Human immunodeficiency virus -1 (HIV-1) –Transactivator of transcription protein (Tat) effects on Macrophage polarization

Abstract

The human immunodeficiency virus (HIV) relies on its encoded proteins to orchestrate cellular mechanisms for its replication and to induce inflammatory responses that recruit and compromise lymphocytes. Among them is the HIV trans-activator protein (Tat). Tat is required for the viral replication and enhances the infection of HIV in the host organism. Tat may also have an impact on the functions of the macrophage, an important player in pathological changes of AIDS patients. Some evidence exists that may suggest a more M2 like behavior of HIV infected macrophage. Tat has been shown to down-regulate P53 in macrophages. HIV infected macrophage had higher amount of arginase and became a major source of HIV viral load in patients with late stage AIDS. In this study, we investigated the possible role of Tat in the functional polarization of macrophages, a process that switches macrophage function between pro- inflammation (M1) and promotion of tissue repair and healing (M2). Effects of Tat on the macrophage were studied with human monocytic THP-1 cells that have been stably transfected with wild type Tat, or N terminus segment of Tat 1-48 aa or C terminus segment of Tat 37-86aa. Lipopolysaccharide (LPS), an activator of M1 macrophage, was used to activate these THP-1 cells. Exposure to LPS led to significant increase in inducible nitric oxide synthase (iNOS) in un-transfected THP-1 cells, GFP transfected cells, and cells with Tat 37-86 aa. However, THP-1 cells expressing wild type Tat or Tat 1-48aa showed no increase in iNOS whereas a rise in arginase was observed in Tat 1-48aa after LPS exposure. We also studied SOCS 1 and SOCS 3 expression and observed a greater SOCS 1 induction only in clones that had elevated iNOS in response to LPS. Wild-type Tat had no effect on SOCS 1 expression and cells with Tat1-48aa showed a decrease in SOCS 1. Cells expressing Tat 1-48aa displayed reduced HDAC 3 and SOCS 3 levels. Our data demonstrated that wild type Tat and Tat 1-48aa may impair or diminish the response of THP-1 cells to LPS. Our data may also suggest that wild- type Tat and Tat1-48aa have conditioned THP-1 cells towards M2 polarization. This may also suggest that cells expressing wild- type Tat or Tat 1-48aa may exhibit M2 behaviours.