HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Related articles in The JI Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Milush, J. M. Articles by Sodora, D. L. Search for Related Content PubMed PubMed Citation Articles by Milush, J. M. Articles by Sodora, D. L.

Virally Induced CD4⁺ T Cell Depletion Is Not Sufficient to Induce AIDS in a Natural Host¹

Jeffrey M. Milush^*, Jacqueline D. Reeves, Shari N. Gordon, Dejiang Zhou^*,#, Alagar Muthukumar^*, David A. Kosub^*, Elizabeth Chacko^*, Luis D. Giavedoni, Chris C. Ibegbu^¶, Kelly S. Cole^||, John L. Miamidian, Mirko Paiardini, Ashley P. Barry^¶,**, Silvija I. Staprans^¶,, Guido Silvestri and Donald L. Sodora^2,*

^* University of Texas Southwestern Medical Center, Dallas, TX 75390; Monogram Biosciences, South San Francisco, CA 94080; University of Pennsylvania, Philadelphia, PA 19104; Southwest Foundation for Biomedical Research, San Antonio, TX 78245; ^¶ Emory Vaccine Center, Atlanta, GA 30329; ^|| University of Pittsburgh School of Medicine, Pittsburgh, PA 15261; ^# University of California San Diego, La Jolla, CA 92093; ^** Trimeris, Morrisville, NC 27560; and Merck Vaccine Division, West Point, PA 19486

Peripheral blood CD4⁺ T cell counts are a key measure for assessing disease progression and need for antiretroviral therapy in HIV-infected patients. More recently, studies have demonstrated a dramatic depletion of mucosal CD4⁺ T cells during acute infection that is maintained during chronic pathogenic HIV as well as SIV infection. A different clinical disease course is observed during the infection of natural hosts of SIV infection, such as sooty mangabeys (Cercocebus atys), which typically do not progress to AIDS. Previous studies have determined that SIV⁺ mangabeys generally maintain healthy levels of CD4⁺ T cells despite having viral replication comparable to HIV-infected patients. In this study, we identify the emergence of a multitropic (R5/X4/R8-using) SIV infection after 43 or 71 wk postinfection in two mangabeys that is associated with an extreme, persistent (>5.5 years), and generalized loss of CD4⁺ T cells (5–80 cells/µl of blood) in the absence of clinical signs of AIDS. This study demonstrates that generalized CD4⁺ T cell depletion from the blood and mucosal tissues is not sufficient to induce AIDS in this natural host species. Rather, AIDS pathogenesis appears to be the cumulative result of multiple aberrant immunologic parameters that include CD4⁺ T cell depletion, generalized immune activation, and depletion/dysfunction of non-CD4⁺ T cells. Therefore, these data provide a rationale for investigating multifaceted therapeutic strategies to prevent progression to AIDS, even following dramatic CD4 depletion, such that HIV⁺ humans can survive normal life spans analogous to what occurs naturally in SIV⁺ mangabeys.

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 supported by National Institutes of Health Grants R01 AI035522 (to D.L.S.) and R21 AI060451 (to D.L.S.) and RR-00165 (Yerkes Primate Center). J.M.M. and D.K. were supported in part by training grants from the National Institute of Allergy and Infectious Diseases (5T32 AI07520 and 5T32 AI005284, respectively). J.D.R. was supported by Fellowship 106437-34-RFGN from the American Foundation for AIDS Research and National Institutes of Health Grant R21 AI058701.

² Address correspondence and reprint requests to Dr. Donald Sodora, Seattle Biomedical Research Institute, 307 Westlake Avenue N, Seattle, WA 98109. E-mail address: Don.Sodora{at}SBRI.org

³ Abbreviations used in this paper: env, envelope glycoprotein; SHIV, simian HIV; SM, sooty mangabey; HSP, heat shock protein; IPP, isopentenyl pyrophosphate; wpi, week postinfection.

