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Resistance to Apoptosis in HIV-Infected CD4⁺ T Lymphocytes Is Mediated by Macrophages: Role for Nef and Immune Activation in Viral Persistence¹

Ulrich Mahlknecht^2,*, Cheng Deng^2,, Michael C. Lu, Thomas C. Greenough, John L. Sullivan, William A. O’Brien and Georges Herbein^3,

^* Department of Hematology/Oncology, University of Frankfurt, Frankfurt am Main, Germany; Department of Internal Medicine, Division of Infectious Diseases, University of Texas Medical Branch, Galveston, TX 77555; and Department of Pediatrics, University of Massachusetts Medical School, Worcester, MA 01605

Apoptosis or programmed cell death may play a critical role in AIDS pathogenesis through depletion of both CD4⁺ and CD8⁺ T lymphocytes. Using a reporter virus, a recombinant HIV infectious clone expressing the green fluorescent protein (GFP), apoptosis was measured in productively infected CD4⁺ T lymphocytes, in the presence and absence of autologous macrophages. The presence of macrophages in the culture increased the frequency of nonapoptotic GFP-positive productively infected CD4⁺ T lymphocytes. The appearance of nonapoptotic productively infected CD4⁺ T lymphocytes in the culture required intercellular contacts between macrophages and PBLs and the expression of the HIV Nef protein. The presence of macrophages did not reduce apoptosis when CD4⁺ T lymphocytes were infected with a GFP-tagged virus deleted for the nef gene. TNF- (TNF) expressed on the surface of macrophages prevented apoptosis in nef-expressing, productively infected CD4⁺ T lymphocytes. Similarly, following TNF stimulation, apoptosis was diminished in Jurkat T cells transfected with a nef-expressing plasmid. TNF stimulation of nef-expressing Jurkat T cells resulted in NF-B hyperactivation, which has been shown to deliver anti-apoptotic signals. Our results indicate that intercellular contacts with macrophages increase the rate of productively infected nonapoptotic CD4⁺ T lymphocytes. The survival of productively infected CD4⁺ T lymphocytes requires Nef expression as well as activation by TNF expressed on the surface of macrophages and might participate in the formation and maintenance of viral reservoirs in HIV-infected persons.

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