.22 .......G.......... 45.8mo.24 .......G...A...... 45.8mo.27 .......G.......... 45.8mo.7 ...*...G.......... 45.8mo.47 .......G.......... 45.8mo.43 .......G...A...... 45.12mo.7 .....E.G.......... 45.12mo.8 .....E.G.......... 45.12mo.17 .....E..K......... 45.12mo.19 .....E.G..........
K460E,D462G/K460E [ (V5) ] __________________ 45.2wks.9 TRDGGKTDRNDTEIFRPG 45.2wks.8 .................. 45.2wks.A5 .................. 45.2wks.A2 .................. 45.2wks.A4 .................. 45.2wks.B12 .................. 45.2wks.B9 .................. 45.2wks.B1 .................. 45.2wks.B8 .................. 45.2wks.B10 .................. 45.2wks.TA1 .................. 45.2wks.B4 .................. 45.4mo.14 .......G.......... 45.4mo.19 .....---.......... 45.4mo.20 .......G.......... 45.4mo.23 .......G.......... 45.4mo.26 .......G.......... 45.4mo.3 .......G.......... 45.4mo.7 .......G.......... 45.8mo.40 .....E............ 45.8mo.9 .......G.......... 45.8mo.15 .......G.......... 45.8mo.18 .......G...A...... 45.8mo.22 .......G.......... 45.8mo.24 .......G...A...... 45.8mo.27 .......G.......... 45.8mo.7 ...*...G.......... 45.8mo.47 .......G.......... 45.8mo.43 .......G...A...... 45.12mo.7 .....E.G.......... 45.12mo.8 .....E.G.......... 45.12mo.17 .....E..K......... 45.12mo.19 .....E.G..........
Moore et al., PLoS Pathogens, in press
Summary of autologous neutralizing antibody targets Summary of autologous neutralizing antibody targets and escape mutationsand escape mutations
CAP88 CAP210CAP177CAP45
C3V4 α2-helix
V1V2 V1V2 V1V2
α2-helix
V1V2V1V2V1V2V5
α2-helix
NeutralizationTargets
Escapemutations
Early targets
Later targets
Early escape mutations
Later escape mutations
Not known
5 10 15 20 25 30
0
25
50
75
100
% Neutralization
100
1000
10000
100000
1000000
VL (overall)WT VL (VL x proportion WT)Mut VL (VL x proportion Mut)
Weeks p.i.
% n
eutr
aliz
atio
n a
t 1:
45d
ilu
tio
n
VL
(cop
ies / ml)
5 10 15 20 25 300
25
50
75
100 Wildtype (I339)Mutant (I339N)
% Neutralization
0
25
50
75
100
Weeks p.i.
% n
eutr
aliz
atio
n a
t 1:
45d
ilu
tio
n
% o
f po
pu
lation
Do autologous nAbs affect viral load?
