HIV-1–induced activation of CD4+ T cells creates new targets for HIV-1 infection in human lymphoid tissue ex vivo

Abstract

We demonstrate mechanisms by which HIV-1 appears to facilitate its own infection in ex vivo-infected human lymphoid tissue. In this system, HIV-1 readily infects various CD4 ؉ T cells, but productive viral infection was supported predominantly by activated T cells expressing either CD25 or HLA-DR or both (CD25/ HLA-DR) but not other activation markers: There was a strong positive correlation (r ‫؍‬ 0.64, P ‫؍‬ .001) between virus production and the number of CD25 ؉ / HLA-DR IntroductionCD4 ϩ T lymphocytes are the major target for HIV-1 infection, 1 and their loss is the hallmark of HIV-1 disease. [2][3][4] It is well established that the critical event of HIV-1 infection occurs in lymphoid tissue where T lymphocytes expressing CD4 constitute a highly heterogeneous population different in many parameters, in particular, their activation status. [5][6][7][8] Unlike single cell cultures in vitro, the tissue microenvironment provides conditions for both activated and nonactivated cells to be productively infected. 9,10 Nevertheless, CD4 ϩ T-cell activation is thought to be a major factor in facilitating HIV-1 infection of these cells. 11,12 This, and several other observations, have led to the widely accepted hypothesis that tissue activation is a major force, driving HIV-1 disease progression (for review, see Grossman et al 13,14 ). The fraction of activated T lymphocytes and other cell types is increased in HIV-1-infected patients, and we have recently documented distorted activation pattern of lymphocytes in lymph nodes and tonsils from HIV-1-infected patients. 15 However, the patterns of activation determining cell susceptibility to productive HIV-1 infection, the contribution of nonactivated cells to the viral load, and the relationship between activation status and cell loss in lymphoid tissues remain largely unknown, in part because of the lack of an adequate experimental model to address these problems.Here, to reveal mechanisms connecting cell activation and HIV-1 infection, we used ex vivo-infected human lymphoid tissues. These tissues support productive HIV-1 infection ex vivo without exogenous activation 16,17 that is needed to efficiently infect peripheral blood mononuclear cells (PBMCs); such conditions are unlikely to reflect the conditions of cell activation in vivo even remotely. Moreover, in ex vivo tissues, similar to in vivo, 10,18 both activated and nonactivated cells become productively infected, 19 providing an experimental system to address some aspects of cell activation in HIV-1-infected human lymphoid tissue.By comparing matched infected and noninfected lymphoid tissues from individual donors, we demonstrated here that viral load in this system depends on the number of activated target cells, but only of a particular pattern, CD25 ϩ /HLA-DR ϩ . Furthermore, we found that viral infection mobilizes new HIV-1 cell targets by activating uninfected cells to express the very same pattern of markers that is associated with the efficient HIV-1 replication. HIV-1 infection of these cells drives th...

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