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Abstract
Non-infectious X4 but not R5 HIV-1 virions inhibit humoral immune responses in human lymphoid tissue ex vivo
Grivel J.-C.1, Fitzgerald W.S.2, sylwester A.1, Lifson J.3, Margolis L.B.1
1National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892-1855, United States of America, 2NASA-NIH Center for Three-Dimensional Tissue Culture, Bethesda, MD 20892-1855, United States of America, 3AIDS Vaccine Program, SAIC Frederick, Inc., National Cancer Institute-Frederick, Frederick, MD 21702-1201, United States of America
Introduction: Ex vivo HIV-1 infection of human lymphoid tissue recapitulates some aspects of in vivo infection, including a severe depletion of CD4+ T cells and suppression of humoral immune responses to recall antigens or to polyclonal stimuli. To isolate the mechanisms of suppression of immune responses from T cell depletion, we used inactivated virions that do not deplete CD4+ T cells in human lymphoid tissues ex vivo.
Methods: Humoral immune response of the tissue was evaluated by antigen-specific and total immunoglobulin productions after ex vivo challenge with Tetanus toxoid and pokeweed mitogen. Immunoglobulin production of these tissues was compared with that following exposure to AT-2 inactivated HIV-1.
Results: : AT-2 inactivated X4, but not R5 HIV-1 virions, even with only a brief exposure, inhibited antibody responses in human lymphoid tissue ex vivo. The efficiency of this inhibition was comparable to that mediated by infectious virus. The inhibition is dependent on the maintenance of native X4 virion structure since neither baculovirus-expressed gp120, nor heat-denatured AT-2-inactivated X4 virus inhibited immune responses of ex vivo human lymphoid tissue. Moreover, the virus itself is only required to trigger suppression of B cell responses; the suppressive activity is maintained without the continuous presence of virions and can be transferred by conditioned medium.
Conclusions: Thus, neither productive viral infection, nor CD4+ T cell depletion are necessary to mediate HIV-induced inhibition of antibody production in human lymphoid tissue in ex vivo. This phenomenon is mediated by soluble immunosuppressive factor(s) (ISF) secreted by lymphoid tissue exposed to viral particles.
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