Simian-human immunodeficiency virus (SHIV) challenge stocks are critical for preclinical testing of vaccines, antibodies, and other interventions aimed to prevent HIV-1. A major unmet need for the field has been the lack of a SHIV challenge stock expressing circulating recombinant form 01_AE (CRF01_AE) env sequences. We therefore sought to develop mucosally transmissible SHIV challenge stocks containing HIV-1 CRF01_AE env derived from acutely HIV-1 infected individuals from Thailand. SHIV-AE6, SHIV-AE6RM, and SHIV-AE16 contained env sequences that were >99% identical to the original HIV-1 isolate and did not require in vivo passaging. These viruses exhibited CCR5 tropism and displayed a tier 2 neutralization phenotype. These challenge stocks efficiently infected rhesus monkeys by the intrarectal route, replicated to high levels during acute infection, and established chronic viremia in a subset of animals. SHIV-AE16 was titrated for use in single, high dose as well as repetitive, low dose intrarectal challenge studies. These SHIV challenge stocks should facilitate the preclinical evaluation of vaccines, monoclonal antibodies, and other interventions targeted at preventing HIV-1 CRF01_AE infection.
References
[1]
Harouse JM, Gettie A, Eshetu T, Tan RC, Bohm R, Blanchard J, et al. Mucosal transmission and induction of simian AIDS by CCR5-specific simian/human immunodeficiency virus SHIV(SF162P3). J Virol. 2001;75: 1990–1995. pmid:11160699 doi: 10.1128/jvi.75.4.1990-1995.2001
[2]
Lu Y, Salvato MS, Pauza CD, Li J, Sodroski J, Manson K, et al. Utility of SHIV for testing HIV-1 vaccine candidates in macaques. J Acquir Immune Defic Syndr Hum Retrovirol. 1996;12: 99–106. pmid:8680896 doi: 10.1097/00042560-199606010-00001
[3]
Siddappa NB, Watkins JD, Wassermann KJ, Song R, Wang W, Kramer VG, et al. R5 clade C SHIV strains with tier 1 or 2 neutralization sensitivity: tools to dissect env evolution and to develop AIDS vaccines in primate models. PLoS ONE. 2010;5: e11689. doi: 10.1371/journal.pone.0011689. pmid:20657739
[4]
Bandaranayake RM, Kolli M, King NM, Nalivaika EA, Heroux A, Kakizawa J, et al. The effect of clade-specific sequence polymorphisms on HIV-1 protease activity and inhibitor resistance pathways. J Virol. 2010;84: 9995–10003. doi: 10.1128/JVI.00505-10. pmid:20660190
[5]
Kijak GH, Tovanabutra S, Rerks-Ngarm S, Nitayaphan S, Eamsila C, Kunasol P, et al. Molecular evolution of the HIV-1 Thai epidemic between the time of RV144 immunogen selection to the execution of the vaccine efficacy trial. J Virol. 2013;87: 7265–7281. doi: 10.1128/JVI.03070-12. pmid:23576510
[6]
Rerks-Ngarm S, Pitisuttithum P, Nitayaphan S, Kaewkungwal J, Chiu J, Paris R, et al. Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand. N Engl J Med. 2009;361: 2209–2220. doi: 10.1056/NEJMoa0908492. pmid:19843557
[7]
Haynes BF, Gilbert PB, McElrath MJ, Zolla-Pazner S, Tomaras GD, Alam SM, et al. Immune-correlates analysis of an HIV-1 vaccine efficacy trial. N Engl J Med. 2012;366: 1275–1286. doi: 10.1056/NEJMoa1113425. pmid:22475592
[8]
Rolland M, Edlefsen PT, Larsen BB, Tovanabutra S, Sanders-Buell E, Hertz T, et al. Increased HIV-1 vaccine efficacy against viruses with genetic signatures in Env V2. Nature. 2012;490: 417–420. doi: 10.1038/nature11519. pmid:22960785
[9]
