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* Université Paris 7-Denis Diderot, Faculté de Médecine, Assistance Publique-Hôpitaux de Paris (AP-HP), Centre Hospitalier Universitaire Xavier Bichat, Service d’Immunologie et d’Hématologie, Paris, France; Institut National de la Santé et de la Recherche Médicale (INSERM), Unité 773, Paris, France;
Institut Pasteur, Unité de Physiopathologie des Infections Lentivirales, Paris, France;
INSERM, Unité 841, Faculté de Médecine de Créteil, Créteil, France;
AP-HP, Hôpital Henri Mondor, Créteil, France;
¶ Institut Pasteur, Dakar, Sénégal;
|| Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA 19129;
# BIOQUAL, Rockville, MD 20850
We used pathogenic and nonpathogenic simian models of SIV infection of Chinese and Indian rhesus macaque (RMs) and African green monkeys (AGMs), respectively, to investigate the relationship between polymorphonuclear neutrophil (PMN) death and the extent of viral replication and disease outcome. In this study, we showed that PMN death increased early during the acute phase of SIV infection in Chinese RMs and coincided with the peak of viral replication on day 14. The level of PMN death was significantly more severe in RMs that progressed more rapidly to AIDS and coincided with neutropenia. Neutropenia was also observed in Indian RMs and was higher in non-Mamu-A*01 compared with Mamu-A*01 animals. In stark contrast, no changes in the levels of PMN death were observed in the nonpathogenic model of SIVagm-sab (sabaeus) infection of AGMs despite similarly high viral replication. PMN death was a Bax and Bak-independent mitochondrial insult, which is prevented by inhibiting calpain activation but not caspases. We found that BOB/GPR15, a SIV coreceptor, is expressed on the PMN surface of RMs at a much higher levels than AGMs and its ligation induced PMN death, suggesting that SIV particle binding to the cell surface is sufficient to induce PMN death. Taken together, our results suggest that species-specific differences in BOB/GPR15 receptor expression on PMN can lead to increased acute phase PMN death. This may account for the decline in PMN numbers that occurs during primary SIV infection in pathogenic SIV infection and may have important implications for subsequent viral replication and disease progression.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was funded by grants from the Agence Nationale de Recherches sur le Sida et les Hépatites Virales, Sidaction, Fondation de France, and Fondation pour la Recherche Médicale (to J.E.) and in part by National Institutes of Health Grant R01 AI62437 (to P.D.K.). C.E. holds an Assistance Publique-Hôpitaux de Paris mobility post-doctoral position. S.F. was supported by a grant from Fonds d’Études et de Recherche du Corps Médical des Hôpitaux de Paris.
2 This work is dedicated to the memory of Bruno Hurtrel.
3 Address correspondence and reprint requests to Dr. Jérome Estaquier, Institut National de la Santé et de la Recherche Médicale, Unité 841, Faculté de Médecine de Créteil, 8 Rue du Général Sarail, 94010 Créteil, France. E-mail address: estaquier{at}yahoo.fr
4 Abbreviations used in this paper: PMN, polymorphonuclear neutrophil; 7-AAD, 7-amino-actinomycin D; AGM, African green monkey; AID50, 50% animal infectious dose; ALLN, N-acetyl-Leu-Leu-Nle; DiOC6, 3,3'-dihexyloxacarbocyanine iodide; 
m, mitochondrial transmembrane potential; NHP, nonhuman primate; RM, rhesus macaque; ROS, reactive oxygen species; z-VAD-fmk, N-benzyloxycarbonyl-Val-Ala-DL-Asp(Ome)-fluoromethylketone.
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