Paucity of CD4 (cid:1) CCR5 (cid:1) T cells is a typical feature of natural SIV hosts

In contrast to lentiviral infections of humans and macaques, simian immunodeficiency virus (SIV) infection of natural hosts is nonpathogenic despite high levels of viral replication. However, the mechanisms underlying this absence of disease are unknown. Here we report that natural hosts for SIV infection express remarkably low levels of CCR5 on CD4+ T cells isolated from blood, lymph nodes, and mucosal tissues. Given that this immunologic feature is found in 5 different species of natural SIV hosts (sooty mangabeys, African green monkeys, mandrills, sun-tailed monkeys, and chimpanzees) but is absent in 5 nonnatural/recent hosts (humans, rhesus, pigtail, cynomolgus macaques, and baboons), it may represent a key feature of the coevolution between the virus and its natural hosts that led to a nonpathogenic infection. Beneficial effects of low CCR5 expression on CD4+ T cells may include the reduction of target cells for viral replication and a decreased homing of activated CD4+ T cells to inflamed tissue.

[1]  F. Barré-Sinoussi,et al.  Impact of Viral Factors on Very Early In Vivo Replication Profiles in Simian Immunodeficiency Virus SIVagm-Infected African Green Monkeys , 2005, Journal of Virology.

[2]  A S Perelson,et al.  Dynamics of HIV-1 and CD4+ lymphocytes in vivo. , 1997, AIDS.

[3]  William J. Kaiser,et al.  Divergent Host Responses during Primary Simian Immunodeficiency Virus SIVsm Infection of Natural Sooty Mangabey and Nonnatural Rhesus Macaque Hosts , 2005, Journal of Virology.

[4]  F. Gao,et al.  Origin of HIV-1 in the chimpanzee Pan troglodytes troglodytes , 1999, Nature.

[5]  D. Ho,et al.  Human immunodeficiency virus type 2 (HIV-2) seroprevalence and characterization of a distinct HIV-2 genetic subtype from the natural range of simian immunodeficiency virus-infected sooty mangabeys , 1997, Journal of virology.

[6]  D. Ho,et al.  Natural Infection of a Homozygous Δ24 CCR5 Red-capped Mangabey with an R2b-Tropic Simian Immunodeficiency Virus , 1998, The Journal of experimental medicine.

[7]  B. Korber,et al.  An African HIV-1 sequence from 1959 and implications for the origin of the epidemic , 1998, Nature.

[8]  K. Mansfield,et al.  Dynamics of CCR5 Expression by CD4+ T Cells in Lymphoid Tissues during Simian Immunodeficiency Virus Infection , 2000, Journal of Virology.

[9]  Martin A. Nowak,et al.  Viral dynamics in human immunodeficiency virus type 1 infection , 1995, Nature.

[10]  A. Haase Perils at mucosal front lines for HIV and SIV and their hosts , 2005, Nature Reviews Immunology.

[11]  Z. Grossman,et al.  CD4+ T-cell depletion in HIV infection: Are we closer to understanding the cause? , 2002, Nature Medicine.

[12]  P. Roques,et al.  Primary Simian Immunodeficiency Virus SIVmnd-2 Infection in Mandrills (Mandrillus sphinx) , 2006, Journal of Virology.

[13]  R. Siliciano,et al.  Resting CD4+ T Lymphocytes but Not Thymocytes Provide a Latent Viral Reservoir in a Simian Immunodeficiency Virus-Macaca nemestrina Model of Human Immunodeficiency Virus Type 1-Infected Patients on Highly Active Antiretroviral Therapy , 2003, Journal of Virology.

[14]  M. Peeters,et al.  Isolation and partial characterization of an HIV-related virus occurring naturally in chimpanzees in Gabon. , 1989, AIDS.

[15]  F. Barré-Sinoussi,et al.  High Levels of Viral Replication during Primary Simian Immunodeficiency Virus SIVagm Infection Are Rapidly and Strongly Controlled in African Green Monkeys , 2000, Journal of Virology.

