TRANSFORMING GROWTH-FACTOR-BETA AND NONCYTOPATHIC MECHANISMS OF IMMUNODEFICIENCY IN HUMAN-IMMUNODEFICIENCY-VIRUS INFECTION

This study examines the contribution of transforming growth factor β (TGFβ), one of the most potent endogenous immunosuppressive factors, to the development of immunodeficiency in human immunodeficiency virus (HIV) infection. Increased titers of TGFβ were found in supernatants of peripheral blood mononuclear cells (PBMCs) from HIV-infected donors as compared to uninfected controls (P < 0.001). This correlated closely with defective responses of CD4+ lymphocytes to the recall antigens tuberculin purified protein derivative or tetanus toxoid. The addition of TGFβ-neutralizing antibody to PBMCs partially restored these defective T-cell responses. Furthermore, purified TGFβ or HIV+ PBMC culture supernatants preferentially inhibited proliferation of CD4+ lymphocytes as compared to CD8+ cells. The increased expression of the TGFβ protein was associated with increased TGFβ mRNA as determined by a polymerase chain reaction assay. This increase in TGFβ protein and mRNA was due to a selective upregulation of the TGFβ1 isoform. These results indicate that overexpression of TGFβ1 occurs in HIV-infected individuals and that this cytokine can contribute to impaired immune functions and to depletion of CD4+ T lymphocytes.