7-fold 4-fold
CENTRE FOR THE AIDS PROGRAMME OF CENTRE FOR THE AIDS PROGRAMME OF RESEARCH IN SOUTH AFRICARESEARCH IN SOUTH AFRICACCAPRISAAPRISA CAPRISA is a UNAIDS CAPRISA is a UNAIDS
Collaborating Centre for HIV Collaborating Centre for HIV Prevention ResearchPrevention Research
CENTRE FOR THE AIDS PROGRAMME OF CENTRE FOR THE AIDS PROGRAMME OF RESEARCH IN SOUTH AFRICARESEARCH IN SOUTH AFRICACCAPRISAAPRISA CAPRISA is a UNAIDS CAPRISA is a UNAIDS
Collaborating Centre for HIV Collaborating Centre for HIV Prevention ResearchPrevention Research
The relationship between autologous nAbs and the development of cross-neutralizing breadth
A vaccine should aim to elicit cross-neutralizing antibodies
The specificities of antibodies in sera with neutralization breadth are largely unknown (Binley et al, 2008; Sather et al, 2009; Gray
et al, in press )
The mechanisms that lead to the development of breadth are not known – likely to be dependent in part on the autologous infecting envelopes (Rademeyer et al, 2007)
The contribution of autologous neutralizing antibodies to the development of breadth has not been explored
CENTRE FOR THE AIDS PROGRAMME OF CENTRE FOR THE AIDS PROGRAMME OF RESEARCH IN SOUTH AFRICARESEARCH IN SOUTH AFRICACCAPRISAAPRISA CAPRISA is a UNAIDS CAPRISA is a UNAIDS
Collaborating Centre for HIV Collaborating Centre for HIV Prevention ResearchPrevention Research
CENTRE FOR THE AIDS PROGRAMME OF CENTRE FOR THE AIDS PROGRAMME OF RESEARCH IN SOUTH AFRICARESEARCH IN SOUTH AFRICACCAPRISAAPRISA CAPRISA is a UNAIDS CAPRISA is a UNAIDS
Collaborating Centre for HIV Collaborating Centre for HIV Prevention ResearchPrevention Research
The Neutralizing Antibody Response at 3 Years post-infection shows increased breadth
ConC Du156 Du422 CAP206 CAP210 CAP228 ZM53M ZM135M ZM197M ZM214M CAAN AC10 6535 Q23 Q842
12 1 8 E8 51 PB12 PL10a PB7 PL15 5342 0.29 3 17 d12
CAP8 >1245 299 48 <45 <45 <45 <45 <45 51 <45 155 169 439 636 <45 40%
CAP40 <45 <45 <45 <45 <45 <45 <45 46 <45 <45 <45 <45 <45 <45 <45 0%CAP45 nd <45 <45 <45 <45 <45 <45 <45 <45 <45 <45 <45 <45 <45 <45 0%CAP61 nd <45 <45 <45 <45 <45 <45 <45 <45 <45 <45 <45 <45 <45 <45 0%CAP65 nd <45 <45 <45 <45 <45 <45 <45 <45 <45 <45 <45 <45 <45 <45 0%CAP84 nd <45 <45 <45 <45 <45 <45 <45 <45 <45 <45 <45 <45 69 <45 0%CAP85 nd 276 74 <45 <45 <45 <45 <45 201 <45 <45 <45 172 <45 <45 20%CAP88 nd <45 <45 <45 <45 <45 <45 <45 <45 <45 <45 <45 <45 <45 <45 0%CAP129 341 <45 <45 <45 <45 166 <45 <45 51 56 <45 <45 151 <45 <45 20%CAP137 <45 <45 <45 <45 <45 <45 <45 <45 <45 <45 <45 <45 <45 <45 <45 0%CAP177 1053 219 106 <45 122 145 <45 162 <45 <45 261 787 386 626 <45 67%
CAP200 nd <45 <45 <45 <45 <45 <45 <45 <45 <45 <45 <45 <45 <45 187 7%CAP206 <45 692 388 >1245 <45 <45 <45 107 751 <45 <45 111 <45 736 <45 43%
