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Author: Roche, Michael ×

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    Adaptation of the intact proviral DNA assay to a nanowell-based digital PCR platform
    Tumpach, C ; Cochrane, CR ; Kim, Y ; Ong, J ; Rhodes, A ; Angelovich, TA ; Churchill, MJ ; Lewin, SR ; Telwatte, S ; Roche, M (MEDISCRIPT LTD, 2023-06)
    Quantification of intact proviruses is a critical measurement in HIV cure studies both in vitro and in vivo. The widely adopted 'intact proviral DNA assay' (IPDA), designed to discriminate and quantify genetically intact HIV proviruses based on detection of two HIV sequence-specific targets, was originally validated using Bio-Rad's droplet digital PCR technology (ddPCR). Despite its advantages, ddPCR is limited in multiplexing capability (two-channel) and is both labor- and time intensive. To overcome some of these limitations, we utilized a nanowell-based digital PCR platform (dPCR, QIAcuity from Qiagen) which is a fully automated system that partitions samples into nanowells rather than droplets. In this study we adapted the IPDA assay to the QIAcuity platform and assessed its performance relative to ddPCR. The dPCR could differentiate between intact, 5' defective and 3' defective proviruses and was sensitive to single HIV copy input. We found the intra-assay and inter-assay variability was within acceptable ranges (with coefficient of variation at or below 10%). When comparing the performance of the IPDA in ex vivo CD4+ T cells from people with HIV on antiretroviral therapy, there was a strong correlation in the quantification of intact (rs = 0.93; p < 0.001) and 3' defective proviruses (rs = 0.96; p < 0.001) with a significant but less strong correlation for 5' defective proviruses (rs = 0.7; p = 0.04). We demonstrate that the dPCR platform enables sensitive and accurate quantification of genetically intact and defective proviruses similar to the ddPCR system but with greater speed and efficiency. This flexible system can be further optimized in the future, to detect up to 5 targets, enabling a more precise detection of intact and potentially replication-competent proviruses.
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    Regional Analysis of Intact and Defective HIV Proviruses in the Brain of Viremic and Virally Suppressed People with HIV
    Angelovich, TA ; Cochrane, CR ; Zhou, J ; Tumpach, C ; Byrnes, SJ ; Eddine, JJ ; Waring, E ; Busman-Sahay, K ; Deleage, C ; Jenkins, TA ; Hearps, AC ; Turville, S ; Gorry, PR ; Lewin, SR ; Brew, BJ ; Estes, JD ; Roche, M ; Churchill, MJ (WILEY, 2023-10)
    Here, we provide the first regional analysis of intact and defective HIV reservoirs within the brain. Brain tissue from both viremic and virally suppressed people with HIV (PWH) harbored HIV pol DNA in all regions tested, with lower levels present in basal ganglia and cerebellum relative to frontal white matter. Intact proviruses were primarily found in the frontal white matter but also detected in other brain regions of PWH, demonstrating frontal white matter as a major brain reservoir of intact, potentially replication competent HIV DNA that persists despite antiretroviral therapy. ANN NEUROL 2023;94:798-802.
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    8th IAS Conference on HIV Pathogenesis, Treatment and Prevention (IAS 2015).
    Pate, KM ; Pohlmeyer, C ; Walker-Sperling, V ; Foote, J ; Najarro, K ; Cryer, C ; Salgado, M ; Gama, L ; Engle, E ; Shirk, E ; Queen, S ; Chioma, S ; Vermillion, M ; Bullock, B ; Li, M ; Lyons, C ; Adams, R ; Zink, C ; Clements, J ; Mankowski, J ; Blankson, J ; Micci, L ; Ryan, E ; Fromentin, R ; Benne, C ; Chomont, N ; Lifson, J ; Paiardini, M ; Lee, S ; Chomont, N ; Fromentin, R ; Silicano, R ; Silicano, J ; Richman, D ; O'Doherty, U ; Palmer, S ; Burbelo, P ; Deeks, S ; Ghneim, K ; Ahlers, J ; Fourati, S ; Shive, C ; Cameron, M ; Mukerjee, P ; Ghannoum, M ; Rodriguez, B ; Deeks, S ; Lederman, M ; Sekaly, R ; Frange, P ; Faye, A ; Avettand-Fenoel, V ; Bellaton, E ; Deschamps, D ; Angin, M ; Caillat-Zucman, S ; Peytavin, G ; Le Chenadec, J ; Warszawski, J ; Rouzioux, C ; Saez-Cirion, A ; Chang, C ; Cameron, P ; Elliott, J ; Perelson, A ; Roche, M ; Dantanarayana, A ; Solomon, A ; Naranbhai, V ; Tenakoon, S ; Hoh, R ; McMahon, J ; Sikaris, K ; Hartogensis, W ; Bacchetti, P ; Hecht, F ; Lifson, J ; Deeks, S ; Lewin, S ; Byrareddy, S ; Arthos, J ; Cicala, C ; Reimann, K ; Parslow, T ; Santangelo, P ; Villinger, F ; Fauci, A ; Ansari, A ; George, M ; Weiser, B ; Burger, H ; Lewy, T ; Anastos, K ; Asmuth, D ; Somsouk, M ; Hunt, P ; Min, Z ; Miller, C ; Li, XD ; Hinkle, J ; Shaw, A ; Weaver, E ; Klein, G ; Viljoen, K ; Wendoh, J ; Karaoz, U ; Brodie, E ; Mulder, N ; Botha, G ; Kidzeru, E ; Butcher, J ; Gray, C ; Rosenthal, K ; Abimiku, A ; Cameron, B ; Stintzi, A ; Jaspan, H ; Schafer, J ; Evans, T ; Li, H ; Reeves, RK ; Kroon, M ; Dunning, L ; Hsiao, M ; Myer, L ; Crowell, CS ; Maiga, AI ; Sylla, M ; Taiwo, B ; Koné, N ; Murphy, RL ; Marcelin, A-G ; Traore, B ; Fofana, DB ; Chadwick, EG ; Ásbjörnsdóttir, KH ; Slyker, JA ; Wamalwa, D ; De Rosa, S ; Hughes, JP ; Rowhani-Rahbar, A ; Chohan, BH ; Benki-Nugent, S ; Tapia, K ; John-Stewart, GC ; Kizito, H ; Gaur, A ; Prasitsuebsai, W ; Rakhmanina, N ; Chokephaibulkit, K ; Fourie, J ; Bekker, L-G ; Shao, Y ; Bennett, S ; Quirk, E ; Prasitsuebsai, W ; Teeraananchai, S ; Truong, KH ; Ananworanich, J ; Chau, V ; Van Nguyen, L ; Kosalaraksa, ; Kurniati, N ; Sudjaritruk, T ; Chokephaibulkit, K ; Singtoroj, T ; Kerr, SJ ; Sohn, AH ; Lombaard, J ; Bunupuradah, T ; Flynn, P ; Ramapuram, J ; Ssali, F ; Crauwels, H ; Hoogstoel, A ; Van Eygen, V ; Stevens, M ; Boven, K ; Jao, J ; Myer, L ; Phillips, T ; Petro, G ; Zerbe, A ; Abrams, EJ ; Hanrahan, C ; Martinson, N ; Link-Barnes, G ; Msandiwa, R ; Chaisson, R ; Golub, J ; Evans, DH ; Schnippel, K ; Budgell, E ; Shearer, K ; Berhanu, R ; Long, L ; Rosen, S ; Schultze, A ; Efsen, AMW ; Post, FA ; Panteleev, A ; Furrer, H ; Miller, R ; Losso, MH ; Toibaro, J ; Skrahin, A ; Miro, JM ; Caylà, JA ; Girardi, E ; Bruyand, M ; Obel, N ; Podlekareva, DN ; Lundgren, JD ; Mocroft, A ; Kirk, O ; Baddeley, A ; Doherty, M ; Kanchar, A ; Matteelli, A ; Timimi, HB ; Getahun, H ; Hosseinipour, M ; Bisson, G ; Miyahara, S ; Sun, X ; Moses, A ; Riviere, C ; Kirui, FK ; Badal-Faesen, S ; Lagat, D ; Nyirenda, M ; Naidoo, K ; Hakim, J ; Mugyenyi, P ; Henostroza, G ; Leger, PD ; Lama, JR ; Mohapi, L ; Alave, J ; Mave, V ; Veloso, VG ; Pillay, S ; Kumarasamy, N ; Bao, J ; Hogg, E ; Jones, L ; Zolopa, A ; Kumwenda, J ; Gupta, A ; Cohen, M ; Chen, Y ; McCauley, M ; Gamble, T ; Hosseinipour, M ; Kumarasamy, N ; Hakim, J ; Kumwenda, N ; Brum, T ; Grinsztejn, B ; Godbole, S ; Chariyalertsak, S ; Santos, RB ; Mayer, K ; Hoffman, I ; Eshleman, S ; Piwowar-Manning, E ; Ou, S-S ; Cottle, L ; Makhema, J ; Mills, L ; Panchia, R ; Badal-Faesen, S ; Eron, J ; Gallant, J ; Havlir, D ; Swindells, S ; Elharrar, V ; Burns, D ; Taha, T ; Nielsen, K ; Celentano, D ; Essex, M ; Fleming, T ; Jean, K ; Puren, A ; Cutler, E ; Singh, B ; Bouscaillou, J ; Rain-Taljaard, R ; Taljjard, D ; Lissouba, P ; Peytavin, G ; Auvert, B ; Jenkins, L ; Nordio, J ; Vasarhelyi, K ; Nunez, A ; Barrios, R ; Rutherford, A ; Iwuji, C ; Dray-Spira, R ; Calmy, A ; Larmarange, J ; Orne-Gliemann, J ; Dabis, F ; Pillay, D ; Porter, K ; Barnabas, R ; van Rooyen, H ; Tumwesigye, E ; Brantley, J ; Baeten, J ; van Heerden, A ; Turyamureeba, B ; Joseph, P ; Krows, M ; Hughes, J ; Celum, C ; Eshleman, SH ; Hudelson, SE ; Ou, SS ; Redd, AD ; Swanstrom, R ; Porcella, SF ; Chen, YQ ; Piwowar-Manning, E ; McCauley, M ; Gamble, T ; Sievers, M ; Martens, CA ; Bruno, D ; Ping, L-H ; Dukhovlinova, E ; Quinn, TC ; Kumwenda, J ; Maliwichi, M ; Nhando, N ; Akelo, V ; Moyo, S ; Panchia, R ; Kumarasamy, N ; Chotirosniramit, N ; Rocha, MM ; Bustorff, F ; Grinsztejn, B ; Mayer, KH ; Hughes, JP ; Cohen, MS ; Haas, AD ; Tenthani, L ; Msukwa, MT ; Jahn, A ; Midiani, D ; Mhango, E ; Gadabu, O ; Tal, K ; Spörri, A ; Egger, M ; Chimbwandira, F ; van Oosterhout, JJ ; Keiser, O ; Rosenberg, N ; Mtande, T ; Saidi, F ; Stanley, C ; Jere, E ; Mwangomba, L ; Kumwenda, K ; Mofolo, I ; Mwale, M ; Chauma, A ; Miller, WC ; Hoffman, I ; Hosseinipour, MC ; Buzdugan, R ; McCoy, SI ; Watadzaushe, C ; Dufour, M-SK ; Petersen, M ; Dirawo, J ; Mushavi, A ; Mujuru, HA ; Mahomva, A ; Engelsmann, B ; Hakobyan, A ; Mugurungi, O ; Cowan, FM ; Padian, NS ; Lallemant, M ; Amzal, B ; Urien, S ; Sripan, P ; Cressey, T ; Ngo-Giang-Huong, N ; Rawangban, B ; Sabsanong, P ; Siriwachirachai, T ; Jarupanich, T ; Kanjanavikai, P ; Wanasiri, P ; Koetsawang, S ; Jourdain, G ; Le Cœur, S ; Ochoa-Moreno, I ; Mangenah, C ; Buzdugan, R ; Padian, NS ; Mccoy, SI ; Cowan, FM ; Bautista-Arredondo, S ; Wambura, M ; Hayes, R ; Grund, J ; Kapiga, S ; Mahler, H ; Mshana, G ; Kuringe, E ; Plotkin, M ; Bock, N ; Larke, N ; Changalucha, J ; Weiss, H ; Thirumurthy, H ; Akello, I ; Murray, K ; Masters, S ; Maman, S ; Omanga, E ; Agot, K ; Duwve, J ; Hoover, K ; Conrad, C ; Galang, R ; Hillman, D ; Hoots, B ; Patel, M ; Peters, P ; Pontones, P ; Roseberry, J ; Shields, J ; Waterhouse, D ; Weidle, P ; Galang, RR ; Gentry, J ; Peters, PJ ; Blosser, SJ ; Chapman, EL ; Conrad, C ; Duwve, JM ; Ganova-Raeva, L ; Heneine, W ; Hillman, D ; Jia, H ; Liu, L ; Luo, W ; Lovchik, J ; Masciotra, S ; Owen, SM ; Perez, A ; Peyrani, P ; Pontones, P ; Ramachandran, S ; Roseberry, JC ; Sandoval, M ; Shankar, A ; Thai, H ; Xia, G ; Khudyakov, Y ; Switzer, WM ; Mannheimer, S ; Hirsch-Moverman, Y ; Loquere, A ; Franks, J ; Hughes, J ; Ou, S-S ; Amico, KR ; Hendrix, C ; Dye, BJ ; Piwowar-Manning, E ; Marzinke, M ; Elharrar, V ; Stirratt, M ; Grant, RM ; Holtz, TH ; Chitwarakorn, A ; Curlin, ME ; Hughes, J ; Amico, KR ; Hendrix, C ; Dye, BJ ; Anderson, PL ; Ou, S-S ; Elharrar, V ; Eshleman, SH ; Stirratt, M ; Grant, RM ; Doherty, M ; Beusenberg, M ; Asamoah-Odei, E ; Lule, F ; Pendse, R ; Ghidinelli, M ; Lo, Y-R ; Reidner, G ; Donoghoe, M ; Vitoria, M ; Hirnschall, G ; Levi, J ; Raymond, A ; Pozniak, A ; Vernazza, P ; Kohler, P ; Ford, N ; Hill, A ; Wolff, M ; Cortes, CP ; Shepherd, BE ; Giganti, M ; Gowan, CM ; Rawat, A ; Uebel, KE ; Moore, D ; Yassi, A ; Wilkinson, L ; Harley, B ; Jacobs, S ; Cragg, C ; Kriel, E ; Solomon, S ; Peton, N ; Jennings, K ; Youngleson, M ; Grimsrud, A ; Joy, J ; Liang, R ; McCloskey, R ; Nguyen, T ; Brumme, C ; Colley, G ; Hogg, R ; Montaner, J ; Harrigan, PR ; Poon, A ; Klein, K ; Ratcliff, A ; Nickel, G ; Nankya, I ; Lobritz, M ; Gao, Y ; Shattock, R ; Arts, E ; Kinloch, NN ; Macmillan, DR ; Le, AQ ; Cotton, LA ; Mccloskey, R ; Bangsberg, DR ; Buchbinder, S ; Carrington, M ; Fuchs, J ; Harrigan, PR ; Koblin, B ; Markowitz, M ; Mayer, K ; Milloy, MJ ; Schechter, MT ; Wagner, T ; Walker, BD ; Carlson, JM ; Poon, AFY ; Brumme, ZL ; Mesplède, T ; Anstett, K ; Osman, N ; Hassounah, S ; Liang, J ; Han, Y ; Wainberg, M ; Demeulemeester, J ; Vets, S ; Schrijvers, R ; Madlala, P ; De Maeyer, M ; De Rijck, J ; Ndung'u, T ; Debyser, Z ; Gijsbers, R ; Prentice, H ; Tomaras, G ; Geraghty, D ; Apps, R ; Fong, Y ; Ehrenberg, P ; Rolland, M ; Kijak, G ; Nelson, W ; Decamp, A ; Shen, X ; Yates, N ; Zolla-Pazner, S ; Nitayaphan, S ; Rerks-Ngarm, S ; Pitisuttithum, P ; Ferrari, G ; Montefiori, D ; McElrath, J ; Bailer, R ; Koup, R ; O'Connell, R ; Robb, M ; Michael, N ; Kim, J ; Thomas, R ; Peterson, C ; Wang, J ; Polacino, P ; Holmes, M ; Hu, S-L ; Gregory, P ; Kiem, H-P ; Kaminski, R ; Hu, W ; Zhang, Y ; Karn, J ; Khalili, K ; Chew, G ; Fujita, T ; Clayton, K ; Ishii, N ; Abdel-Mohsen, M ; Liegler, T ; Hecht, F ; Ostrowski, M ; Shikuma, C ; Maurer, M ; Korman, A ; Deeks, S ; Ndhlovu, L ; Karn, J ; Das, B ; Dobrowolski, C ; Scully, E ; Deeks, S ; Gandhi, M ; Johnston, R ; Bunupuradah, T ; Kiertiburanakul, S ; Avihingsanon, A ; Chetchotisakd, P ; Techapornroong, M ; Leerattanapetch, N ; Kantipong, P ; Bowonwatanuwong, C ; Banchongkit, S ; Klinbuayaem, V ; Mekviwattanawan, S ; Nimitvilai, S ; Jirajariyavej, S ; Prasithsirikul, W ; Munsakul, W ; Bhakeecheep, S ; Chaivooth, S ; Phanuphak, P ; Cooper, DA ; Apornpong, T ; Kerr, SJ ; Emery, S ; Ruxrungtham, K ; Mills, T ; Andrade, J ; Diperri, G ; Van Lunzen, J ; Koenig, E ; Elion, R ; Cavassini, M ; Madruga, JV ; Brunetta, J ; Shamblaw, D ; Dejesus, E ; Cohen, C ; Plummer, A ; Liu, Y ; McCallister, S ; Gupta, S ; Pozniak, A ; Arribas, J ; Post, F ; Bloch, M ; Gathe, J ; Benson, P ; Custodio, J ; Abram, M ; Wei, X ; Cheng, A ; McCallister, S ; Fordyce, M ; Gatell, J ; Raffi, F ; Plettenberg, A ; Smith, D ; Portilla, J ; Hoffmann, C ; Arasteh, K ; Thompson, M ; Hagins, D ; Morales-Ramirez, J ; Xu, X ; Teppler, H ; Trahan, M-J ; Lamarre, V ; Metras, M-E ; Lapointe, N ; Kakkar, F ; Hwang, C ; Schürmann, D ; Sobotha, C ; Boffito, M ; Sevinsky, H ; Ray, N ; Ravindran, P ; Xiao, H ; Krystal, M ; Dicker, I ; Grasela, D ; Lataillade, M ; Brunet, L ; Moodie, EE ; Young, J ; Walmsley, S ; Hull, M ; Cooper, C ; Klein, MB ; Naggie, S ; Cooper, C ; Saag, M ; Yang, JC ; Stamm, LM ; Pang, PS ; McHutchison, JG ; Dieterich, D ; Sulkowski, MS ; Wyles, D ; Eron, JJ ; Lalezari, J ; Wang, C ; Ruane, PJ ; Blick, G ; Bhatti, L ; Hu, YB ; Co, M ; Gibbons, K ; Trinh, R ; Sulkowski, MS ; Casado, JL ; Bañon, S ; Quereda, C ; Moreno, A ; Elías, MJP ; Moreno, S ; Saeed, S ; Rollet-Kurhajec, K ; Strumpf, EC ; Klein, MB ; Rockstroh, JK ; Nelson, M ; Katlama, C ; Lalezari, J ; Mallolas, J ; Bloch, M ; Matthews, G ; Saag, MS ; Zamor, P ; Orkin, C ; Gress, J ; Shaughnessy, M ; Klopfer, S ; Platt, HL ; Robertson, M ; Sulkowski, M ; Lacombe, K ; Fontaine, H ; Dhiver, C ; Rosenthal, E ; Metivier, S ; Antonini-Michelle, T ; Valantin, MA ; Miailhes, P ; Harent, S ; Batisse, D ; Pageaux, G-P ; Aumaitre, H ; Dominguez, S ; Chas, J ; Allegre, T ; Lafeuillade, A ; De Truchis, P ; De Ledinghen, V ; Leroy, V ; Billaud, E ; Sogni, P ; Dabis, F ; Wittkop, L ; Duvivier, C ; Filipovics, A ; Fedchuk, L ; Bennai, Y ; Salmon, D ; Karim, QA ; Leask, K ; Kharsany, A ; Humphries, H ; Ntombela, F ; Samsunder, N ; Baxter, C ; Frohlich, J ; van der Elst, L ; Karim, SA ; Thirumurthy, H ; Masters, S ; Rao, S ; Murray, K ; Omanga, E ; Agot, K ; Marshall, BDL ; Elston, B ; Dobrer, S ; Montaner, J ; Kerr, T ; Wood, E ; Milloy, M-J ; Czaicki, N ; Njau, P ; Bautista-Arredondo, S ; Simba, O ; Padian, N ; McCoy, S ; Haber, N ; Tanser, F ; Herbst, K ; Pillay, D ; Bärnighausen, T ; Pettifor, A ; MacPhail, C ; Selin, A ; Gomez-Olivé, X ; Hughes, J ; Wagner, R ; Mabuza, W ; Mokoena, I ; Eshleman, S ; Piwowar-Manning, E ; Twine, R ; Julien, A ; Marcus, C ; Andrew, P ; Wang, J ; Xing, Y ; McKinstry, L ; Hamilton, E ; Agyei, Y ; Allison, S ; Sato, P ; Townley, E ; Tollman, S ; Kahn, K ; Solomon, MM ; Schechter, M ; Liu, AY ; McMahan, V ; Guanira, JV ; Hance, RJ ; Chariyalertsak, S ; Mayer, KH ; Grant, RM ; Liu, A ; Cohen, S ; Vittinghoff, E ; Anderson, P ; Doblecki-Lewis, S ; Bacon, O ; Chege, W ; Elion, R ; Buchbinder, S ; Kolber, M ; Henderson, F ; Taylor, A ; Chirwa, L ; Williams, T ; Borkowf, C ; Kasonde, M ; Mutanhaurwa, R ; Matlhaba, O ; Hageman, K ; Casillas, P ; Hosek, S ; Rudy, B ; Landovitz, R ; Kapogiannis, B ; Siberry, G ; Liu, N ; Rutledge, B ; Brothers, J ; Rooney, J ; Wilson, CM ; Hoagland, B ; Veloso, VG ; De Boni, RB ; Madruga, JV ; Kallas, EG ; Fernandes, NM ; Moreira, RI ; Liu, AY ; Grinsztejn, B ; Nair, G ; Justman, JE ; Piper, J ; Marzinke, M ; Hendrix, C ; Dai, J ; Pan, J ; Galaska, B ; Levy, L ; Shwartz, J ; McGowan, I ; Dezutti, C ; Xu, J ; Tang, W ; Zou, H ; Mahapatra, T ; Hu, Q ; Fu, G ; Wang, Z ; Lu, L ; Zhuang, M ; Chen, X ; Fu, J ; Yu, Y ; Lu, J ; Jiang, Y ; Geng, W ; Han, X ; Shang, H ; Wimonsate, W ; Pattanasin, S ; Sriporn, A ; Luechai, P ; Satumay, K ; Tippanonth, N ; Promda, N ; Holtz, T ; Chitwarakorn, A ; Dunne, E ; Chan, G ; Bennett, A ; Buskin, S ; Dombrowski, J ; Golden, M ; Grosso, A ; Stahlman, S ; Mothopeng, T ; Taruberekera, N ; Ouedraogo, G ; Ky-Zerbo, O ; Pitche, V ; Anato, S ; Sithole, B ; Mabuza, X ; Ceesay, N ; Diouf, D ; Trapence, G ; Umar, E ; Baral, S ; Khosropour, CM ; Katz, DA ; Dombrowski, JC ; Golden, MR ; Bavinton, BR ; Jin, F ; Prestage, G ; Zablotska, I ; Grinsztejn, B ; Phanuphak, N ; Friedman, RK ; Grulich, AE ; Sathane, I ; Horth, R ; Boothe, M ; Baltazar, CS ; Young, P ; Fisher, H ; Teodoro, E ; Gouveia, ML ; Lane, T ; Mcfarland, W ; Booth, R ; Davis, J ; Dvoryak, S ; Brewster, J ; Strathdee, S ; Latkin, C ; Joseph, B ; Milloy, MJ ; Nguyen, HH ; Bui, DD ; Dinh, TTT ; Nguyen, MS ; Tran, HT ; Le Hai Nguyen, ; Van Nguyen, TT ; Vu, QD ; Nhan, T ; Le, AKA ; Nguyen, BC ; Suthar, A ; Lo, Y-R ; Pham, HT ; Le, MG ; Nguyen, HL ; Kato, M ; Richardson, L ; Kerr, T ; Hogg, B ; Guillemi, S ; Montaner, J ; Wood, E ; Milloy, M-J ; Cousien, A ; Leclerc, P ; Morissette, C ; Bruneau, J ; Roy, É ; Yazdanpanah, Y ; Cox, J ; Bershteyn, A ; Klein, D ; Oishi, K ; Eckhoff, P ; Leisegang, R ; Mcmahon, J ; Hislop, M ; Stinson, K ; Boulle, A ; Elliott, J ; Maartens, G ; Kim, A ; Nganga, L ; Mukui, I ; Wamicwe, J ; Mwanyumba, S ; Bowen, N ; Wiesner, L ; De Cock, K ; Han, L ; Tang, W ; Best, J ; Zhang, Y ; Kim, J ; Liu, F ; Mollan, K ; Hudgens, M ; Bayus, B ; Terris-Prestholt, F ; Galler, S ; Yang, L ; Peeling, R ; Volberding, P ; Ma, B ; Yang, B ; Huang, S ; Fenton, K ; Wei, C ; Tucker, J ; Dombrowski, JC ; Hughes, JP ; Buskin, SE ; Simoni, JM ; Katz, D ; Fleming, M ; Nunez, A ; Golden, MR ; Schmitz, K ; Scheepers, E ; Okonji, E ; Kawooya, V ; Yotebieng, M ; Thirumurthy, H ; Moracco, KE ; Kawende, B ; Chalachala, JL ; Wenzi, LK ; Ravelomanana, NLR ; Edmonds, A ; Thompson, D ; Okitolonda, E ; Behets, F ; Musarandega, R ; Mahomva, A ; Robinson, J ; Tumbare, E ; Sen, PD ; Hakobyan, A ; Mushavi, A ; Domercant, JW ; Puttkammer, N ; Lu, L ; Francois, K ; Duncan, D ; Grand'Pierre, R ; Lowrance, D ; Adler, M ; Tih, PM ; Katayi, E ; Mboh, E ; Bonje, E ; Lem, E ; Awa, JC ; Lim, JR ; Duncan, D ; Petit, L ; Bianchi, F ; Welty, T ; Achu, MN ; Tayong, G ; Tene, G ; Mosoko, JJ ; Bolu, O ; Kieffer, MP ; Woelk, G ; Mpofu, D ; Cathcart, R ; Okala, SG ; King, DF ; Shattock, RJ ; Jacob, RA ; Moyo, T ; Schomaker, M ; Abrahams, F ; Pujol, BG ; Dorfman, J ; Valenzuela-Ponce, H ; Ávila-Ríos, S ; Garrido-Rodríguez, D ; García-Téllez, T ; Soto-Nava, M ; Escamilla-Gómez, T ; García-Morales, C ; Cortés-Álvarez, J ; Hernández-Juan, R ; Murakami-Ogasawara, A ; Mejía-Villatoro, C ; Pascale, J ; Porras, G ; Quant, C ; Lorenzana, I ; Meza, R ; Palou, E ; Manzanero, M ; Reyes-Terán, G ; Mailiiard, RB ; Smith, KN ; Piazza, P ; Mullins, JI ; Rinaldo, CR ; Planas, D ; Gosselin, A ; Monteiro, P ; Goulet, J-P ; Da Fonseca, S ; Cléret-Buhot, A ; Jenabian, M-A ; Routy, J-P ; Ancuta, P ; Jensen, K ; dela Pena-Ponce, MG ; Piatak, M ; Jacobs, W ; Fennelly, G ; Mollan, K ; Hudgens, M ; Kozlowski, P ; Amedee, A ; Estes, J ; Lifson, J ; Van Rompay, K ; Larsen, M ; De Paris, K ; Malatinkova, E ; De Spiegelaere, W ; Bonczkowski, P ; Kiselinova, M ; Vervisch, K ; Trypsteen, W ; Johnson, M ; Verhofstede, C ; de Looze, D ; Murray, C ; Loes, SK-D ; Vandekerckhove, L ; Fletcher, JLK ; Pinyakorn, S ; de Souza, M ; Akapirat, S ; Trichavaroj, R ; Pankam, T ; Kroon, E ; Colby, D ; Prueksakaew, P ; Suttichom, D ; Kim, JH ; Phanuphak, P ; Phanuphak, N ; Ananworanich, J ; Vandendriessche, A ; Mourez, T ; Lemée, V ; Debab, Y ; Peytavin, G ; Ladner, J ; Caron, F ; Plantier, J-C ; Leporrier, J ; Colby, D ; Phanuphak, N ; Sirivichayakul, S ; Prueksakaew, P ; Saengtawan, P ; Trichavaroj, R ; Crowell, T ; Kim, J ; Ananworanich, J ; Phanuphak, P ; Argento, E ; Duff, P ; Bingham, B ; Nguyen, P ; Strathdee, S ; Shannon, K ; Namey, E ; Perry, B ; Headley, J ; Yao, KA ; Ouattara, M ; Shighata, C ; Ferguson, M ; Lane, T ; Sibanyoni, M ; Manyuchi, A ; Osmand, T ; Marr, A ; Grasso, M ; Isdahl, Z ; Mutanha, N ; Makhubela, P ; Silima, M ; Zuma, N ; Struthers, H ; McIntyre, J ; Rees, H ; Venter, F ; Lancaster, K ; Lungu, T ; Hosseinipour, M ; Chadwick, K ; Dibb, Z ; Go, VF ; Pence, BW ; Powers, KA ; Hoffman, IF ; Miller, WC ; Sedaghat, A ; Karamouzian, M ; Sharifi, H ; Mirzazadeh, A ; Shokoohi, M ; Haghdoost, A ; Schwartz, S ; Lambert, A ; Phaswana-Mafuya, N ; Holland, C ; Kose, Z ; Mcingana, M ; Sweitzer, S ; Baral, S ; Grimsrud, A ; Lesosky, M ; Kalombo, C ; Bekker, L-G ; Myer, L ; Caballero, P ; Da Silva, CM ; Da Cruz, M ; Plazy, M ; ElFarouki, K ; Iwuji, C ; Okesola, N ; Orne-Gliemann, J ; Larmarange, J ; Newell, M-L ; Pillay, D ; Dabis, F ; Dray-Spira, R ; Rebeiro, PF ; Cesar, C ; Shepherd, BE ; De Boni, RB ; Cortés, C ; Rodriguez, F ; Belaunzarán-Zamudio, P ; Pape, JW ; Padgett, D ; Hoces, D ; McGowan, CC ; Cahn, P ; Pilcher, C ; Hatano, H ; Dasgupta, A ; Jones, D ; Torres, S ; Calderon, F ; Ospina-Norvell, C ; Hartogensis, W ; Demicco, E ; Geng, E ; Gandhi, M ; Havlir, D ; Wagner, A ; Njuguna, I ; Mugo, C ; Inwani, I ; Maleche-Obimbo, E ; Sherr, K ; Wamalwa, D ; John-Stewart, G ; Slyker, J ; Bandason, T ; Mchugh, G ; Ferrand, R ; Munyati, S ; Kranzer, K ; Chonzi, P ; Elyanu, P ; Magongo, E ; Asire, B ; Lukabwe, I ; Bitimwine, H ; Katureebe, C ; Achii, P ; Mulema, V ; Dziuban, E ; Sugandhi, N ; Musiime, V ; Namuwenge, N ; Musinguzi, J ; Manno, EC ; Bamford, A ; Conejo, PR ; Marquez, L ; Mellado, MJ ; Muñoz-Fernández, MÁ ; Spoulou, V ; Klein, N ; Ananworanich, J ; Della Negra, M ; Ziegler, JB ; Meanson, E ; Lyall, H ; Shingadia, D ; Di Biagio, A ; Giacomet, V ; Vibeke, R ; de Sousa Marques, HH ; Salo, E ; Volokha, A ; Scherpbier, HJ ; Niehues, T ; Levy, J ; Marczynska, M ; Mardarescu, M ; Reliquet, V ; Giaquinto, C ; Bernardi, S ; Palma, P ; Ronen, K ; Mcgrath, C ; Langat, A ; Kinuthia, J ; Omolo, D ; Singa, B ; Katana, A ; Nganga, L ; John-Stewart, G ; Krebs, E ; Min, JE ; Barrios, R ; Montaner, J ; Nosyk, B ; Kelly, S ; Shattock, A ; Kerr, C ; Stuart, R ; Papoyan, A ; Grigoryan, T ; Hovhannisyan, R ; Grigoryan, S ; Wilson, D ; Rajkotia, Y ; Zang, O ; Nguimkeu, P ; Djurovic, I ; Estill, J ; Ford, N ; Salazar-Vizcaya, L ; Haas, A ; Blaser, N ; Egger, M ; Habiyambere, V ; Keiser, O ; Chuma, B ; Koseki, S ; Musau, S ; Johns, B ; Gatome-Munyua, A ; Honermann, B ; Millett, G ; Lindsey, K ; Wijayaratne, S ; Sherwood, J ; MacAllister, J ; Le, A ; Taylor, J ; Dong, W ; McCloskey, R ; Woods, C ; Hayashi, K ; Milloy, M-J ; Harrigan, PR ; Poon, AF ; Brumme, ZL ; Garrido-Rodriguez, D ; Avila-Rios, S ; Valenzuela-Ponce, H ; García-Tellez, T ; Quiroz-Morales, V ; García-Morales, C ; Soto-Nava, M ; Murakami-Ogasawara, A ; Fernandez-Lopez, JC ; Terán, GR ; Alcami, J ; Bermejo, M ; Descours, B ; Mateos, E ; Lederman, MM ; Benkirane, M ; Coiras, M ; Purcell, D ; Jacobson, J ; Harty, L ; Jarman, K ; Lackovic, K ; Khoury, G ; Mota, T ; Lee, M ; Bernardi, G ; Saleh, S ; Sonza, S ; Lewin, S ; Capoferri, A ; Sievers, M ; Redd, A ; Cash, A ; Xu, D ; Porcella, SF ; Quinn, T ; Siliciano, RF ; Levis, M ; Ambinder, RF ; Durand, CM ; Lee, S-K ; Zhou, S ; Archin, N ; Margolis, D ; Swanstrom, R ; Alcaide, M ; Chisembele, M ; Malupande, E ; Arheart, K ; Jones, D ; Fischl, M ; Vicol, LA ; Hornsberger, A ; Pick, N ; Van Schalkwyk, J ; Bloomenthal, D ; Christilaw, J ; Money, D ; Pyra, M ; Heffron, R ; Mugo, NR ; Nanda, K ; Thomas, KK ; Celum, C ; Kourtis, AP ; Baeten, JM ; Ajibola, G ; Shapiro, R ; Zash, R ; Holmes, L ; Batlang, O ; Ramogothobeng, K ; Chilisa, F ; Bennett, K ; Makhema, J ; Lockman, S ; Powis, K ; Lippman, SA ; Pettifor, AP ; Neilands, TB ; MacPhail, C ; Peacock, D ; Maman, S ; Twine, R ; Selin, A ; Kahn, K ; Derksen, L ; Muula, A ; van Oosterhout, J ; van Lettow, M ; Matengeni, A ; Sodhi, S ; Katz, D ; Golden, M ; Hughes, J ; Farquhar, C ; Stekler, J ; Lippman, SA ; Moran, ME ; Ventura, A ; Castillo, LS ; Buchbinder, S ; Treves-Kagan, S ; Sevelius, JM ; Mavedzenge, SN ; Sibanda, E ; Mavengere, Y ; Hatzold, K ; Mugurungi, O ; Ncube, G ; Cowan, F ; Muffih, PT ; Mboh, E ; Fang, E ; Wainfen, W ; Fon, H ; Welty, T ; Shields, R ; Golden, M ; Bachireddy, C ; Izenberg, J ; Soule, M ; Dvoryak, S ; Altice, F ; Nosyk, B ; Min, JE ; Evans, E ; Li, L ; Liu, L ; Lima, V ; Wood, E ; Montaner, J ; Beletsky, L ; Gonzalez-Zuniga, P ; Rangel, G ; Werb, D ; Arredondo, J ; Strathdee, SA ; Lambdin, BH ; Nyandindi, C ; Bruce, D ; Sabuni, N ; Magimba, A ; Matiko, E ; Milloy, M-J ; Kerr, T ; Hogg, R ; Guillemi, S ; Montaner, J ; Wood, E ; Merlini, E ; Iannuzzi, F ; Bai, F ; Trunfio, M ; Bonora, S ; Calcagno, A ; Cannizzo, ES ; Basilissi, M ; Bini, T ; Monforte, AD ; Marchetti, G ; O'Brien, M ; Manches, O ; Wilen, C ; Wu, V ; Sunseri, N ; Bhardwaj, N ; Bego, MG ; Côté, ÉA ; Aschman, N ; Mercier, J ; Weissenhorn, W ; Cohen, ÉA ; Turrini, F ; Kajaste-Rudnitski, A ; Marelli, SS ; Van Lint, C ; Das, AT ; Berkout, B ; Vicenzi, E ; Simpson, S ; deSilva, T ; Yindom, L-M ; Leligdowicz, A ; Vincent, T ; Rowland-Jones, S ; Webb, GM ; Chew, GM ; Fujita, T ; Burwitz, BJ ; Wu, HL ; Reed, JS ; Hammond, KB ; Hansen, SG ; Maurer, M ; Korman, AJ ; Ndhlovu, LC ; Sacha, JB ; Esser, S ; Geisel, MHM ; Arendt, M ; Schulze, C ; Holzendorf, V ; Warnke, A ; Brockmeyer, NH ; Hower, M ; Schadendorf, D ; Neumann, T ; Eisele, L ; Erbel, R ; Moebus, S ; Jöckel, K-H ; Reinsch, N ; Hamzah, L ; Tiraboschi, JM ; Toby, M ; Iveson, H ; Mant, C ; John, C ; Burling, K ; Kulasegaram, R ; Teague, A ; Post, FA ; Fox, J ; Grant, P ; Kitch, D ; McComsey, G ; Collier, A ; Koletar, S ; Erlandson, K ; Yin, M ; Bartali, B ; Ha, B ; Melbourne, K ; Brown, T ; Sudjaritruk, T ; Bunupuradah, T ; Aurpibul, L ; Kosalaraksa, ; Kurniati, N ; Puthanakit, T ; Spinner, CD ; Kern, KE ; Noe, S ; von Werder, A ; Schwerdtfeger, C ; Schmid, RM ; Zink, A ; Wolf, E ; Iakoubov, R ; Paraskevis, D ; Nikolopoulos, G ; Sypsa, V ; Psichogiou, M ; Malliori, M ; Friedman, SR ; Hatzakis, A ; Thompson, LH ; Wertheim, JO ; Reza, T ; Wylie, JL ; Emmanuel, F ; Brooks, J ; Blanchard, JF ; Sandstrom, P ; Tee, KK ; Kantor, R ; Sungkanuparph, S ; Takebe, Y ; Li, P ; Ditangco, R ; Phanuphak, P ; Sirisanthana, T ; Sim, B ; Ratanasuwan, W ; Kantipong, P ; Mustafa, M ; Merati, TP ; Jiamsakul, A ; Singtoroj, T ; Kamarulzaman, A ; Sulaberidze, L ; Mirzazadeh, A ; Chikovani, I ; Shengelia, N ; Tsereteli, N ; Gotsadze, G ; Mulawa, M ; Reyes, H ; Foshee, V ; Halpern, C ; Kajula, L ; Maman, S ; Treves-Kagan, S ; Ayadi, AE ; Pettifor, A ; MacPhail, C ; Twine, R ; Maman, S ; Kahn, K ; Lippman, SA ; Camlin, CS ; Ssemmondo, E ; Chamie, G ; Kwarisiima, D ; Sang, N ; Bukusi, EA ; Cohen, CR ; Kamya, MR ; Havlir, D ; Schley, A ; Skowronska, E ; Okonji, E ; Scheepers, E ; Feldacker, C ; Myers, S ; Cesar, F ; Parades, Z ; Ferrao, C ; Citao, SC ; Mudender, F ; Golden, M ; Mark, J ; Kinuthia, J ; Osoti, A ; Gone, M ; Asila, V ; Parikh, S ; Krakowiak, D ; Betz, B ; Richardson, B ; Roxby, A ; Farquhar, C ; Pina, C ; Dange, A ; Neytra, S ; Kambli, H ; Karambe, S ; Chhabra, R ; Patel, V ; Ndlovu, B ; Hermanus, T ; Tumba, N ; Moore, P ; Jaggernath, M ; Walker, BD ; Morris, L ; Ndung'u, T ; Leitman, EM ; Hurst, J ; Mori, M ; Matthews, PC ; Frahm, N ; Kublin, J ; Gray, GE ; Goulder, PJ ; Demarco, T ; Rountree, W ; Hora, B ; Chen, Y ; Keinonen, S ; Racz, L ; Daniell, L ; Louzao, R ; Sanchez, A ; Busch, M ; Denny, T ; Gao, F ; Johnson, A ; Jacob, R ; Haeryfar, M ; Dikeakos, J ; Mohammed, T ; Gaseitsiwe, S ; Matlhagela, K ; Matsheka, M ; Moyo, S ; Musonda, R ; Moukambi, F ; Rabezanahary, H ; Rodrigues, V ; Estaquier, J ; Ndjoyi-Mbiguino, A ; Nzengui, GFN ; Kamdem, HM ; Bélec, L ; Viana, R ; Xaba, T ; Stojiljkovic, T ; Gunther, N ; Wallis, C ; Grimsrud, A ; Cornell, M ; Schomaker, M ; Fox, MP ; Orrell, C ; Prozesky, H ; Stinson, K ; Tanser, F ; Egger, M ; Myer, L ; Nsumba, MS ; Barbara, C ; Musomba, RZ ; Kaimal, A ; Ivan, K ; Isaac, L ; Laurence, J ; Rosalind, P-R ; Andrew, K ; Khan, A ; Hans, L ; Gonzales, L ; Carmona, S ; Hsiao, N-Y ; Brophy, J ; Lee, T ; Sauve, L ; Bitnun, A ; Singer, J ; Kakkar, F ; Lapointe, N ; Alimenti, A ; Money, D ; Vaudry, W ; Samson, L ; Singer, J ; Bitnun, A ; Lee, T ; Samson, L ; Brophy, J ; Money, D ; Alimenti, A ; Vaudry, W ; Kakkar, F ; Lapointe, N ; Sauve, L ; du Lou, AD ; Pannetier, J ; Ravalihasy, A ; Gosselin, A ; Supervie, V ; Bajos, N ; Lert, F ; Lydie, N ; Dray-Spira, R ; Kerani, R ; Herbeck, J ; Buskin, S ; Dombrowski, J ; Bennett, A ; Barash, E ; Barbee, L ; Golden, M ; Chang, L ; Grabowski, MK ; Ssekubugu, R ; Nalugoda, F ; Reynolds, S ; Lessler, J ; Moore, S ; Quinn, T ; Gray, R ; Serwadda, D ; Wawer, M ; Ramachandran, A ; Manabe, Y ; Rajasingham, R ; Shah, M ; Schwarz, M ; Flick, R ; Harawa, M ; Simon, K ; Kim, M ; Robison, J ; Ahmed, S ; Schramm, B ; Tayea, A ; Wolters, L ; Nicholas, S ; Masiku, CW ; Zolowere, DB ; Mhango, E ; Kandulu, JR ; Etard, J-F ; Amaros, I ; Szumilin, E ; Gueguen, M ; Ndulue, N ; Etsetowaghan, A ; Gabriel, C ; Ibrahim, J ; Seclen-Palacin, J ; Natumanya, E ; Nabitaka, L ; Bitarakwate, E ; Ismail, S ; Moshgabadi, N ; Galli, R ; Daly, A ; Ko, SMS ; Zhang, M ; Westgard, T ; Bulpitt, A ; Shackleton, CR (Wiley, 2015)
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    Multiply spliced HIV RNA is a predictive measure of virus production ex vivo and in vivo following reversal of HIV latency
    Zerbato, JM ; Khoury, G ; Zhao, W ; Gartner, MJ ; Pascoe, RD ; Rhodes, A ; Dantanarayana, A ; Gooey, M ; Anderson, J ; Bacchetti, P ; Deeks, SG ; McMahon, J ; Roche, M ; Rasmussen, TA ; Purcell, DFJ ; Lewin, SR (ELSEVIER, 2021-03)
    BACKGROUND: One strategy being pursued to clear latently infected cells that persist in people living with HIV (PLWH) on antiretroviral therapy (ART) is to activate latent HIV infection with a latency reversing agent (LRA). Surrogate markers that accurately measure virus production following an LRA are needed. METHODS: We quantified cell-associated unspliced (US), multiply spliced (MS) and supernatant (SN) HIV RNA by qPCR from total and resting CD4+ T cells isolated from seven PLWH on ART before and after treatment ex vivo with different LRAs, including histone deacetylase inhibitors (HDACi). MS and plasma HIV RNA were also quantified from PLWH on ART (n-11) who received the HDACi panobinostat. FINDINGS: In total and resting CD4+ T cells from PLWH on ART, detection of US RNA was common while detection of MS RNA was infrequent. Primers used to detect MS RNA, in contrast to US RNA, bound sites of the viral genome that are commonly mutated or deleted in PLWH on ART. Following ex vivo stimulation with LRAs, we identified a strong correlation between the fold change increase in SN and MS RNA, but not the fold change increase in SN and US RNA. In PLWH on ART who received panobinostat, MS RNA was significantly higher in samples with detectable compared to non0detectable plasma HIV RNA. INTERPRETATION: Following administration of an LRA, quantification of MS RNA is more likely to reflect an increase in virion production and is therefore a better indicator of meaningful latency reversal. FUNDING: NHMRC, NIH DARE collaboratory.
