SIV infection of two natural host species, sooty mangabeys and African green monkeys (AGMs), is rarely pathogenic. A trio of newly published studies evaluate the changes in gene expression that result from SIV infection in these animals compared to rhesus macaques, in which SIV typically causes T cell loss and simian AIDS. A novel feature of the research is that gene expression is analyzed from very early time points (~3 days onwards) in order to capture any transient changes during acute infection. All three studies report the same key finding: sooty mangabeys and AGMs initially mount an immune response to SIV that is accompanied by massive changes in gene expression, but these changes largely resolve after acute infection. In contrast, altered gene expression – particularly involving genes related to immune activation - persists in pathogenic SIV infection of rhesus macaques. These new papers refute a prior theory that SIV is generally non-pathogenic in sooty mangabeys and AGMs because their immune systems essentially ignore the virus.
The studies place a particular focus on genes related to the production of type 1 interferons and interferon-stimulated genes (ISGs) due to a previous report suggesting that sooty mangabey dendritic cells fail to produce interferon after exposure to SIV. The gene expression data clearly show that interferons and ISGs are massively but transiently upregulated during acute SIV infection in both sooty mangabeys and AGMs. In rhesus macaques, there is also a massive increase in expression of interferon genes and ISGs during acute SIV infection and these genes remain persistently upregulated into the chronic phase.
The research team led by Steven Bosinger also analyzes differences between sooty mangabeys and rhesus macaques by grouping genes together into seven broad categories: cell-mediated immune response, humoral immune response, inflammatory response, immune cell trafficking, cell death, cell cycle and hematopoiesis (click on the image to the left to see detail). The striking contrast that emerges from this analysis is that genes involved in cell mediated, humoral and inflammatory immune responses are more strongly upregulated at day 10 after infection in sooty mangabeys compared to rhesus macaques, but by day 180 this difference is reversed. Cell cycle gene upregulation also disappears by day 180 in sooty mangabeys but remains significantly upregulated in rhesus macques, consistent with pathogenic SIV infection causing increased T cell turnover. In both sooty mangabeys and AGMs, the rapid curtailment of immune activation after acute infection is associated with the upregulation of genes known to be involved in downmodulating immune responses.
The overall picture conveyed by the data is that sooty mangabeys and AGMs make a potent innate and adaptive immune response against SIV immediately after infection, but this immune response resolves (despite the fact that relatively high levels of SIV replication persist in the chronic phase). In contrast, rhesus macaques make a weaker initial response and continue to mount responses throughout the course of infection. A systems biology analysis by Bosinger and colleagues identifies the T cell exhaustion marker LAG3 as being a strong correlate of persistent immune activation in macaques, perhaps suggesting that T cell dysfunction plays an important role in the unresolved immune response against SIV in these animals.
J. Clin. Invest. doi:10.1172/JCI40115.
Global genomic analysis reveals rapid control of a robust innate response in SIV-infected sooty mangabeys (free access to full text)
Steven E. Bosinger1,2, Qingsheng Li3, Shari N. Gordon1, Nichole R. Klatt1, Lijie Duan3, Luoling Xu2, Nicholas Francella1, Abubaker Sidahmed2, Anthony J. Smith3, Elizabeth M. Cramer1, Ming Zeng3, David Masopust3, John V. Carlis4, Longsi Ran2, Thomas H. Vanderford1, Mirko Paiardini1, R. Benjamin Isett5, Don A. Baldwin1,5, James G. Else6, Silvija I. Staprans7, Guido Silvestri1,6, Ashley T. Haase3 and David J. Kelvin2,8
1 Department of Pathology and Laboratory Medicine, and Microbiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA. 2 Division of Experimental Therapeutics, University Health Network, Toronto, Ontario, Canada. 3 Department of Microbiology, Medical School, University of Minnesota, Minneapolis, Minnesota, USA. 4 Department of Computer Science and Engineering, Institute of Technology, University of Minnesota, Minneapolis, Minnesota, USA. 5 Penn Microarray Facility, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA. 6 Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA. 7 Merck Vaccines and Infectious Diseases, Merck and Co., West Point, Pennsylvania, USA. 8 Division of Immunology, International Institute of Infection and Immunity, Shantou University Medical College, Shantou, Guangdong, People’s Republic of China.
Authorship note: Steven E. Bosinger and Qingsheng Li, as well as Guido Silvestri, Ashley T. Haase, and David J. Kelvin, contributed equally to this work.
Natural SIV infection of sooty mangabeys (SMs) is nonprogressive despite chronic virus replication. Strikingly, it is characterized by low levels of immune activation, while pathogenic SIV infection of rhesus macaques (RMs) is associated with chronic immune activation. To elucidate the mechanisms underlying this intriguing phenotype, we used high-density oligonucleotide microarrays to longitudinally assess host gene expression in SIV-infected SMs and RMs. We found that acute SIV infection of SMs was consistently associated with a robust innate immune response, including widespread upregulation of IFN-stimulated genes (ISGs) in blood and lymph nodes. While SMs exhibited a rapid resolution of ISG expression and immune activation, both responses were observed chronically in RMs. Systems biology analysis indicated that expression of the lymphocyte inhibitory receptor LAG3, a marker of T cell exhaustion, correlated with immune activation in SIV-infected RMs but not SMs. Our findings suggest that active immune regulatory mechanisms, rather than intrinsically attenuated innate immune responses, underlie the low levels of immune activation characteristic of SMs chronically infected with SIV.
