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Death of CD4⁺ T Cells from Lymph Nodes during Primary SIVmac251 Infection Predicts the Rate of AIDS Progression¹

Unité de Physiopathologie des Infections Lentivirales, Institut Pasteur, Paris, France

Immunological and virological events that occur during the earliest stages of SIV infection are now considered to have a major impact on subsequent disease progression. In the present study, we demonstrate a clear correlation between progression to AIDS and the rate of in vitro CD4⁺ (but not CD8⁺) T cell death in lymph nodes. The dying CD4⁺ T cells were effector memory T cells, which are critical for the immune response to pathogens. However, there was no correlation between the rate of the viral replication within lymph nodes and the extent of Fas ligand-mediated death, despite the increased sensitivity of CD4⁺ T cells to death in response to recombinant human Fas ligand. CD4⁺ T cell death was caspase and apoptosis-inducing factor independent but was clearly associated with mitochondrion damage. Interestingly, higher expression levels of the active form of Bak, a proapoptotic molecule involved in mitochondrial membrane permeabilization, were observed in SIV-infected macaques progressing more rapidly to AIDS. Finally, we demonstrated that the strain of SIV we used requires CCR5 and BOB/GRP15 molecules as coreceptors and caused death of unstimulated noncycling primary CD4⁺ T cells. Altogether, these results demonstrate that CD4⁺ T cell death occurring early after SIV infection is a crucial determinant of progression to AIDS and that it is mediated by the intrinsic death pathway.

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 a grant from the Agence Nationale de Recherches sur le Sida (ANRS) (to J.E.); a doctoral fellowship from ANRS (to L.V.); and a postdoctoral fellowship from Sidaction (to F.P.).

² This work is dedicated to Bruno Hurtrel.

³ Address correspondence and reprint requests to Dr. J. Estaquier, Unité de Physiopathologie des Infections Lentivirales, Institut Pasteur, 28 rue du Docteur Roux, 75724 Paris cedex 15, France. E-mail address: jestaqui{at}pasteur.fr

⁴ Abbreviations used in this paper: LN, lymph node; AIF, apoptosis-inducing factor; Bcl-2, B cell lymphoma; MP, moderate progressor; SP, slow progressor; rhCD95L, recombinant human Fas ligand molecule; zVAD-fmk, Z-Val-Ala-Asp-fluoromethylketone; DiOC₆, 3,3'-dihexyloxacarbocyanine iodide; MOI, multiplicity of infection; ddI, didanosine; TEM, effector memory T cells; TDT, terminal differentiated effector T cells; MFI, mean of fluorescence intensity; ROS, reactive oxygen species.

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