[16]  A. Perelson,et al.  Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection , 1995, Nature.

[17]  J. McCune,et al.  The dynamics of CD4+ T-cell depletion in HIV disease , 2001, Nature.

[18]  Andreas Meyerhans,et al.  Genetic organization of a chimpanzee lentivirus related to HIV-1 , 1990, Nature.

[19]  D. Ho,et al.  Primary SIVsm isolates use the CCR5 coreceptor from sooty mangabeys naturally infected in west Africa: a comparison of coreceptor usage of primary SIVsm, HIV-2, and SIVmac. , 1998, Virology.

[20]  F. Barré-Sinoussi,et al.  Antiinflammatory profiles during primary SIV infection in African green monkeys are associated with protection against AIDS. , 2005, The Journal of clinical investigation.

[21]  V. Maino,et al.  Insufficient Production and Tissue Delivery of CD4+Memory T Cells in Rapidly Progressive Simian Immunodeficiency Virus Infection , 2004, The Journal of experimental medicine.

[22]  J. Levy,et al.  An AIDS-like condition induced in baboons by HIV-2. , 1994, Science.

[23]  F. Barré-Sinoussi,et al.  High Levels of Viral Replication Contrast with Only Transient Changes in CD4+ and CD8+ Cell Numbers during the Early Phase of Experimental Infection with Simian Immunodeficiency Virus SIVmnd-1 in Mandrillus sphinx , 2002, Journal of Virology.

[24]  Qingsheng Li,et al.  Peak SIV replication in resting memory CD4+ T cells depletes gut lamina propria CD4+ T cells , 2005, Nature.

[25]  Martin Meier-Schellersheim,et al.  CD4 T Cell Depletion Is Linked Directly to Immune Activation in the Pathogenesis of HIV-1 and HIV-2 but Only Indirectly to the Viral Load1 , 2002, The Journal of Immunology.

[26]  F. Barré-Sinoussi,et al.  Simian Immunodeficiency Virus SIVagm.sab Infection of Caribbean African Green Monkeys: a New Model for the Study of SIV Pathogenesis in Natural Hosts , 2006, Journal of Virology.

[27]  Christine Hogan,et al.  Primary HIV-1 Infection Is Associated with Preferential Depletion of CD4+ T Lymphocytes from Effector Sites in the Gastrointestinal Tract , 2004, The Journal of experimental medicine.

[28]  Philip R. Johnson,et al.  Molecular Cloning of SIV From Sooty Mangabey Monkeys , 1989, Journal of medical primatology.

[29]  C. Apetrei,et al.  The Call of the Wild : What Can Be Learned from Studies of SIV Infection of Natural Hosts ? , 2006 .

[30]  D. Price,et al.  CD4+ T Cell Depletion during all Stages of HIV Disease Occurs Predominantly in the Gastrointestinal Tract , 2004, The Journal of experimental medicine.

[31]  Charles R. Brown,et al.  Immunodeficiency in the Absence of High Viral Load in Pig-Tailed Macaques Infected with Simian Immunodeficiency Virus SIVsun or SIVlhoest , 2005, Journal of Virology.

[32]  P. Johnson,et al.  Induction of AIDS by simian immunodeficiency virus from an African green monkey: species-specific variation in pathogenicity correlates with the extent of in vivo replication , 1995, Journal of virology.

[33]  S. Staprans,et al.  Simian Immunodeficiency Virus Replicates to High Levels in Naturally Infected African Green Monkeys without Inducing Immunologic or Neurologic Disease , 2001, Journal of Virology.

[34]  Guido Silvestri,et al.  Turnover of lymphocytes and conceptual paradigms in HIV infection. , 2003, The Journal of clinical investigation.

[35]  John W. Mellors,et al.  Predictive Value of Immunologic and Virologic Markers After Long or Short Duration of HIV‐1 Infection , 2002, Journal of acquired immune deficiency syndromes.