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    A clinical trial of non-invasive imaging with an anti-HIV antibody labelled with copper-64 in people living with HIV and uninfected controls
    McMahon, JH ; Zerbato, JM ; Lau, JSY ; Lange, JL ; Roche, M ; Tumpach, C ; Dantanarayana, A ; Rhodes, A ; Chang, J ; Rasmussen, TA ; Mackenzie, CA ; Alt, K ; Hagenauer, M ; Roney, J ; O'Bryan, J ; Carey, A ; McIntyre, R ; Beech, P ; O'Keefe, GJ ; Wichmann, CW ; Scott, FE ; Guo, N ; Lee, S-T ; Liu, Z ; Caskey, M ; Nussenzweig, MC ; Donnelly, PS ; Egan, G ; Hagemeyer, CE ; Scott, AM ; Lewin, SR (ELSEVIER, 2021-03)
    BACKGROUND: A research priority in finding a cure for HIV is to establish methods to accurately locate and quantify where and how HIV persists in people living with HIV (PLWH) receiving suppressive antiretroviral therapy (ART). Infusing copper-64 (64Cu) radiolabelled broadly neutralising antibodies targeting HIV envelope (Env) with CT scan and positron emission tomography (PET) identified HIV Env in tissues in SIV infected non-human primates . We aimed to determine if a similar approach was effective in people living with HIV (PLWH). METHODS: Unmodified 3BNC117 was compared with 3BNC117 bound to the chelator MeCOSar and 64Cu (64Cu-3BNC117) in vitro to assess binding and neutralization. In a clinical trial 64Cu-3BNC117 was infused into HIV uninfected (Group 1), HIV infected and viremic (viral load, VL >1000 c/mL; Group 2) and HIV infected aviremic (VL <20 c/mL; Group 3) participants using two dosing strategies: high protein (3mg/kg unlabeled 3BNC117 combined with <5mg 64Cu-3BNC117) and trace (<5mg 64Cu-3BNC117 only). All participants were screened for 3BNC117 sensitivity from virus obtained from viral outgrowth. Magnetic resonance imaging (MRI)/PET and pharmacokinetic assessments (ELISA for serum 3BNC117 concentrations and gamma counting for 64Cu) were performed 1, 24- and 48-hours post dosing. The trial (clincialtrials.gov NCT03063788) primary endpoint was comparison of PET standard uptake values (SUVs) in regions of interest (e.g lymph node groups and gastrointestinal tract). FINDINGS: Comparison of unmodified and modified 3BNC117 in vitro demonstrated no difference in HIV binding or neutralisation. 17 individuals were enrolled of which 12 were dosed including Group 1 (n=4, 2 high protein, 2 trace dose), Group 2 (n=6, 2 high protein, 4 trace) and Group 3 (n=2, trace only). HIV+ participants had a mean CD4 of 574 cells/microL and mean age 43 years. There were no drug related adverse effects and no differences in tissue uptake in regions of interest (e.g lymph node gut, pharynx) between the 3 groups. In the high protein dosing group, serum concentrations of 3BNC117 and gamma counts were highly correlated demonstrating that 64Cu-3BNC117 remained intact in vivo. INTERPRETATION: In PLWH on or off ART, the intervention of infusing 64Cu-3BNC117 and MRI/PET imaging over 48 hours, was unable to detect HIV-1 env expression in vivo. Future studies should investigate alternative radiolabels such as zirconium which have a longer half-life in vivo. FUNDING: Funded by the Alfred Foundation, The Australian Centre for HIV and Hepatitis Virology Research with additional support from the Division of AIDS, National Institute of Allergy and Infectious Disease, US National Institutes of Health (USAI126611). JHM and SRL are supported by the Australian National Health and Medical Research Council.
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    Understanding the mechanisms driving the spread of subtype C HIV-1
    Gartner, MJ ; Roche, M ; Churchill, MJ ; Gorry, PR ; Flynn, JK (ELSEVIER, 2020-03)
    Human immunodeficiency virus type 1 (HIV-1) subtype C (C-HIV) is the most prevalent form of HIV-1 globally, accounting for approximately 50% of infections worldwide. C-HIV is the predominant and near-exclusive subtype in the low resource regions of India and Southern Africa. Given the vast diversity of HIV-1 subtypes, it is curious as to why C-HIV constitutes such a large proportion of global infections. This enriched prevalence may be due to phenotypic differences between C-HIV isolates and other viral strains that permit enhanced transmission efficiency or, pathogenicity, or might due to the socio-demographics of the regions where C-HIV is endemic. Here, we compare the mechanisms of C-HIV pathogenesis to less prominent HIV-1 subtypes, including viral genetic and phenotypic characteristics, and host genetic variability, to understand whether evolutionary factors drove C-HIV to predominance.
