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Development of a Database for Caribbean HIV Molecular Diversity: Relevance to HIV Vaccines & Therapy

Institute of Human Virology Division of Epidemiology and Prevention. Development of a Database for Caribbean HIV Molecular Diversity: Relevance to HIV Vaccines & Therapy. Farley R. Cleghorn MD, MPH Division of Epidemiology and Prevention Institute of Human Virology University of Maryland

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Development of a Database for Caribbean HIV Molecular Diversity: Relevance to HIV Vaccines & Therapy

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  1. Institute of Human Virology Division of Epidemiology and Prevention Development of a Database for Caribbean HIV Molecular Diversity:Relevance to HIV Vaccines & Therapy Farley R. Cleghorn MD, MPH Division of Epidemiology and Prevention Institute of Human Virology University of Maryland March 6, 2004 Santo Domingo Cleghorn 20020349

  2. A, B, AB recombinant CRF02_AG, other recombinants A Insufficient data B CRF01_AE, B C B, BF recombinant F,G,H,J,K,CRF01 other recombinants D B, C, BC recombinant GLOBAL DISTRIBUTION OF HIV-1 SUBTYPES AND RECOMBINANTS F. McCutchan & J. Carr, 2003

  3. Institute of Human Virology Division of Epidemiology and Prevention A Distinctive Clade B HIV-1 is Heterosexually Transmitted in Trinidad & Tobago:Epidemiologic Characterization of Trinidad Isolates Characterized for Phylogenetic Analysis N.A. = North American; STD = Sexually Transmitted Disease; GUD = Genital Ulcerative Disease Cleghorn et al, Proc Natl Acad Sci USA, 27 (19); 10532-10537, 2000.

  4. A Distinctive Clade B HIV-1 is Heterosexually Transmitted in Trinidad & Tobago: Comparison of Trinidad Consensus V3 loop sequence to Prototypic B Results I Institute of Human Virology Division of Epidemiology and Prevention B-subtype CTRPNNNTRK SIHIGPGRAF YTTGEIIGDI RQAHC RH0011 .......... .......Q.. .-........ ..... QZ2226 .........R ..P.....V. .-........ ..... QZ2269 .......... .V.....K.. .-........ ..... QZ2291 .......... ...L...A.. F-........ ..... QZ2313 .......... G.P....SV. .-........ ..... QZ2432 .......... G......G.. .T..D..... .K... QZ2551 .I........ ........T. .-........ ..... QZ2704 .......... .......SV. .-........ ..... QZ4734 .......... ..N....... .-........ ..... QZ6698 ....S....R ...F...A.. .-........ ..... QH0016 .......... .....A.K.L .-........ ..... QH0020 .......... ..P....SV. .-........ ..... QH0060 .........R ...M...KV. .-........ ..... QH0065 .......... G.T....SV. .-........ ..... QH0132 .........R G..M...K.Y F-........ ..... QH0136 .........R D.T.....V. .-........ ..... QH0515 .......... ....EA.K.L .-........ ..... QH0550 .........R D.A....KV. .-......N. ..... QH0605 .......... G......KV. C-....V... ..... QH0679 .......... .......... .A......N. ..... QH0692 ....G..... .......... .A..D..... ..... QH0705 .......... ...L.A...L .-........ ..... QH0788 .........E ..N....... .Y........ ..... QH0791 .......... G.T.....VS .-....V... ..V.. QH0850 .......... ...L.A.K.L .-........ ..... QH0864 .........R ...M...K.L F-........ ..... QH0865 .......... ..P....... .A......N. ..... QH0908 .........R GVT.....V. .-...VT... ..... QH0944 .I........ .......... .-..D..... ..... QH1116 .......... ...M.....L .-........ ..... QH1420 .......... ...L.A...L .-........ ..... Trinidad .......... .......... .-........ ..... Consensus Cleghorn et al, Proc Natl Acad Sci USA, 27 (19); 10532-10537, 2000.

  5. Institute of Human Virology Division of Epidemiology and Prevention A Distinctive Clade B HIV-1 is Heterosexually Transmitted in Trinidad & Tobago: Mean Pairwise Genetic Distances of Trinidad HIV-1 “Signature” C2-V5 Sequences by Year Only those samples with the threonine deletion (N=25) were used for this analysis, which calculates a summary measure per annum of inter-case sequence variability. Cleghorn et al, Proc Natl Acad Sci USA, 27 (19); 10532-10537, 2000.

  6. Institute of Human Virology Division of Epidemiology and Prevention A Distinctive Clade B HIV-1 is Heterosexually Transmitted in Trinidad & Tobago: HIV-1 in Trinidad: A significant subcluster within the B subtype QH0132 QH0791 QZ6698 QH0908 QH0944 QZ2291 QH0020 QZ4734 QH0065 QZ2704 RH0011 QZ2313 QH1420 QH0550 QH0705 QH0864 QZ2551 QZ2226 QH0850 QZ2269 QH0136 QH0016 QH0605 QH0515 93 QH0060 QH1116 QH0865 QH0679 QH0788 QH0692 Trinidad QZ2432 Trinidad* 100 Thailand SFMHS Envelope, C2-V5 .10 Cleghorn et al, Proc Natl Acad Sci USA, 27 (19); 10532-10537, 2000.