CAP217 <45 309 136 624 121 <45 <45 424 <45 <45 <45 <45 <45 <45 <45 33%CAP221 <45 <45 <45 <45 <45 <45 <45 <45 <45 <45 <45 <45 <45 <45 <45 0%CAP222 <45 <45 <45 <45 71 <45 <45 53 <45 <45 <45 <45 <45 <45 <45 0%CAP225 nd <45 <45 <45 <45 <45 <45 <45 <45 <45 <45 <45 <45 <45 <45 0%CAP228 nd <45 <45 <45 <45 310 <45 <45 <45 <45 <45 <45 46 69 <45 0%CAP229 nd <45 <45 <45 <45 <45 <45 <45 <45 <45 <45 <45 46 <45 <45 0%CAP239 187 <45 786 <45 52 <45 <45 <45 <45 <45 <45 <45 170 576 <45 27%CAP244 nd <45 <45 <45 <45 <45 <45 <45 <45 <45 <45 <45 <45 96 <45 0%CAP248 >1245 160 147 841 511 535 <45 <45 98 <45 <45 <45 210 331 248 60%
CAP255 392 520 334 <45 <45 <45 <45 <45 <45 <45 81 49 112 624 <45 33%CAP256 >1245 >1245 >1245 >1245 >1245 >1245 >1245 69 216 920 <45 48 581 >1245 658 80%CAP257 >1245 143 147 78 <45 95 99 63 84 386 <45 <45 88 615 373 40%
CAP261 193 62 <45 <45 64 66 <45 <45 131 <45 <45 <45 <45 <45 <45 13%CAP262 104 <45 <45 <45 <45 <45 <45 <45 <45 <45 <45 <45 <45 <45 <45 7%CAP264 <45 47 <45 183 <45 <45 57 86 <45 <45 <45 <45 <45 <45 <45 7%
nd: not done
% viruses neutralized
Viruses (ID50 titer)
Serum ID
Subtype C Subtype B Subtype A
See poster by Maphuti Madiga, MOPEA003 - “Development of intra- and inter-subtype cross-neutralizing antibodies in HIV-1 subtype C infection”
CAP256 80%
0 25 50 75 100 125 15010
100
1000
10000
100000 CAP256 (AUTOLOGOUS)
Weeks PI
ID50
Development of the autologous neutralizing response in CAP256
Note: CAP256 was super-infected at about 13 weeks p.i. – Carolyn Williamson et al, unpublished data
0 25 50 75 100 12510
100
1000
10000CAP25684-256-84 V1V2CAP84
super-infection(13 w eeks p.i.)
weeks p.i.
Tit
re
Specificity of the autologous neutralizing response in CAP256
Use of heterologous chimeric envelopes suggest an initial (unknown) specificity, followed by an anti-V1V2 response
0 25 50 75 100 125 15010
100
1000
10000
100000
CAP210
ZM53M
ZM109F
ZM233M
WITO4160
Q23
+6CAP256 (AUTOLOGOUS)
Weeks PI
ID50
Development of the heterologous neutralizing response in CAP256
0 25 50 75 100 125 15010
100
1000
10000
100000
CAP206
CAP210
CAP239
CAP63
CAP255
Du156
Du422
ZM53M
ZM109F
ZM197M
ZM233M
WITO4160
6535
Q23
+6 +9CAP256 (AUTOLOGOUS)
CAP45
Weeks PI
ID50
Development of the heterologous neutralizing response in CAP256
0 25 50 75 100 125 15010
100
1000
10000
100000
CAP8
CAP61
CAP206
CAP210
CAP239
CAP228
CAP63
CAP255
CAP84
Du156
Du422
ZM53M
ZM109F
ZM197M
ZM233M
WITO4160
6535
Q461
Q23
Q842
Q168
+6 +9 +2 +1 +4CAP256 (AUTOLOGOUS)
CAP45
Weeks PI
ID50
Development of the heterologous neutralizing response in CAP256
See poster by Maphuti Madiga, MOPEA003 - “Development of intra- and inter-subtype cross-neutralizing antibodies in HIV-1 subtype C infection”
CAP256(autologous)
0 25 50 75 100 12510
100
1000
10000CAP25684-256-84 V1V2CAP84
super-infection(13 weeks p.i.)
weeks p.i.
Tit
re
CAP45
0 25 50 75 100 12510
100
1000
10000
100000
CAP84
CAP45 G384-45-84 V1V2
weeks p.i.
Tit
re
CAP63
0 25 50 75 100 12510
100
1000
CAP88 B5
CAP63 A988-63-88 V1V2
weeks p.i.
Tit
re
CAP210
0 25 50 75 100 12510
100
1000
10000
100000
CAP8484-210-84 V1V2CAP210
weeks p.i.
Tit
re
CAP239
0 25 50 75 100 12510
100
1000
10000
CAP84
CAP23984-239-84 V1V2
weeks p.i.
Tit
re
CAP255
0 25 50 75 100 12510
100
1000
CAP84
CAP25584-255-84 V1V2
weeks p.i.
