Topical Gel Formulation of Broadly Neutralizing Anti-HIV-1 Monoclonal Antibody VRC01 Confers Protection Against HIV-1 Vaginal Challenge in a Humanized Mouse Model

Overview

Journal Virology

Specialty Microbiology

Date 2012 Jul 27

PMID 22832125

Citations 52

Authors

Milena Veselinovic

C Preston Neff

Leila R Mulder

Ramesh Akkina

Affiliations

Soon will be listed here.

Abstract

The new generation broadly neutralizing antibody VRC01 against HIV-1 shows great potential as a topically administered microbicide to prevent sexual transmission. We evaluated its efficacy in a RAG-hu humanized mouse model of vaginal HIV-1 transmission. Mice were challenged vaginally with R5 tropic HIV-1 BaL an hour after intravaginal application of the VRC01 (1 mg/ml concentration) gel. A combination of four first generation bNAbs, namely b12, 2F5, 4E10 and 2G12, was used as a positive efficacy control whereas a non-specific dengue MAb 4G2 was used as negative control. Our results showed that seven out of nine VRC01 antibody administered mice and all of the mice receiving the four bNAb antibody combination were protected against HIV-1 challenge. These findings demonstrate the efficacy of the new bNAb VRC01 as a topical microbicide to protect against HIV-1 vaginal transmission and highlight the use of the RAG-hu mouse model for testing HIV prevention strategies.

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References

Denton P, Othieno F, Martinez-Torres F, Zou W, Krisko J, Fleming E . One percent tenofovir applied topically to humanized BLT mice and used according to the CAPRISA 004 experimental design demonstrates partial protection from vaginal HIV infection, validating the BLT model for evaluation of new microbicide candidates. J Virol. 2011; 85(15):7582-93. PMC: 3147928. DOI: 10.1128/JVI.00537-11. View

Omar R, Bergeron M . The future of microbicides. Int J Infect Dis. 2011; 15(10):e656-60. DOI: 10.1016/j.ijid.2011.05.001. View

Hofmann-Lehmann R, Vlasak J, Rasmussen R, Jiang S, Li P, Baba T . Postnatal pre- and postexposure passive immunization strategies: protection of neonatal macaques against oral simian-human immunodeficiency virus challenge. J Med Primatol. 2002; 31(3):109-19. DOI: 10.1034/j.1600-0684.2002.01014.x. View

Fox J . HIV drugs made in tobacco. Nat Biotechnol. 2011; 29(10):852. DOI: 10.1038/nbt1011-852. View

Sun Z, Denton P, Estes J, Othieno F, Wei B, Wege A . Intrarectal transmission, systemic infection, and CD4+ T cell depletion in humanized mice infected with HIV-1. J Exp Med. 2007; 204(4):705-14. PMC: 2118553. DOI: 10.1084/jem.20062411. View

Parren P, Marx P, Hessell A, Luckay A, Harouse J, Cheng-Mayer C . Antibody protects macaques against vaginal challenge with a pathogenic R5 simian/human immunodeficiency virus at serum levels giving complete neutralization in vitro. J Virol. 2001; 75(17):8340-7. PMC: 115078. DOI: 10.1128/jvi.75.17.8340-8347.2001. View

Klasse P, Shattock R, Moore J . Antiretroviral drug-based microbicides to prevent HIV-1 sexual transmission. Annu Rev Med. 2007; 59:455-71. DOI: 10.1146/annurev.med.59.061206.112737. View

Ruprecht R, Hofmann-Lehmann R, Rasmussen R, Liska V, Vlasak J, Xu W . Protection of neonatal macaques against experimental SHIV infection by human neutralizing monoclonal antibodies. Transfus Clin Biol. 2001; 8(4):350-8. DOI: 10.1016/s1246-7820(01)00187-2. View

Neff C, Kurisu T, Ndolo T, Fox K, Akkina R . A topical microbicide gel formulation of CCR5 antagonist maraviroc prevents HIV-1 vaginal transmission in humanized RAG-hu mice. PLoS One. 2011; 6(6):e20209. PMC: 3105981. DOI: 10.1371/journal.pone.0020209. View

10.

Hessell A, Rakasz E, Poignard P, Hangartner L, Landucci G, Forthal D . Broadly neutralizing human anti-HIV antibody 2G12 is effective in protection against mucosal SHIV challenge even at low serum neutralizing titers. PLoS Pathog. 2009; 5(5):e1000433. PMC: 2674935. DOI: 10.1371/journal.ppat.1000433. View

11.

Denton P, Garcia J . Humanized mouse models of HIV infection. AIDS Rev. 2011; 13(3):135-48. PMC: 3741405. View

12.

Veazey R, Ketas T, Dufour J, Moroney-Rasmussen T, Green L, Klasse P . Protection of rhesus macaques from vaginal infection by vaginally delivered maraviroc, an inhibitor of HIV-1 entry via the CCR5 co-receptor. J Infect Dis. 2010; 202(5):739-44. PMC: 2916941. DOI: 10.1086/655661. View

13.

Shultz L, Brehm M, Bavari S, Greiner D . Humanized mice as a preclinical tool for infectious disease and biomedical research. Ann N Y Acad Sci. 2012; 1245:50-4. PMC: 3514446. DOI: 10.1111/j.1749-6632.2011.06310.x. View

14.

Denton P, Estes J, Sun Z, Othieno F, Wei B, Wege A . Antiretroviral pre-exposure prophylaxis prevents vaginal transmission of HIV-1 in humanized BLT mice. PLoS Med. 2008; 5(1):e16. PMC: 2194746. DOI: 10.1371/journal.pmed.0050016. View

15.

Kelly C, Shattock R . Specific microbicides in the prevention of HIV infection. J Intern Med. 2011; 270(6):509-19. DOI: 10.1111/j.1365-2796.2011.02454.x. View

16.

Wu X, Zhou T, Zhu J, Zhang B, Georgiev I, Wang C . Focused evolution of HIV-1 neutralizing antibodies revealed by structures and deep sequencing. Science. 2011; 333(6049):1593-602. PMC: 3516815. DOI: 10.1126/science.1207532. View

17.

Akkina R, Berges B, Palmer B, Remling L, Neff C, Kuruvilla J . Humanized Rag1-/- γc-/- mice support multilineage hematopoiesis and are susceptible to HIV-1 infection via systemic and vaginal routes. PLoS One. 2011; 6(6):e20169. PMC: 3114781. DOI: 10.1371/journal.pone.0020169. View

18.

Neff C, Ndolo T, Tandon A, Habu Y, Akkina R . Oral pre-exposure prophylaxis by anti-retrovirals raltegravir and maraviroc protects against HIV-1 vaginal transmission in a humanized mouse model. PLoS One. 2011; 5(12):e15257. PMC: 3006206. DOI: 10.1371/journal.pone.0015257. View

19.

Berges B, Akkina S, Folkvord J, Connick E, Akkina R . Mucosal transmission of R5 and X4 tropic HIV-1 via vaginal and rectal routes in humanized Rag2-/- gammac -/- (RAG-hu) mice. Virology. 2008; 373(2):342-51. PMC: 3092740. DOI: 10.1016/j.virol.2007.11.020. View

20.

Walker L, Phogat S, Chan-Hui P, Wagner D, Phung P, Goss J . Broad and potent neutralizing antibodies from an African donor reveal a new HIV-1 vaccine target. Science. 2009; 326(5950):285-9. PMC: 3335270. DOI: 10.1126/science.1178746. View