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Journal of Virology, June 2002, p. 6016-6026, Vol. 76, No. 12
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.12.6016-6026.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Rhesus Macaque Resistance to Mucosal Simian Immunodeficiency Virus Infection Is Associated with a Postentry Block in Viral Replication

Bo Peng,1 Rebecca Voltan,1 Lulu Lim,1 Yvette Edghill-Smith,1 Sanjay Phogat,2 Dimiter S. Dimitrov,2 Kamalpreet Arora,1 Michel Leno,1 Soe Than,3 Ruth Woodward,3 Phillip D. Markham,3 Martin Cranage,4 and Marjorie Robert-Guroff1*

Basic Research Laboratory, National Cancer Institute, Bethesda, Maryland 20892,1 Laboratory of Experimental and Computational Biology, National Cancer Institute-Frederick, National Institutes of Health, Frederick, Maryland 21702,2 Advanced BioScience Laboratories, Inc., Kensington, Maryland 20895,3 Centre for Applied Microbiology and Research, Salisbury, Wiltshire SP4 OJG, United Kingdom4

Received 24 January 2002/ Accepted 11 March 2002

Elucidation of the host factors which influence susceptibility to human immunodeficiency virus or simian immunodeficiency virus (SIV) infection and disease progression has important theoretical and practical implications. Rhesus macaque 359, a vaccine control animal, resisted two successive intravaginal challenges with SIVmac251 and failed to seroconvert. Here, after an additional intrarectal SIVmac32H challenge, macaque 359 remained highly resistant to infection. Viral RNA (106 copies/ml) was observed in plasma only at week 2 postchallenge. Virus isolation and proviral DNA were positive only once at week eight postchallenge. The animal remained seronegative and cleared SIV in vivo. Its blood and lymph node cells obtained at 49 weeks after intrarectal challenge did not transmit SIV to a naive macaque. We found that the resistance of macaque 359 to SIV infection was not due to a high level of CD8+ suppressor activity but to an inherent resistance of its CD4+ T cells. To elucidate the basis for the unusually strong resistance of macaque 359 to SIV infection in vivo and in vitro, we investigated early events of viral infection and replication in CD4+ cells of macaque 359, including expression and mutation screening of SIV coreceptors and analysis of viral entry and reverse transcription. Mutation screening revealed no genetic alteration in SIV coreceptors. PCR analysis revealed a significant delay in production of early in vitro reverse transcription intermediates in macaque 359 cells compared to susceptible controls, but cell fusion assays showed that SIV entered the CD4+ CCR5+ cells of macaque 359 as readily as cells of macaques susceptible to SIV infection. Our results suggest that the resistance of macaque 359 to SIV infection is due to a postentry block in viral replication and implicate a cellular inhibitory mechanism in its CD4+ T cells. Identification of this host mechanism will help further elucidate the biochemistry of reverse transcription and may suggest therapeutic strategies. Determining the prevalence of this host resistance mechanism among macaques may lead to better design of SIV pathogenesis and vaccine studies.

* Corresponding author. Mailing address: Basic Research Laboratory, National Cancer Institute, 41 Library Dr., Bldg. 41, Rm. D804, Bethesda, MD 20892-5055. Phone: (301) 496-2114. Fax: (301) 496-8394. E-mail: guroffm{at}exchange.nih.gov.

Journal of Virology, June 2002, p. 6016-6026, Vol. 76, No. 12
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.12.6016-6026.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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