Parker ZF, Iyer SS, Wilen CB, Parrish NF, Chikere KC, Lee F-H, et al. Transmitted/Founder and Chronic HIV-1 Envelope Proteins Are Distinguished by Differential Utilization of CCR5. J Virol. 2013;87: 2401–2411. doi: 10.1128/JVI.02964-12. pmid:23269796
[10]
Parrish NF, Gao F, Li H, Giorgi EE, Barbian HJ, Parrish EH, et al. Phenotypic properties of transmitted founder HIV-1. Proc Natl Acad Sci USA. 2013;110: 6626–6633. doi: 10.1073/pnas.1304288110. pmid:23542380
[11]
Keele BF, Giorgi EE, Salazar-Gonzalez JF, Decker JM, Pham KT, Salazar MG, et al. Identification and characterization of transmitted and early founder virus envelopes in primary HIV-1 infection. Proc Natl Acad Sci USA. 2008;105: 7552–7557. doi: 10.1073/pnas.0802203105. pmid:18490657
[12]
Whitney JB, Hill AL, Sanisetty S. et al. Rapid seeding of the viral reservoir prior to SIV viraemia in rhesus monkeys. Nature. 2014;512: 74–77 doi: 10.1038/nature13594. pmid:25042999
[13]
Ananworanich J, Schuetz A, Vandergeeten C, Sereti I, de Souza M, Rerknimitr R, et al. Impact of multi-targeted antiretroviral treatment on gut T cell depletion and HIV reservoir seeding during acute HIV infection. PLoS ONE. 2012;7: e33948. doi: 10.1371/journal.pone.0033948. pmid:22479485
[14]
Chang H-W, Tartaglia LJ, Whitney JB, Lim S-Y, Sanisetty S, Lavine CL, et al. Generation and evaluation of clade C simian-human immunodeficiency virus challenge stocks. J Virol. 2015;89: 1965–1974. doi: 10.1128/JVI.03279-14. pmid:25473043
[15]
Montefiori DC. Measuring HIV neutralization in a luciferase reporter gene assay. Methods Mol Biol. 2009;485: 395–405. doi: 10.1007/978-1-59745-170-3_26. pmid:19020839
[16]
Sarzotti-Kelsoe M, Bailer RT, Turk E, Lin C-L, Bilska M, Greene KM, et al. Optimization and validation of the TZM-bl assay for standardized assessments of neutralizing antibodies against HIV-1. J Immunol Methods. 2014;409: 131–146. doi: 10.1016/j.jim.2013.11.022. pmid:24291345
[17]
Palmer S, Wiegand AP, Maldarelli F, Bazmi H, Mican JM, Polis M, et al. New real-time reverse transcriptase-initiated PCR assay with single-copy sensitivity for human immunodeficiency virus type 1 RNA in plasma. J Clin Microbiol. 2003;41: 4531–4536. pmid:14532178 doi: 10.1128/jcm.41.10.4531-4536.2003
[18]
Liao H-X, Bonsignori M, Alam SM, McLellan JS, Tomaras GD, Moody MA, et al. Vaccine induction of antibodies against a structurally heterogeneous site of immune pressure within HIV-1 envelope protein variable regions 1 and 2. Immunity. 2013;38: 176–186. doi: 10.1016/j.immuni.2012.11.011. pmid:23313589
[19]
Etemad-Moghadam B, Sun Y, Nicholson EK, Fernandes M, Liou K, Gomila R, et al. Envelope glycoprotein determinants of increased fusogenicity in a pathogenic simian-human immunodeficiency virus (SHIV-KB9) passaged in vivo. J Virol. 2000;74: 4433–4440. pmid:10756060 doi: 10.1128/jvi.74.9.4433-4440.2000
[20]
Wrin T, Loh TP, Vennari JC, Schuitemaker H, Nunberg JH. Adaptation to persistent growth in the H9 cell line renders a primary isolate of human immunodeficiency virus type 1 sensitive to neutralization by vaccine sera. J Virol. 1995;69: 39–48. pmid:7983734
Barouch DH, Stephenson KE, Borducchi EN, Smith K, Stanley K, McNally AG, et al. Protective efficacy of a global HIV-1 mosaic vaccine against heterologous SHIV challenges in rhesus monkeys. Cell. 2013;155: 531–539. doi: 10.1016/j.cell.2013.09.061. pmid:24243013
