Transfer of Human CD4⁺T Lymphocytes Producing Beta Interferon in Hu-PBL-SCID Mice Controls Human Immunodeficiency Virus Infection

Abstract

Beta interferon (IFN-β) exerts pleiotropic antiretroviral activities and affects many different stages of the human immunodeficiency virus (HIV) infectious cycle in IFN-treated cells. To explore whether transfer of genetically engineered human CD4+ T cells producing constitutively low amounts of IFN-β can eradicate HIV in vivo, we developed a new Hu-PBL-SCID mouse model supporting a persistent, replicative HIV infection maintained by periodic reinoculations of activated human CD4+ T cells. Transferring human CD4+ T cells containing the IFN-β retroviral vector drastically reduced the preexisting HIV infection and enhanced CD4+ T-cell survival and Th1 cytokine expression. Furthermore, in 40% of the Hu-PBL-SCID mice engrafted with IFN-β-transduced CD4+ T cells, HIV-1 was undetectable in vivo as well as after cocultivation of mouse tissues with human phytohemagglutinin-stimulated lymphoblasts. These results indicate that a therapeutic strategy based upon IFN-β transduction of CD4+ T cells may be an approach to controlling a preexisting HIV infection and allowing immune restoration.

Role for plasmacytoid dendritic cells in anti‐HIV innate immunity

“…The correlation between high type I IFN production and low viral loads or high CD4 T‐cell counts indicates a role for these IFN in the control of HIV replication. IFN‐α and ‐β have a strong antiviral activity that was evidenced on HIV‐1 itself in vitro 56 , 57 , 58 , 59 and in murine models in vivo 60 , 61 , 62 .…”

A non‐classical ISRE/ISGF3 pathway mediates induction of RANTES gene transcription by type I IFNs

“…This chemokine highly expressed in some HIV‐infected patients that do not progress to AIDS inhibits HIV infection [7]. Previously, we have observed the induction of RANTES production in several cell types (T lymphocytes, macrophages and dendritic cells) that constitutively express an IFN‐β transgene [8–10]. In macrophages, the resistance against HIV, markedly enhanced by IFN‐β, was virtually suppressed by RANTES‐neutralizing antibody [9].…”

Gene therapy in interventional pulmonology: Interferon gene delivery with focus on thoracic malignancies

“…Preclinical models of interferon gene therapy for infectious and inflammatory conditions HIV Studies have shown inhibition of HIV replication in cell lines by incorporating IFN-α, IFN-β, and IFN-γ genes under the control of HIV long terminal repeat [63,64]. Another strategy has been IFN-β gene transduction of CD4(+) T cells to produce a continuous low-dose expression of IFN-β in controlling HIV infection and allowing immune restoration in mouse models [65,66]. A comparison of interferon gene therapy and gene therapy with other modalities concluded that gene therapy using CD4 immunoadhesin was more efficient in a SCID mouse model, although expression of IFN genes did result in a marked reduction in HIV viral load [67].…”