Tit
re
Specificity of the heterologous neutralizing response in CAP256 mirrors the specificity of the autologous
response
V1V2 involved in epitope V1V2 not involved in epitope
Conclusions
One or two potent but highly-type specific neutralizing antibody specificities develop in the first year of infection
The C3 and V1V2 regions are frequent targets, and changes in these regions directly mediate escape
These antibody specificities arise sequentially with titers waning as escape occurs
CENTRE FOR THE AIDS PROGRAMME OF CENTRE FOR THE AIDS PROGRAMME OF RESEARCH IN SOUTH AFRICARESEARCH IN SOUTH AFRICACCAPRISAAPRISA CAPRISA is a UNAIDS CAPRISA is a UNAIDS
Collaborating Centre for HIV Collaborating Centre for HIV Prevention ResearchPrevention Research
CENTRE FOR THE AIDS PROGRAMME OF CENTRE FOR THE AIDS PROGRAMME OF RESEARCH IN SOUTH AFRICARESEARCH IN SOUTH AFRICACCAPRISAAPRISA CAPRISA is a UNAIDS CAPRISA is a UNAIDS
Collaborating Centre for HIV Collaborating Centre for HIV Prevention ResearchPrevention Research
Conclusions
Autologous nAbs were temporally associated with decreased viral load in CAP88, which was abrogated by escape mutations
In CAP256, antibodies mediating autologous neutralization contributed to heterologous neutralization and this involved determinants in the V1V2 region.
CENTRE FOR THE AIDS PROGRAMME OF CENTRE FOR THE AIDS PROGRAMME OF RESEARCH IN SOUTH AFRICARESEARCH IN SOUTH AFRICACCAPRISAAPRISA CAPRISA is a UNAIDS CAPRISA is a UNAIDS
Collaborating Centre for HIV Collaborating Centre for HIV Prevention ResearchPrevention Research
CENTRE FOR THE AIDS PROGRAMME OF CENTRE FOR THE AIDS PROGRAMME OF RESEARCH IN SOUTH AFRICARESEARCH IN SOUTH AFRICACCAPRISAAPRISA CAPRISA is a UNAIDS CAPRISA is a UNAIDS
Collaborating Centre for HIV Collaborating Centre for HIV Prevention ResearchPrevention Research
Acknowledgements
CAPRISA 002 Salim Abdool Karim (PI, UKZN)Koleka Mlisana (co-chair, UKZN)Carolyn Williamson (co-chair, UCT)CAPRISA 002 study team
NICD Lynn Morris Nthabeleng RanchobeBronwen LambsonElin GrayMaphuti MadigaEleanor CaveSarah CohenMary Phoswa
UCTCarolyn WilliamsonMelissa Rose-AbrahamsGama BandaweFlorette Treurnicht
CAPRISA is supported by the National Institute of Allergy and infectious Disease (NIAID), National Institutes of Health (NIH) (grant# AI51794), the National Research Foundation (grant # 67385), the Columbia University-Southern African Fogarty AIDS International Training and Research Programme (AITRP) funded by the Fogarty International Center, NIH (grant # D43TW00231) and a training grant from LifeLab, a biotechnology centre of the South African Government Department of Science and Technology.Columbia University - Southern Africa Fogarty AIDS International Training and Research Program (AITRP)
CENTRE FOR THE AIDS PROGRAMME OF CENTRE FOR THE AIDS PROGRAMME OF RESEARCH IN SOUTH AFRICARESEARCH IN SOUTH AFRICACCAPRISAAPRISA CAPRISA is a UNAIDS CAPRISA is a UNAIDS
Collaborating Centre for HIV Collaborating Centre for HIV Prevention ResearchPrevention Research
CENTRE FOR THE AIDS PROGRAMME OF CENTRE FOR THE AIDS PROGRAMME OF RESEARCH IN SOUTH AFRICARESEARCH IN SOUTH AFRICACCAPRISAAPRISA CAPRISA is a UNAIDS CAPRISA is a UNAIDS
Collaborating Centre for HIV Collaborating Centre for HIV Prevention ResearchPrevention Research