Type I Interferon Is a Powerful Inhibitor of in Vivo HIV-1 Infection and Preserves Human CD4+ T Cells from Virus-Induced Depletion in SCID Mice Transplanted with Human Cells

Abstract

Although several studies are available on the in vitro inhibitory activities of type I interferon (IFN) on HIV-1 replication, the role of these cytokines in the pathogenesis of AIDS is still matter of conjecture. Both beneficial and adverse effects have been envisaged and considered as a possible rationale for the development of either IFN or anti-IFN therapies in HIV-1-infected patients. In the present study, we have evaluated the efficacy of human type I IFN on HIV-1 infection and virus-induced depletion of human CD4 T cells in two models established in SCID mice. In SCID mice transplanted with human U937 cells (U937-SCID mouse model), continuous treatment with type I consensus IFN (CIFN) resulted in a total suppression of HIV-1 infection. This inhibitory effect was superior to that obtained after AZT treatments. Results from an ensemble of experiments in SCID mice transplanted with either control or genetically modified human U937 cells transduced with a Tat-inducible IFN-alpha gene (LTR-IFN-A2 U937) indicated that low levels of IFN-alpha, produced locally as a result of virus infection, were extremely effective in inhibiting acute HIV infection and virus replication. Of interest, LTR-IFN-A2 U937 cells conferred a strong anti-HIV-1 protection to coinjected bystander U937 cells. Notably, experiments with SCID mice reconstituted with human PBL (hu-PBL-SCID mouse model) showed that treatment with CIFN inhibited HIV-1 replication more effectively than AZT treatment. Remarkably, treatment with CIFN resulted in a clear-cut protection from the virus-induced depletion of human CD4 T cells, which was also associated with the generation of an antibody response toward HIV-1 antigens in 50% of the virus-injected xenografts. These results suggest that type I IFN efficiently preserves human CD4(+) cells from virus-induced damage in hu-PBL-SCID mice, not only by inducing an antiviral state in target cells but also by stimulating anti-HIV-1 human immune responses in vivo.

Inability of Plasmacytoid Dendritic Cells To Directly Lyse HIV-Infected Autologous CD4 + T Cells despite Induction of Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand

“…3A). Based on several reports, including ours, describing a profound impairment in IFN-␣ production by PDC during chronic viremia following TLR engagement (13,14,49) and because IRF-7 has been identified as the key player in induced type I IFN production (45, 46), we measured levels of intracellular IRF-7 in PDC. Using a polyclonal antibody that recognizes total IRF-7 (phosphorylated and unphosphorylated forms [16,31,56]), we observed that the constitutive intracellular levels of IRF-7 were lower in circulating PDC from chronically HIV-1-infected subjects than in those from uninfected control subjects (P Ͻ 0.002) (Fig.…”

“…ϩ T cells (49). Thus, controversy remains on the role of IFN-␣ as an indirect or direct inducer of apoptosis of CD4 ϩ T cells through PDC/TRAIL induction, whereas the possibility that IFN-␣ acts as an antiviral agent by controlling HIV-1 replication and thus reducing virally mediated T-cell loss appears to be supported by several studies (reviewed in references 26, 47, and 58).…”

Induction of Protective Immune Responses against R5 Human Immunodeficiency Virus Type 1 (HIV-1) Infection in hu-PBL-SCID Mice by Intrasplenic Immunization with HIV-1-Pulsed Dendritic Cells: Possible Involvement of a Novel Factor of Human CD4+T-Cell Origin

“…against these cytokines did not interfere significantly with the suppressive activity under the present assay conditions. The involvement of human IFN-␣/␤, which have been implicated in anti-HIV-1 protective activity in SCID mice (12), is also unlikely, since X4 HIV-1 infection of PBMC was not suppressed by the factor under the same experimental conditions. Since neutralizing antibodies against IL-4, IL-10, and IFN-␤ alone or in combination showed a marginal blocking effect (20 to 35%) against the present factor, it remains to be resolved whether IL-4, IL-10, and IFN-␤, which are known to suppress R5 HIV-1, work synergistically with the present HIV-1 suppressor factor or whether the factor shares epitopes with these molecules and is thus partially cross-reactive with these cytokines.…”

Dendritic cells from HIV-1 infected individuals are less responsive to toll-like receptor (TLR) ligands

“…These agonists stimulate dendritic cells to produce type I interferon (IFN-α/β) and cytokines essential in the development and maintenance of immune responses. Production of IFN-α/β by pDC is essential in antiviral innate immunity through direct inhibition of viral replication (19) and induction of an antiviral state in neighboring cells (20). In addition, IFN-α has a strong adjuvant effect on a variety of immune cells including monocytes, mDC, NK cells, and B and T lymphocytes (21).…”