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Journal of Virology, April 2004, p. 4037-4047, Vol. 78, No. 8
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.8.4037-4047.2004

Induction of Autoantibodies to CCR5 in Macaques and Subsequent Effects upon Challenge with an R5-Tropic Simian/Human Immunodeficiency Virus

Bryce Chackerian,1* Lindsey Briglio,2 Paul S. Albert,3 Douglas R. Lowy,1 and John T. Schiller1

Laboratory of Cellular Oncology,1 Animal Sciences Branch,2 Biometric Research Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 208923

Received 5 September 2003/ Accepted 22 December 2003

Antibodies against CCR5, the major coreceptor for human immunodeficiency virus type 1 (HIV-1), may have antiviral potential as viral fusion inhibitors. In this study, we generated a virus-like particle (VLP)-based vaccine that effectively breaks B-cell tolerance and elicits autoantibodies against CCR5 in pig-tailed macaques. Initial studies in mice identified a polypeptide comprising the N-terminal domain of pig-tailed macaque CCR5 fused to streptavidin that, when conjugated at high density to bovine papillomavirus major capsid protein L1 VLPs, induced high-titer immunoglobulin G (IgG) that bound to a macaque CCR5-expressing cell line in vitro. In macaques, CCR5 peptide-conjugated VLP preparations induced high-avidity anti-CCR5 IgG autoantibody responses, and all five immunized macaques generated IgG that could block infection of CCR5-tropic simian/human immunodeficiency virus SHIVSF162P3 in vitro. Although the anti-CCR5 IgG titers declined with time, autoantibody levels were boosted upon revaccination. Vaccinated macaques remained healthy for a period of over 3 years after the initial immunization, and no decline in the number of CCR5-expressing T cells was detected. To test the prophylactic efficacy of CCR5 autoantibodies, immunized macaques were challenged with SHIVSF162P3. Although the plasma-associated virus in half of six control macaques declined to undetectable levels, viral loads were lower, declined more rapidly, and eventually became undetectable in all five macaques in which CCR5 autoantibodies had been elicited. In addition, in the four vaccinated macaques with higher autoantibody titers, viral loads and time to control of viremia were significantly decreased relative to controls, indicating the possibility that CCR5 autoantibodies contributed to the control of viral replication.

* Corresponding author. Mailing address: Laboratory of Cellular Oncology, National Cancer Institute, 37 Convent Dr., Room 4106, Bethesda, MD 20892-4263. Phone: (301) 496-6539. Fax: (301) 480-5322. E-mail: brycec{at}nih.gov.

Journal of Virology, April 2004, p. 4037-4047, Vol. 78, No. 8
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.8.4037-4047.2004




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