  7. A E C A_Q2317 A_UG037 AE_CAR402 AE_CM240 C_C2220 C_BR025 G G_HH8793 100 F G_SE6165 100 F_F9363 100 F_BZ126 100 J J_SE9280 100 100 J_SE9173 D 100 D_ELI B_OYI D_NDK B_SF2 100 B_MN QH0692 86 100 QH0788 QH0865 QZ4734 100 QH0550 QH0679 QH0060 QH0908 QH0605 QH1420 QH0016 Whole Envelope QH1116 QH0864 QH0850 QH0136 QH0944 QH0515 QH0132 QH0065 QH0705 QH0020 B QH0791 Institute of Human Virology Division of Epidemiology and Prevention .10 A Distinctive Clade B HIV-1 is Heterosexually Transmitted in Trinidad & Tobago:Phylogenetic Analysis of Whole Envelope Sequences from 22 Trinidad HIV-1 Isolates Cleghorn et al, Proc Natl Acad Sci USA, 27 (19); 10532-10537, 2000.

  8. Institute of Human Virology Division of Epidemiology and Prevention A Distinctive Clade B HIV-1 is Heterosexually Transmitted in Trinidad & Tobago:Conclusions These results demonstrated that: • Clade B HIV-1 is circulating in Trinidad & Tobago • Distinguished only by genetic marker from prototypic strains, but phenotypically identical • Strong founder effect from North American HIV-1 • Relatively stable V3 loop • Diversity occurring at standard rate • Canonical clade B HIV-1 can generate a typical heterosexual epidemic Cleghorn et al, Proc Natl Acad Sci USA, 27 (19); 10532-10537, 2000.

  9. Institute of Human Virology Division of Epidemiology and Prevention New Testing Strategy to Detect Early HIV-1 Infection for Use in Incidence Estimates and for Clinical and Prevention Purposes Robert S. Janssen; Glen A. Satten; Farley R. Cleghorn; Susan L. Stramer; Bhupat D. Rawal; Thomas R. O'Brien; Barbara J. Weiblen; Frederick M. Hecht; Noreen Jack; James O. Kahn; Margaret A. Chesney; Michael P. Busch Plot of standardized 3A11-LS optical density (OD) values of specimens obtained since estimated day of seroconversion on 3A11 assay. JAMA Vol. 280, pp. 42-48, Jul. 1, 1998

  10. Stages of early HIV infection N I P* POS WB Ab RNA • LS EIA defined stages LS-Ab p24 Ag 0 I II III IV V VI VII 0 25 50 75 100 125 150 175 200 Days from HIV Exposure M. Busch et al 2001

  11. Determination of Tdt for OTDV at SOD of 0.4 1.00 Lowness extrapolation .80 .60 OTDV SOD .40 .20 0.00 0 10 20 30 40 50 60 70 80 90 100 Cleghorn, 2000 DAYS POST SEROCONVERSION

  12. Standardized Optical Density Cut-off Value Days 95% C.I. & AIDS Misclassified 0.50 97 93, 103 1.5 0.75 133 127, 140 4.2 1.00 170 162, 183 5.0 1.25 210 199, 227 6.9 1.50 249 230, 277 7.6 2.00 336 314, 400 8.4 LS-EIA Window Period EstimatesOrganon Teknika Corporation’s Vironostika Less-Sensitive EIA * CDCApril 2001

  13. Institute of Human Virology Division of Epidemiology and Prevention Calculating Incidence using S/LS data Idt = ndt/N (Ts/Tdt) 100 Idt = Incidence per annum ndt= number detuned as recent N = number of detuned plus negatives Ts = Calendar time in days of sampling Tdt = Estimate of time (#days) between Sensitive and Less Sensitive Assays I = Pdt x 365/Tdt I = Incidence Pdt = prevalence of detuned (recent samples) Tdt = average time to detune sample in days

  14. Institute of Human Virology Division of Epidemiology and Prevention Cleghorn et al, International AIDS Meeting,Barcelona, 2002 • A serological 2 stage detuned algorithm can accurately • ascertain recent seroconverters for pathogenesis studies; • 2) Loss to follow-up of recent cases is significantly reduced; • 3) Incidence estimates suitable for program planning and • vaccine trials can be generated; • 5) Technology transfer allows local ownership of methodology, • allowing application to other activities such as sentinel studies • for program planning and interventions.

