Antibodies to H1 histone from the sera of HIV‐infected patients recognize and catalyze site‐specific degradation of this histone

Abstract

Histones and their posttranslational modifications have key roles in chromatin remodeling and gene transcription. Besides intranuclear functions, histones act as damage-associated molecules when they are released into the extracellular space. Administration of histones to animals leads to systemic inflammatory and toxic responses. Autoantibodies with enzymatic activities (abzymes) are distinctive feature of some autoimmune and viral diseases. Electrophoretically and immunologically homogeneous IgGs containing no canonical enzymes were isolated from sera of human immunodeficiency virus-infected patients by chromatography on several affinity sorbents. In contrast to canonical proteases (trypsin, chymotrypsin, and proteinase K), IgGs from human immunodeficiency virus-infected patients purified by affinity chromatography on Sepharose containing immobilized histones specifically recognized and hydrolyzed only histones but not many other tested globular proteins. Using matrix-assisted laser desorption/ionization mass spectrometry, the sites of H1 histone (193 amino acids [AAs]) cleavage by anti-H1 histone IgGs were determined for the first time. It was shown that 1 cluster of 2 major and 4 moderate sites of cleavage is located at the beginning (106-112 AAs) of the known antigenic determinants disposed at the long C-terminal sequence of H1. Two clusters of minor and very weak sites of the protein cleavage correspond to middle (8 sites, 138-158 AAs) and terminal (5 sites, 166-176 AAs) parts of the antigenic determinants. It was shown that in contrast to canonical proteases, N-terminal part of H1 histone (1-136 AAs) containing no antigenic determinants is an unpredictably very resistant against hydrolysis by abzymes, while it can be easily cleavage by canonical proteases. Because histones act as damage-associated molecules, abzymes against H1 and other histones can play important role in pathogenesis of acquired immune deficiency syndrome and probably other different diseases.

Autoantibodies in HIV‐infected patients: Cross site‐specific hydrolysis of H1 histone and myelin basic protein

“…It should be assumed that analogous regularities can also occur in the case of sequence‐dependent proteases. Therefore, it is not surprising that proteolytic antiprotein abzymes usually catalyze only their specific proteins .…”

“…Apoptotic cells are considered as the primary antigens and immunogens sources in SLE, MS, and other AI pathologies [23]. Antibodies hydrolyzing all five human histones (H1, H2a, H2b, H3, and H4) were revealed in the sera of HIV-infected patients [24][25][26][27].…”

“…HIV-dependent activation of B lymphocytes results in the production of auto-Abs to many various human cell components [28,32,36,37]. In addition, IgGs and/or IgMs from sera of AIDS patients hydrolyze DNA [38], HIV-1 reverse transcriptase [39], integrase [40][41][42][43], and histones [24][25][26][27]. It was shown that 100% of IgGs of 32 HIV-infected patients efficiently cleavage from one to five human histones [24][25][26][27].…”

“…In addition, IgGs and/or IgMs from sera of AIDS patients hydrolyze DNA [38], HIV-1 reverse transcriptase [39], integrase [40][41][42][43], and histones [24][25][26][27]. It was shown that 100% of IgGs of 32 HIV-infected patients efficiently cleavage from one to five human histones [24][25][26][27]. Thus, abzymes against histones can play an important negative role in the pathogenesis of AIDS and probably in the development of different various AI diseases.…”

“…It was shown that MBPhydrolyzing activity is an intrinsic property of antibodies from the blood of HIV-infected patients. As mentioned above, the abzymes against any protein usually specifically hydrolyze only this, but not other control proteins [3][4][5]; according to previous data only anti-MBP antibodies hydrolyze MBP [13][14][15][19][20][21], while histones are split only by anti-histones abzymes [24][25][26][27]. Till yet in the literature, there were no data on cross-hydrolysis of proteins with antibodies against different proteins [3][4][5][6][7][8][9][10][11][12][13][14][15].…”