Anti-HIV State but Not Apoptosis Depends on IFN Signature in CD4+ T Cells

Abstract

To gain insights into the molecular mechanisms underlying early host responses to HIV in the CD4+ T cell target population, we examined gene expression in CD4+ T cells isolated 24 h after ex vivo HIV infection of lymphocyte aggregate cultures derived from human tonsils. Gene profiling showed a distinct up-regulation of genes related to immune response and response to virus, notably of IFN-stimulated genes (ISGs), irrespective of the coreceptor tropism of the virus. This mostly IFN-α-dependent gene signature suggested the involvement of plasmacytoid dendritic cells, a principal component of the antiviral immune response. Indeed, depletion of plasmacytoid dendritic cells before HIV inoculation abrogated transcriptional up-regulation of several ISGs and resulted in increased levels of HIV replication. Treatment with a blocking anti-IFN-αR Ab yielded increased HIV replication; conversely, HIV replication was decreased in pDC-depleted cultures treated with IFN-α. Among up-regulated ISGs was also TRAIL, indicating a potential role of the IFN signature in apoptosis. However, a blocking anti-TRAIL Ab did not abrogate apoptosis of CD4+ T cells in CXCR4-tropic HIV-infected cultures, suggesting the involvement of pathways other than TRAIL mediated. We conclude that acute HIV infection of lymphoid tissue results in up-regulation of ISGs in CD4+ T cells, which induces an anti-HIV state but not apoptosis.

Chronic CD4+T-Cell Activation and Depletion in Human Immunodeficiency Virus Type 1 Infection: Type I Interferon-Mediated Disruption of T-Cell Dynamics

“…Here, we used a direct experimental approach with flow cytometry to visualize simultaneously the temporal expression patterns of cyclins A and B 1 in specific activated subsets (CD25 ϩ or HLA-DR ϩ ) of CD4 ϩ T cells and found no difference between the temporal expression patterns of cyclins A and B 1 in activated CD4 ϩ T cells from untreated, viremic HIV ϩ individuals and those of cells from HIV Ϫ individuals or of PHA-activated CD4 ϩ T cells. Our finding that activated CD4 ϩ T cells are under the influence of type I interferons in the setting of HIV-1 infection is consistent with findings of previous studies documenting type I interferon effects in CD4 ϩ T cells from the secondary lymphoid tissues of HIV ϩ individuals (5,32,35,44,53,81). However, we extend these previous studies by specifically studying the subset of activated (CD25 ϩ ) CD4 ϩ T cells from HIV ϩ T-cell response (27) but may also impart strong proliferative and survival signals to CD4 ϩ T cells (46,47).…”

Differential CD4 + T-Lymphocyte Apoptosis and Bystander T-Cell Activation in Rhesus Macaques and Sooty Mangabeys during Acute Simian Immunodeficiency Virus Infection

“…In vitro studies have shown that HIV activates pDCs to increase IFN-␣ production, which in turn upregulates the expression of TRAIL in monocytes and the expression of death receptors DR-5 on CD4 ϩ T lymphocytes (1,14,15). This mechanism is thought to be responsible for the increased susceptibility to CD4…”

Nonpathogenic SIV infection of African green monkeys induces a strong but rapidly controlled type I IFN response

“…It is unclear, however, whether IFN-α has a beneficial or harmful effect in HIV-1 infection. On the one hand, IFN-α could be beneficial, as it has been shown to directly decrease HIV-1 replication in vitro, although only partially (13). Moreover, the IFN-α effect on promoting antiviral adaptive immune responses may also result in reduced virus replication in vivo.…”