Identification of a Potential HIV-Induced Source of Bystander-Mediated Apoptosis in T Cells: Upregulation of TRAIL in Primary Human Macrophages by HIV-1 Tat

HIV-1 uses mononuclear phagocytes (monocytes, tissue macrophages, and dendritic cells) as a vehicle for its own dissemination and as a reservoir for continuous viral replication. The mechanism by which the host immune system clears HIV-1-infected macrophages is not understood. TRAIL may play a role in this process. TRAIL is expressed on the cell membrane of peripheral immune cells and can be cleaved into a soluble, secreted form. The plasma level of TRAIL is increased in HIV-1-infected patients, particularly those with high viral loads. To study the effect of elevated TRAIL on mononuclear phagocytes, we used recombinant human (rh) TRAIL and human monocyte-derived macrophages (MDM) as an in vitro model. Our results demonstrated rhTRAIL-induced apoptosis in HIV-1-infected MDM and inhibited viral replication, while having a reduced effect on uninfected MDM. HIV-1 infection significantly decreased Akt-1 phosphorylation; rhTRAIL exposure further decreased Akt-1 phosphorylation. Infection with a dominant-negative Akt-1 adenovirus potentiated rhTRAIL-induced apoptosis, while constitutively active Akt-1 blocked rhTRAIL-induced apoptosis in HIV-1-infected MDM. From this data we conclude the death ligand TRAIL preferentially provokes apoptosis of HIV-1-infected MDM, and the mechanism is reliant upon the inhibition of Akt-1 phosphorylation. Understanding this mechanism may facilitate the elimination of HIV-1-infected macrophages and lead to new therapeutic avenues for treatment of HIV-1 infection.

Section: Discussionmentioning

confidence: 99%

“…The Ab against caspase-8 detects inactive form (55 kDa). The anti-caspase-9 Ab detects inactive form (48 kDa), and cleaved intermediate (37 Fig. 4).…”

Section: Inhibition Of Akt-1 Phosphorylation Sensitizes Mdm To Trail-mentioning

confidence: 99%

TRAIL-Mediated Apoptosis in HIV-1-Infected Macrophages Is Dependent on the Inhibition of Akt-1 Phosphorylation

Huang

Erdmann

Peng

et al. 2006

“…We hypothesize that virion production by CD4 ϩ T cells is efficient and rapid in the presence of HIV-infected LC and SEB, inducing apoptosis of infected T cells before significant proliferation can occur. HIV-infected LC may have produced pro-apoptotic factors in the presence of SEB, because HIV-infected APCs have previously been reported to produce pro-apoptotic factors, including TNF-␣ (20,21,25), Fas ligand (25), and TNF-related apoptosis-inducing ligand (26,27).…”

Section: Discussionmentioning

confidence: 99%

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

Sugaya

Loré

Koup

et al. 2004

Langerhans cells (LC) are likely initial targets for HIV following sexual exposure to virus and provide an efficient means for HIV to gain access to lymph node T cells. The purpose of this study was to examine the nature of the CD4+ T cell that becomes infected by HIV-infected LC. We infected human LC within tissue explants ex vivo and then, 3 days later, cocultured HIV-infected LC with different subsets of autologous CD4+ T cells. Using multicolor flow cytometric analyses of LC-CD4+ T cell cocultures, we documented that HIV-infected LC preferentially infected memory (as compared with naive) CD4+ T cells. Proliferating and HIV-infected CD4+ memory T cells were more frequently detected in conjugates of LC and autologous CD4+ T cells, suggesting that T cells become activated and preferentially get infected through cluster formation with infected LC, rather than getting infected with free virus produced by single HIV-infected LC or T cells. p24+ Memory CD4+ T cells proliferated well in the absence of superantigen; by contrast, p24+ T cells did not divide or divided only once in the presence of staphylococcal enterotoxin B, suggesting that virus production was rapid and induced apoptosis in these cells before significant proliferation could occur. These results highlight that close interactions between dendritic cells, in this case epidermal LC, and T cells are important for optimal HIV replication within specific subsets of CD4+ T cells. Disrupting cluster formation between LC and memory CD4+ T cells may be a novel strategy to interfere with sexual transmission of HIV.

“…First, the suppression of T cell proliferation could be due to Tat since it is known to play an important role in T cell apoptosis (32,33). The second possibility could be active suppression of the host-protective T cell response due to production of the counteractive disease promoting cytokines such as IL-10 and IL-4.…”

Section: Il-10 Produced By the Splenocytes Mediate The Suppressor Funmentioning

confidence: 99%

HIV-1 Tat Suppresses gp120-Specific T Cell Response in IL-10-Dependent Manner

Gupta

Boppana

Mishra

et al. 2008

A large number of multicomponent vaccine candidates are currently in clinical evaluation, many of which also include the HIV-1 Tat protein, an important regulatory protein of the virus. However, whether Tat, a known immune effector molecule with a well-conserved sequence among different HIV subtypes, affects the immune response to a coimmunogen is not well understood. In this study, using a bicistronic vector expressing both gp120 and Tat, we have analyzed the role of Tat in elicitation of the gp120-specific immune response. The T cell responses to gp120 were greatly diminished in mice coimmunized with Tat as compared with mice immunized with gp120 alone. This immunosuppressive activity of Tat was not confined to viral Ag only because it also suppressed the immune response of unrelated Ag. Analysis of the cytokine profile suggests that Tat induces IL-10 and since IL-10 has been demonstrated to have appreciable T cell inhibitory activity, it is plausible that IL-10 could be responsible for Tat-mediated immunosuppression. Finally, the immunosuppressive effect of Tat was not observed in IL-10-deficient mice, confirming the role of IL-10 in Tat-mediated immunosuppression. Thus, our results demonstrate for the first time that the immunosuppressive effect of Tat is mediated through IL-10 and suggests that Tat-induced IL-10-mediated immune suppression seems to cripple immune surveillance during HIV-1 infection.