by Cynthia L. Bristow, Mariya A. Babayeva, Michelle LaBrunda, Michael P. Mullen, Ronald Winston
The regulation of adult stem cell migration through human hematopoietic tissue involves the chemokine CXCL12 (SDF-1) and its receptor CXCR4 (CD184). In addition, human leukocyte elastase (HLE) plays a key role. When HLE is located on the cell surface (HLECS), it acts not as a proteinase, but as a receptor for a1proteinase inhibitor (a1PI, a1antitrypsin, SerpinA1). Binding of a1PI to HLECS forms a motogenic complex. We previously demonstrated that a1PI deficiency attends HIV-1 disease and that a1PI augmentation produces increased numbers of immunocompetent circulating CD4+ lymphocytes. Herein we investigated the mechanism underlying the a1PI deficiency that attends HIV-1 infection. Methods and Findings
Active a1PI in HIV-1 subjects (median 17 µM, n?=?35) was significantly below normal (median 36 µM, p<0.001, n?=?30). In HIV-1 uninfected subjects, CD4+ lymphocytes were correlated with the combined factors a1PI, HLECS+ lymphocytes, and CXCR4+ lymphocytes (r2?=?0.91, p<0.001, n?=?30), but not CXCL12. In contrast, in HIV-1 subjects with >220 CD4 cells/µl, CD4+ lymphocytes were correlated solely with active a1PI (r2?=?0.93, p<0.0001, n?=?26). The monoclonal anti-HIV-1 gp120 antibody 3F5 present in HIV-1 patient blood is shown to bind and inactivate human a1PI. Chimpanzee a1PI differs from human a1PI by a single amino acid within the 3F5-binding epitope. Unlike human a1PI, chimpanzee a1PI did not bind 3F5 or become depleted following HIV-1 challenge, consistent with the normal CD4+ lymphocyte levels and benign syndrome of HIV-1 infected chimpanzees. The presence of IgG-a1PI immune complexes correlated with decreased CD4+ lymphocytes in HIV-1 subjects. Conclusions
This report identifies an autoimmune component of HIV-1 disease that can be overcome therapeutically. Importantly, results identify an achievable vaccine modification with the novel objective to protect against AIDS as opposed to the current objective to protect against HIV-1 infection.