[36]  Mario Roederer,et al.  Massive infection and loss of memory CD4+ T cells in multiple tissues during acute SIV infection , 2005, Nature.

[37]  R. Webster,et al.  Isolation of a simian immunodeficiency virus related to human immunodeficiency virus type 2 from a west African pet sooty mangabey , 1991, Journal of virology.

[38]  R. Kurth,et al.  High virus loads in naturally and experimentally SIVagm-infected African green monkeys. , 2001, Virology.

[39]  J. Hansen,et al.  Receptor function of CD4 structures from African green monkey and pig-tail macaque for simian immunodeficiency virus, SIVsm, SIVagm, and human immunodeficiency virus type-1. , 1995, Viral immunology.

[40]  B. Gormus,et al.  Isolation of an HTLV-III-related retrovirus from macaques with simian AIDS and its possible origin in asymptomatic mangabeys , 1986, Nature.

[41]  L. Montagnier,et al.  Simian Immunodeficiency Virus Replicates to High Levels in Sooty Mangabeys without Inducing Disease , 1998, Journal of Virology.

[42]  R P Johnson,et al.  Gastrointestinal tract as a major site of CD4+ T cell depletion and viral replication in SIV infection. , 1998, Science.

[43]  L. White,et al.  High levels of SIVmnd-1 replication in chronically infected Mandrillus sphinx. , 2003, Virology.

[44]  R. Koup,et al.  Nonpathogenic SIV infection of sooty mangabeys is characterized by limited bystander immunopathology despite chronic high-level viremia. , 2003, Immunity.

[45]  Charles R. Brown,et al.  Plateau Levels of Viremia Correlate with the Degree of CD4+-T-Cell Loss in Simian Immunodeficiency Virus SIVagm-Infected Pigtailed Macaques: Variable Pathogenicity of Natural SIVagm Isolates , 2005, Journal of Virology.

[46]  D. Ho,et al.  Normal T-Cell Turnover in Sooty Mangabeys Harboring Active Simian Immunodeficiency Virus Infection , 2000, Journal of Virology.

[47]  A S Perelson,et al.  Rapid turnover of T lymphocytes in SIV-infected rhesus macaques. , 1998, Science.

[48]  R. Means,et al.  Diverse Host Responses and Outcomes following Simian Immunodeficiency Virus SIVmac239 Infection in Sooty Mangabeys and Rhesus Macaques , 1998, Journal of Virology.

[49]  P. Fultz,et al.  Spectrum of disease in macaque monkeys chronically infected with SIV/SMM. , 1989, Veterinary immunology and immunopathology.

[50]  C. Kuiken,et al.  Structure and Function of CC-Chemokine Receptor 5 Homologues Derived from Representative Primate Species and Subspecies of the Taxonomic Suborders Prosimii and Anthropoidea , 2003, Journal of Virology.

[51]  S. Staprans,et al.  Perturbations of Cell Cycle Control in T Cells Contribute to the Different Outcomes of Simian Immunodeficiency Virus Infection in Rhesus Macaques and Sooty Mangabeys , 2006, Journal of Virology.

[52]  N. Kiviat,et al.  Increased Virus Replication and Virulence after Serial Passage of Human Immunodeficiency Virus Type 2 in Baboons , 2003, Journal of Virology.

[53]  George M. Shaw,et al.  Simian Immunodeficiency Virus Infection of Chimpanzees , 2005, Journal of Virology.

[54]  Charles R. Brown,et al.  Wide Range of Viral Load in Healthy African Green Monkeys Naturally Infected with Simian Immunodeficiency Virus , 2000, Journal of Virology.

[55]  John P. Moore,et al.  Use of Inhibitors To Evaluate Coreceptor Usage by Simian and Simian/Human Immunodeficiency Viruses and Human Immunodeficiency Virus Type 2 in Primary Cells , 2000, Journal of Virology.