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* 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.
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