Decreased Stimulation of CD4+ T Cell Proliferation and IL-2 Production by Highly Enriched Populations of HIV-Infected Dendritic Cells

Abstract

APC infection and dysfunction may contribute to the immunopathogenesis of HIV disease. In this study, we examined immunologic function of highly enriched populations of HIV-infected monocyte-derived dendritic cells (DC). Compared with uninfected DC, HIV-infected DC markedly down-regulated surface expression of CD4. HIV p24+ DC were then enriched by negative selection of CD4+HIV p24− DC and assessed for cytokine secretion and immunologic function. Although enriched populations of HIV-infected DC secreted increased IL-12p70 and decreased IL-10, these cells were poor stimulators of allogeneic CD4+ T cell proliferation and IL-2 production. Interestingly, HIV-infected DC secreted HIV gp120 and the addition of soluble (s) CD4 (a known ligand for HIV gp120) to DC-CD4+ T cell cocultures restored T cell proliferation in a dose-dependent manner. By contrast, addition of antiretroviral drugs did not affect CD4+ T cell proliferation. Furthermore, recombinant HIV gp120 inhibited proliferation in uninfected cocultures of allogeneic DC and CD4+ T cells, an effect that was also reversed by addition of sCD4. In summary, we show that HIV gp120 produced by DC infected by HIV in vitro impairs normal CD4+ T cell function and that sCD4 completely reverses HIV gp120-mediated immunosuppression. We hypothesize that HIV-infected DC may contribute to impaired CD4+ T cell-mediated immune responses in vivo and that agents that block this particular immunosuppression may be potential immune adjuvants in HIV-infected individuals.

R5 HIV productively infects Langerhans cells, and infection levels are regulated by compoundCCR5polymorphisms

“…mDCs were prepared and infected with HIV as described (37). One million mDCs suspended in 0.5 ml of complete medium with GM-CSF͞IL-4 were preincubated with antibodies or reagents described above for 20 min at 37°C, and then HIV-1 Ba-L (at 1:100 or 1:500 final dilution) was added to cultures.…”

Dynamics of cytokine expression in HIV productively infected primary CD4+ T cells

“…Approaches to evaluate the relationship between cytokines and HIV have relied on (1) evaluating the impact of a particular cytokine on HIV replication in vitro, [1][2][3][4][5] (2) comparing the cytokine expression profile of HIV-infected and uninfected donors, 6,7 and (3) measuring cytokine production from in vitro infected cells. [8][9][10] Analysis of the impact of cytokines on HIV-1 replication in vitro have generally demonstrated that a number of type 1 cytokines (interleukin-1 [IL-1], tumor necrosis factor-␣ [TNF-␣], IL-2, IL-12) up-regulate HIV replication while type 2 cytokines down-modulate HIV (IL-10, transforming growth factor-␤ [TGF-␤]). This relationship is not simplistic given that a combination of type 1 and type 2 cytokines may lead to a synergistic or antagonistic effects on HIV replication [11][12][13][14] ; this result often depends on the combination of cytokines and on the cell type examined, whether lymphocytic or monocytic.…”

HIV-Infected Langerhans Cells Preferentially Transmit Virus to Proliferating Autologous CD4+ Memory T Cells Located within Langerhans Cell-T Cell Clusters

“…It is now clear from numerous in vitro studies that there are at least two pathways by which HIV interacts with DC: 1) CD4-and CCR5-mediated infection by virus and 2) cell surface capture of virus by DC-specific ICAM-3 grabbing nonintegrin and other Ctype lectins (5)(6)(7)(8)(9)(10)(11). Using a tissue explant model, however, we found no evidence that C-type lectins expressed by LC within epithelium are involved in transmission of virus from LC to CD4 ϩ T cells (11).…”