  15. BF Recombinants Subtype F Subtype B BF Recombinants .10 Institute of Human Virology Division of Epidemiology and Prevention Schematic Representation of the evolution Of BF recombinants in South America J. Carr et al, 2002

  16. CRF12_BF Other BF Recombinants F B Genes Reverse Transciptase Protease Institute of Human Virology Division of Epidemiology and Prevention The ProRT amplicon as a screening tool-Latin America J. Carr et al, 2001

  17. Put these together: • Use detuned (S/LS) assay to identify recent infections (current force of epidemic) • Generate incidence estimates, initially focusing on Vaccine Trial Sites • Recover RNA amplicons from recently infected serum suitable for sequencing • Focus on parts of genome (RT/Pro) which delivers data on circulating resistance patterns • Track Molecular diversity of regional epidemic • Expert interpretation of resistance mutations and their significance. NIAID R21 AI057084 2003-2005

  18. 5 Caribbean sites (200 “confirmed” seropos. samples/site) 1,000 seropositive samples DV-SOD 1.0 (IHV) =150 Incidence Estimation 85% 15% N= 850 Established N= 150 Recents Rapid UG S/LS (N=150) NIAID R21 AI057084 2003-2005 10% unconfirmed 90% confirmed recents 15 non-confirmed 135 Recents recents Increase PPV to 100% for true recents Viral genotyping (HJF) DV-SOD 0.4 26% 74% Select 50 SOD > 0.4 SOD < 0.4 (N=99) (N=26) (N=24/73) 26% (N=26) 0-35 days post-SC 74% (N=73) 35-170 days post-SC EPT

  19. Institute of Human Virology Division of Epidemiology and Prevention ~300 ProRT Sequences from South America & 12 Caribbean (Jam & TT) Subtype B Jamaica Trinidad & Tobago BF Recombinants Subtype F Other Subtypes 0.10

  20. Institute of Human Virology Division of Epidemiology and Prevention Trinidad Recently Infected 2001/2002 .10 Early Results: Subtype B Pro/RT only

  21. 01JAM18920 B_U23487 B_896 B_WR27 B_Bol0122 B_BCSG3C B_D31 B_YU2 B_JRCSF B_RL42 B_LAI B_NY5 CRC08656 B_CAM1 CRC08749 CRC08718 B_HAN B_3202A12 CRC08683 B_MN B_OYI CRC08746 CRC08695 CRC08704 Institute of Human Virology Division of Epidemiology and Prevention B_SF2 B_ARCH054 CRC08767 B_RF B_ARMS008 CRC08794 01JAM22731 CRC08693 .10 Subtype B – recent TT & Jam 72 85 ProRT

  22. 1 11 21 31 | | | | 1 CTRPNNNTRK SIHIGPGRAF YTTGXIIGDI RQAHC 35 B consensus 1 .I.......R ..A....A.. ..-.EV.... .K.Y. 34 CRC08718 - new 1 .........R G..M...K.Y F.-.E..... ..... 34 QH0132 1 .........R ...M...KV. ..-.E..... ..... 34 QH0060 1 .......... ..P....SV. ..-.E..... ..... 34 QH0020 1 .........R D.T.....V. ..-.E..... ..... 34 QH0136 1 .......... ..N....... ..-.E..... ..... 34 QZ4734 1 .......... .....A.K.L ..-.E..... ..... 34 QH0016 1 .......... G.T....SV. ..-.E..... ..... 34 QH0065 1 .......... ....EA.K.L ..-.E..... ..... 34 QH0515 1 .........R D.A....KV. ..-.E...N. ..... 34 QH0550 1 .......... G......KV. C.-.E.V... ..... 34 QH0605 1 .......... .......... .A..E...N. ..... 35 QH0679 1 ....G..... .......... .A..D..... ..... 35 QH0692 1 .......... ...L.A...L ..-.E..... ..... 34 QH0705 1 .........E ..N....... .Y..E..... ..... 35 QH0788 1 .......... G.T.....VS ..-.E.V... ..V.. 34 QH0791 1 .......... ...L.A.K.L ..-.E..... ..... 34 QH0850 1 .........R ...M...K.L F.-.E..... ..... 34 QH0864 1 .......... ..P....... .A..E...N. ..... 35 QH0865 1 .........R GVT.....V. ..-.EVT... ..... 34 QH0908 1 .I........ .......... ..-.D..... ..... 34 QH0944 1 .......... ...M.....L ..-.E..... ..... 34 QH1116 1 .......... ...L.A...L ..-.E..... ..... 34 QH1420 Institute of Human Virology Division of Epidemiology and Prevention CRC08718 V3 Loop

  23. Institute of Human Virology Division of Epidemiology and Prevention HIV Incidence Estimates in Trinidad Cleghorn et al, Amer J Epidemiol 147(9):834-839, 1998

  24. Conclusions • The (cost-effective) combination of S/LS assay testing and RNA recovery generates both HIV incidence and HIV molecular diversity; • RT/Pro analysis allows examination of common resistance mutations; • These three critical parameters are at the core of understanding and responding to the HIV/AIDS epidemic in the region;

  25. Collaborators • HJF: Jean Carr, Francine McCutchan • IHV: Niel Constantine, Anne Sill • Trinidad: Noreen Jack, Courtenay Bartholomew • Haiti: Jean Pape, Marie Deschamps • DR: Ernesto Guerrero, Yeycy Donastorg • Jamaica: Peter Figueroa, Evadne Williams • Puerto Rico: Carmen Zorilla, Y. Yamamura

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