Related articles in The JI:

IN THIS ISSUE

The JI 2007 179: 2665-2666. [Full Text]  

This article has been cited by other articles:

				A. Durudas, J. M. Milush, H.-L. Chen, J. C. Engram, G. Silvestri, and D. L. Sodora Elevated Levels of Innate Immune Modulators in Lymph Nodes and Blood Are Associated with More-Rapid Disease Progression in Simian Immunodeficiency Virus-Infected Monkeys J. Virol., December 1, 2009; 83(23): 12229 - 12240. [Abstract] [Full Text] [PDF]

				G. Q. Del Prete, B. Haggarty, G. J. Leslie, A. P. O. Jordan, J. Romano, N. Wang, J. Wang, M. C. Holmes, D. C. Montefiori, and J. A. Hoxie Derivation and Characterization of a Simian Immunodeficiency Virus SIVmac239 Variant with Tropism for CXCR4 J. Virol., October 1, 2009; 83(19): 9911 - 9922. [Abstract] [Full Text] [PDF]

				M. Paiardini, B. Cervasi, J. C. Engram, S. N. Gordon, N. R. Klatt, A. Muthukumar, J. Else, R. S. Mittler, S. I. Staprans, D. L. Sodora, et al. Bone marrow-based homeostatic proliferation of mature T cells in nonhuman primates: implications for AIDS pathogenesis Blood, January 15, 2009; 113(3): 612 - 621. [Abstract] [Full Text] [PDF]

				F. Bibollet-Ruche, B. A. McKinney, A. Duverger, F. H. Wagner, A. A. Ansari, and O. Kutsch The Quality of Chimpanzee T-Cell Activation and Simian Immunodeficiency Virus/Human Immunodeficiency Virus Susceptibility Achieved via Antibody-Mediated T-Cell Receptor/CD3 Stimulation Is a Function of the Anti-CD3 Antibody Isotype J. Virol., October 15, 2008; 82(20): 10271 - 10278. [Abstract] [Full Text] [PDF]

				Y. Fukazawa, A. Miyake, K. Ibuki, K. Inaba, N. Saito, M. Motohara, R. Horiuchi, A. Himeno, K. Matsuda, M. Matsuyama, et al. Small Intestine CD4+ T Cells Are Profoundly Depleted during Acute Simian-Human Immunodeficiency Virus Infection, Regardless of Viral Pathogenicity J. Virol., June 15, 2008; 82(12): 6039 - 6044. [Abstract] [Full Text] [PDF]

				V. Cecchinato, E. Tryniszewska, Z. M. Ma, M. Vaccari, A. Boasso, W.-P. Tsai, C. Petrovas, D. Fuchs, J.-M. Heraud, D. Venzon, et al. Immune Activation Driven by CTLA-4 Blockade Augments Viral Replication at Mucosal Sites in Simian Immunodeficiency Virus Infection J. Immunol., April 15, 2008; 180(8): 5439 - 5447. [Abstract] [Full Text] [PDF]

				D. A. Kosub, G. Lehrman, J. M. Milush, D. Zhou, E. Chacko, A. Leone, S. Gordon, G. Silvestri, J. G. Else, P. Keiser, et al. Gamma/Delta T-Cell Functional Responses Differ after Pathogenic Human Immunodeficiency Virus and Nonpathogenic Simian Immunodeficiency Virus Infections J. Virol., February 1, 2008; 82(3): 1155 - 1165. [Abstract] [Full Text] [PDF]

				S. N. Gordon, N. R. Klatt, S. E. Bosinger, J. M. Brenchley, J. M. Milush, J. C. Engram, R. M. Dunham, M. Paiardini, S. Klucking, A. Danesh, et al. Severe Depletion of Mucosal CD4+ T Cells in AIDS-Free Simian Immunodeficiency Virus-Infected Sooty Mangabeys J. Immunol., September 1, 2007; 179(5): 3026 - 3034. [Abstract] [Full Text] [PDF]