J. Clin. Invest. doi:10.1172/JCI40093.
Béatrice Jacquelin1, Véronique Mayau1, Brice Targat2, Anne-Sophie Liovat1, Désirée Kunkel1, Gaël Petitjean1, Marie-Agnès Dillies3, Pierre Roques4, Cécile Butor5, Guido Silvestri6, Luis D. Giavedoni7, Pierre Lebon8, Françoise Barré-Sinoussi1, Arndt Benecke2,9 and Michaela C. Müller-Trutwin1
1 Institut Pasteur, Unité de Régulation des Infections Rétrovirales, Paris, France. 2 Institut des Hautes ωtudes Scientifiques, Bures-sur-Yvette, France. 3 Institut Pasteur, Plateforme 2, Paris, France. 4 CEA, Division of Immuno-Virology, DSV/iMETI, Fontenay-aux-Roses, and Université Paris-Sud 11, UMR E01, Orsay, France. 5 Laboratoire d’Immunologie Humaine, INSERM U743, and Université Paris Diderot, Paris, France. 6 Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. 7 Southwest National Primate Research Center, Southwest Foundation for Biomedical Research, San Antonio, Texas, USA. 8 Hôpital Saint-Vincent de Paul and Université Paris Descartes, Laboratoire de Virologie, Paris, France. 9 Institut de Recherche Interdisciplinaire, CNRS USR3078, Lille, France.
African green monkeys (AGMs) infected with the AGM type of SIV (SIVagm) do not develop chronic immune activation and AIDS, despite viral loads similar to those detected in humans infected with HIV-1 and rhesus macaques (RMs) infected with the RM type of SIV (SIVmac). Because chronic immune activation drives progressive CD4+ T cell depletion and immune cell dysfunctions, factors that characterize disease progression, we sought to understand the molecular basis of this AGM phenotype. To this end, we longitudinally assessed the gene expression profiles of blood- and lymph node–derived CD4+ cells from AGMs and RMs in response to SIVagm and SIVmac infection, respectively, using a genomic microarray platform. The molecular signature of acute infection was characterized, in both species, by strong upregulation of type I IFN–stimulated genes (ISGs). ISG expression returned to basal levels after postinfection day 28 in AGMs but was sustained in RMs, especially in the lymph node–derived cells. We also found that SIVagm induced IFN-α production by AGM cells in vitro and that low IFN-α levels were sufficient to induce strong ISG responses. In conclusion, SIV infection triggered a rapid and strong IFN-α response in vivo in both AGMs and RMs, with this response being efficiently controlled only in AGMs, possibly as a result of active regulatory mechanisms.
J. Clin. Invest. doi:10.1172/JCI41509.
Olivier Manches, Nina Bhardwaj
Natural nonhuman primate hosts of SIV do not succumb to AIDS despite significant viral replication, a phenomenon attributed to reduced levels of chronic and deleterious “immune activation.” Two studies in this issue of the JCI, by Bosinger et al. and Jacquelin et al., now show that SIV induces vigorous immune activation and upregulation of IFN-stimulated genes in both natural and susceptible hosts, but strikingly, the responses resolve only in the former (see the related articles, doi:10.1172/JCI40115 and 10.1172/JCI40093, respectively). Thus, natural hosts for SIV actively engage mechanisms to abort sustained immune activation and its associated harmful effects.
JVI Accepts, published online ahead of print on 25 November 2009
J. Virol. doi:10.1128/JVI.01496-09
Non pathogenesis of SIV infection is associated with reduced inflammation and recruitment of plasmacytoid dendritic cells to lymph nodes, not to lack of an interferon type I response, during the acute phase.
Laure Campillo-Gimenez, Mireille Laforge, Michèle Fay, Audrey Brussel, Marie-Christine Cumont, Valérie Monceaux, Ousmane Diop, Yves Lévy, Bruno Hurtrel, John Zaunders, Jacques Corbeil, Carole Elbim, and Jérôme Estaquier
INSERM U955, Faculté Créteil Henri Mondor, Créteil, F-94000, France; Université Paris 7 Denis Diderot, Faculté de Médecine, site Bichat, Paris, F-75018, France; Unité de Physiopathologie des Infections Lentivirales, Institut Pasteur, 28 rue du Docteur Roux, Paris, F-75015, France; Institut Pasteur, Dakar, Sénégal; Centre for Applied Medical Research, St Vincent's Hospital, Darlinghurst, NSW, Australia; Université Laval, Centre de Recherche en Infectiologie, G1V 4G2 Québec, Canada; Centre de Recherche des Cordeliers, Université Pierre et Marie Curie – Paris 6, UMR S 872, Paris, F-75006 France; Université Paris Descartes, UMR S 872, Paris, F-75006 France; INSERM, U872, Paris, F-75006,France; Assistance Publique-Hôpitaux de Paris, Hôpital Henri Mondor, Créteil, France
Divergent Toll-like receptor (TLR)-7 and TLR-9 signaling has been proposed to distinguish pathogenic from non pathogenic SIV infection in primate models. Herein, we demonstrate that increased expression of type I IFN in pathogenic rhesus macaques as compared to non pathogenic African green monkeys was associated with the recruitment of plasmacytoid dendritic cells (pDCs) in the lymph nodes and the presence of an inflammatory environment early after infection, instead of a difference in TLR-7/9 response.