HIV-1 Tat mutants in the cysteine-rich region downregulate HLA class II expression in T lymphocytic and macrophage cell lines

Abstract

Human macrophage and T cell lines were stably transfected with HIV-1 wild-type Tat or Tat mutants in the cysteine-rich region displaying trans-dominant negative effects on HIV-1 life cycle. The expression of HLA class I and class II molecules was not affected by wild-type Tat. Tat mutants, instead, profoundly down-regulated in a dose-dependent fashion the expression of class II, but not of class I, in both cell types by acting at the transcriptional level. Down-regulation was manifested on constitutive and IFN-gamma-induced class II gene expression and did not correlate with reduced transcription of the AIR-1 gene product CIITA, the major transcriptional activator of class II genes, indicating that Tat mutants did not act by inhibiting AIR-1 gene expression. Class II down-modulation had important functional implications in macrophages, as both antigen processing and presenting capacity were inhibited. These results represent the first evidence that a modified HIV-1 Tat product can act as a potent immunosuppressor by inhibiting the HLA class II expression necessary for triggering both cellular and humoral responses against pathogens. The use of these HIV-1 Tat mutants also discloses new opportunities to investigate the molecular mechanisms underlying the coordinate HLA class II gene transcription.

Class II Transactivator: Mastering the Art of Major Histocompatibility Complex Expression

“…This correlation is intriguing and suggests that CIITA, not unlike other known positive regulators of HIV LTR (i.e., Tat and NF-B), regulates the transcription and replication of HIV. In contrast, mutations in the cysteine-rich portion of HIV Tat (C22S37G and C37G) decrease class II MHC transcription, leading to diminished class II MHC expression in the THP-1 (monocytic) and H-9 (T-lymphocyte) cell lines, an effect not seen with wild-type Tat (128). Interestingly these mutations can decrease class II MHC transcription without affecting CIITA expression (128), likely through disruptive interaction with transcription elongation factor b (49).…”

A Tat subunit vaccine confers protective immunity against the immune-modulating activity of the human immunodeficiency virus type-1 Tat protein in mice

“…In fact, a preponderance of reports has unequivocally established that Tat possesses a unique biological activity that alters the function of monocytes, dendritic cells (DCs), and CD4 ϩ and CD8 ϩ T cells in vitro (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). In addition, detectable levels of extracellular Tat are found in culture supernatants from cells infected with HIV-1 (20)(21)(22), and Tat is efficiently taken up by a variety of cells (21)(22)(23)(24)(25).…”

The Role of the Nef Protein in MHC-I Downregulation and Viral Immune Evasion by HIV-1

“…This is demonstrated by the fact that Nef deficient mutants, which still express Vpu and Tat, have markedly decreased MHC-I expression achieving only 7% of MHC-I downregulation compared to wild type strains of HIV-1 virus. Furthermore, vpu-and tat -deleted HIV viruses that still expressed Nef failed to significantly downregulate MHC-I molecules [27][28][29].…”