Differential Effects of HIV Type 1 Clade B and Clade C Tat Protein on Expression of Proinflammatory and Antiinflammatory Cytokines by Primary Monocytes

Abstract

The existence of multiple subtypes of HIV-1 worldwide has created new challenges to control HIV-1 infection and associated neuropathogenesis. Previous studies indicate a difference in neuropathogenic manifestations of HIV-1-associated neuroAIDS between clade B-and clade C-infected subjects with clade B being more neuropathogenic than clade C. However, the exact mechanism underlying the differences in the neuropathogenesis by both the subtypes remains elusive. Development of neuroAIDS is associated with a complex interplay between proinflammatory and antiinflammatory cytokines and chemokines. In the current study, we hypothesize that HIV-1 clade B and C Tat protein exert differential effects on human primary monocytes leading to differences in gene and protein expression of cytokines implicated in neuroAIDS. Primary human monocytes were treated with clade B and clade C Tat protein and quantitative real time PCR was performed to determine gene expression of proinflammatory cytokines (IL-6 and TNF-a) and antiinflammatory cytokines (IL-4 and IL-10). Further, cytokine secretion was measured in culture supernatants by ELISA, whereas intracellular cytokine expression was detected by flow cytometry. Results indicate that monocytes treated with Tat B showed significant upregulation of proinflammatory cytokines, IL-6 and TNF-a, as compared to Tat C-treated cultures. However, expression of antiinflammatory molecules and IL-4 and IL-10 was found to be higher in Tat C-treated compared to Tat B-treated cultures. Thus, our result shows for the first time that Tat B and Tat C differentially modulate expression of neuropathogenic molecules that may be correlated with the differences in neuroAIDS manifestation induced by clade-specific infections.

HIV-1 Tat Protein Induces PD-L1 (B7-H1) Expression on Dendritic Cells through Tumor Necrosis Factor Alpha- and Toll-Like Receptor 4-Mediated Mechanisms

“…It has been reported that, among the viral factors, Tat protein interferes with the normal function of the immune system (33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43). HIV-1 Tat is a protein of 14 kDa, composed of 86 to 104 amino acids (aa), that is produced early after HIV-1 infection (41).…”

The Evolving Profile of the Signature Amino Acid Residues in HIV-1 Subtype C Tat

“…Second, at the other four positions (histidine 29, serine 57, proline 60, and glutamic acid 63), the prevalence of the respective signature amino acid appears to be undergoing a change between the two periods of evaluation. While the prevalence of the SAR at three of these locations (29,57, and 60) is progressively decreasing, at position 63, the frequency of the SAR is on the rise. Third, the rate of replacement of the SAR is not uniform.…”

“…The N-terminal domain 1 (aa [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] is rich in proline and acidic amino acid residues. The cysteine-rich domain (CRD, [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40] of Tat plays a critical role in protein dimerization and recruiting P-TEFb, a complex consisting of Cyclin T1 and CDK 9, to the RNA pol complex thereby enhancing transactivation at the level of elongation. [12][13][14] The core domain (CD, [41][42][43][44][45][46][47]…”

“…26,27 Subtype-specific biological differences in Tat have since been reported by many groups, including our own. [28][29][30][31] The significance of the dicysteine motif for Tat function was subsequently bolstered by a study where a recombinant Tat protein containing the dicysteine motif (CCTat), but not the protein lacking the motif (CS-Tat), was cytotoxic to fetal astrocytes and neurons derived from human neuronal progenitor cells. 32 A Tat peptide of subtype B containing the dicysteine motif (CysL 24-51 ) has been implicated in direct monocyte chemotaxis in vitro.…”

Immune reconstitution inflammatory syndrome and the central nervous system

“…These viral products may set up an antigenic gradient leading to infiltration of T cells. One protein with known immune activation capabilities that is produced even under the pressure of ART is the HIV protein Tat, the transactivator of transcription protein [46,47]. Recent anti-Tat vaccination studies have shown a beneficial effect on reducing immune activation in patients as well as increasing regulatory T cell populations [48].…”