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    Human Immunodeficiency Virus (HIV)-Infected CCR6+ Rectal CD4+ T Cells and HIV Persistence On Antiretroviral Therapy
    Anderson, JL ; Khoury, G ; Fromentin, R ; Solomon, A ; Chomont, N ; Sinclair, E ; Milush, JM ; Hartogensis, W ; Bacchetti, P ; Roche, M ; Tumpach, C ; Gartner, M ; Pitman, MC ; Epling, CL ; Hoh, R ; Hecht, FM ; Somsouk, M ; Cameron, PU ; Deeks, SG ; Lewin, SR (OXFORD UNIV PRESS INC, 2020-03-01)
    BACKGROUND: Identifying where human immunodeficiency virus (HIV) persists in people living with HIV and receiving antiretroviral therapy is critical to develop cure strategies. We assessed the relationship of HIV persistence to expression of chemokine receptors and their chemokines in blood (n = 48) and in rectal (n = 20) and lymph node (LN; n = 8) tissue collected from people living with HIV who were receiving suppressive antiretroviral therapy. METHODS: Cell-associated integrated HIV DNA, unspliced HIV RNA, and chemokine messenger RNA were quantified by quantitative polymerase chain reaction. Chemokine receptor expression on CD4+ T cells was determined using flow cytometry. RESULTS: Integrated HIV DNA levels in CD4+ T cells, CCR6+CXCR3+ memory CD4+ T-cell frequency, and CCL20 expression (ligand for CCR6) were highest in rectal tissue, where HIV-infected CCR6+ T cells accounted for nearly all infected cells (median, 89.7%). Conversely in LN tissue, CCR6+ T cells were infrequent, and there was a statistically significant association of cell-associated HIV DNA and RNA with CCL19, CCL21, and CXCL13 chemokines. CONCLUSIONS: HIV-infected CCR6+ CD4+ T cells accounted for the majority of infected cells in rectal tissue. The different relationships between HIV persistence and T-cell subsets and chemokines in rectal and LN tissue suggest that different tissue-specific strategies may be required to eliminate HIV persistence and that assessment of biomarkers for HIV persistence may not be generalizable between blood and other tissues.
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    Longitudinal analysis of subtype C envelope tropism for memory CD4+T cell subsets over the first 3 years of untreated HIV-1 infection
    Gartner, MJ ; Gorry, PR ; Tumpach, C ; Zhou, J ; Dantanarayana, A ; Chang, JJ ; Angelovich, TA ; Ellenberg, P ; Laumaea, AE ; Nonyane, M ; Moore, PL ; Lewin, SR ; Churchill, MJ ; Flynn, JK ; Roche, M (BMC, 2020-08-06)
    BACKGROUND: HIV-1 infects a wide range of CD4+ T cells with different phenotypic properties and differing expression levels of entry coreceptors. We sought to determine the viral tropism of subtype C (C-HIV) Envelope (Env) clones for different CD4+ T cell subsets and whether tropism changes during acute to chronic disease progression. HIV-1 envs were amplified from the plasma of five C-HIV infected women from three untreated time points; less than 2 months, 1-year and 3-years post-infection. Pseudoviruses were generated from Env clones, phenotyped for coreceptor usage and CD4+ T cell subset tropism was measured by flow cytometry. RESULTS: A total of 50 C-HIV envs were cloned and screened for functionality in pseudovirus infection assays. Phylogenetic and variable region characteristic analysis demonstrated evolution in envs between time points. We found 45 pseudoviruses were functional and all used CCR5 to mediate entry into NP2/CD4/CCR5 cells. In vitro infection assays showed transitional memory (TM) and effector memory (EM) CD4+ T cells were more frequently infected (median: 46% and 25% of total infected CD4+ T cells respectively) than naïve, stem cell memory, central memory and terminally differentiated cells. This was not due to these subsets contributing a higher proportion of the CD4+ T cell pool, rather these subsets were more susceptible to infection (median: 5.38% EM and 2.15% TM cells infected), consistent with heightened CCR5 expression on EM and TM cells. No inter- or intra-participant changes in CD4+ T cell subset tropism were observed across the three-time points. CONCLUSIONS: CD4+ T cell subsets that express more CCR5 were more susceptible to infection with C-HIV Envs, suggesting that these may be the major cellular targets during the first 3 years of infection. Moreover, we found that viral tropism for different CD4+ T cell subsets in vitro did not change between Envs cloned from acute to chronic disease stages. Finally, central memory, naïve and stem cell memory CD4+ T cell subsets were susceptible to infection, albeit inefficiently by Envs from all time-points, suggesting that direct infection of these cells may help establish the latent reservoir early in infection.
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    Asn 362 in gp120 contributes to enhanced fusogenicity by CCR5-restricted HIV-1 envelope glycoprotein variants from patients with AIDS
    Sterjovski, J ; Churchill, MJ ; Ellett, A ; Gray, LR ; Roche, MJ ; Dunfee, RL ; Purcell, DF ; Saksena, N ; Wang, B ; Sonza, S ; Wesselingh, SL ; Karlsson, I ; Fenyo, E-M ; Gabuzda, D ; Cunningham, AL ; Gorry, PR (BMC, 2007-12-12)
    BACKGROUND: CCR5-restricted (R5) human immunodeficiency virus type 1 (HIV-1) variants cause CD4+ T-cell loss in the majority of individuals who progress to AIDS, but mechanisms underlying the pathogenicity of R5 strains are poorly understood. To better understand envelope glycoprotein (Env) determinants contributing to pathogenicity of R5 viruses, we characterized 37 full-length R5 Envs from cross-sectional and longitudinal R5 viruses isolated from blood of patients with asymptomatic infection or AIDS, referred to as pre-AIDS (PA) and AIDS (A) R5 Envs, respectively. RESULTS: Compared to PA-R5 Envs, A-R5 Envs had enhanced fusogenicity in quantitative cell-cell fusion assays, and reduced sensitivity to inhibition by the fusion inhibitor T-20. Sequence analysis identified the presence of Asn 362 (N362), a potential N-linked glycosylation site immediately N-terminal to CD4-binding site (CD4bs) residues in the C3 region of gp120, more frequently in A-R5 Envs than PA-R5 Envs. N362 was associated with enhanced fusogenicity, faster entry kinetics, and increased sensitivity of Env-pseudotyped reporter viruses to neutralization by the CD4bs-directed Env mAb IgG1b12. Mutagenesis studies showed N362 contributes to enhanced fusogenicity of most A-R5 Envs. Molecular models indicate N362 is located adjacent to the CD4 binding loop of gp120, and suggest N362 may enhance fusogenicity by promoting greater exposure of the CD4bs and/or stabilizing the CD4-bound Env structure. CONCLUSION: Enhanced fusogenicity is a phenotype of the A-R5 Envs studied, which was associated with the presence of N362, enhanced HIV-1 entry kinetics and increased CD4bs exposure in gp120. N362 contributes to fusogenicity of R5 Envs in a strain dependent manner. Our studies suggest enhanced fusogenicity of A-R5 Envs may contribute to CD4+ T-cell loss in subjects who progress to AIDS whilst harbouring R5 HIV-1 variants. N362 may contribute to this effect in some individuals.
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    Cell-associated HIV RNA and the ratio of HIV RNA to DNA have circadian cycles in HIV-positive individuals on antiretoviral therapy
    Stern, J ; Roche, M ; Solomon, A ; Dantanarayana, A ; Reynaldi, A ; Davenport, MP ; Deeks, SG ; Hartogenesis, W ; Hecht, FM ; Cockerham, L ; Lewin, SR (JOHN WILEY & SONS LTD, 2019-07)