α1Proteinase inhibitor regulates CD4+ lymphocyte levels and is rate limiting in HIV-1 disease.
<h4>Background</h4>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 (HLE(CS)), it acts...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2012-01-01
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| Series: | PLoS ONE |
| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22363634/pdf/?tool=EBI |
| _version_ | 1818460420699062272 |
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| author | Cynthia L Bristow Mariya A Babayeva Michelle LaBrunda Michael P Mullen Ronald Winston |
| author_facet | Cynthia L Bristow Mariya A Babayeva Michelle LaBrunda Michael P Mullen Ronald Winston |
| author_sort | Cynthia L Bristow |
| collection | DOAJ |
| description | <h4>Background</h4>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 (HLE(CS)), it acts not as a proteinase, but as a receptor for α(1)proteinase inhibitor (α(1)PI, α(1)antitrypsin, SerpinA1). Binding of α(1)PI to HLE(CS) forms a motogenic complex. We previously demonstrated that α(1)PI deficiency attends HIV-1 disease and that α(1)PI augmentation produces increased numbers of immunocompetent circulating CD4(+) lymphocytes. Herein we investigated the mechanism underlying the α(1)PI deficiency that attends HIV-1 infection.<h4>Methods and findings</h4>Active α(1)PI 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 α(1)PI, HLE(CS) (+) lymphocytes, and CXCR4(+) lymphocytes (r(2) = 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 α(1)PI (r(2) = 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 α(1)PI. Chimpanzee α(1)PI differs from human α(1)PI by a single amino acid within the 3F5-binding epitope. Unlike human α(1)PI, chimpanzee α(1)PI 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-α(1)PI immune complexes correlated with decreased CD4(+) lymphocytes in HIV-1 subjects.<h4>Conclusions</h4>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. |
| first_indexed | 2024-12-14T23:29:58Z |
| format | Article |
| id | doaj.art-e24040399ee846b39af1961718c3c8fc |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-14T23:29:58Z |
| publishDate | 2012-01-01 |
| publisher | Public Library of Science (PLoS) |
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| series | PLoS ONE |
| spelling | doaj.art-e24040399ee846b39af1961718c3c8fc2022-12-21T22:43:43ZengPublic Library of Science (PLoS)PLoS ONE1932-62032012-01-0172e3138310.1371/journal.pone.0031383α1Proteinase inhibitor regulates CD4+ lymphocyte levels and is rate limiting in HIV-1 disease.Cynthia L BristowMariya A BabayevaMichelle LaBrundaMichael P MullenRonald Winston<h4>Background</h4>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 (HLE(CS)), it acts not as a proteinase, but as a receptor for α(1)proteinase inhibitor (α(1)PI, α(1)antitrypsin, SerpinA1). Binding of α(1)PI to HLE(CS) forms a motogenic complex. We previously demonstrated that α(1)PI deficiency attends HIV-1 disease and that α(1)PI augmentation produces increased numbers of immunocompetent circulating CD4(+) lymphocytes. Herein we investigated the mechanism underlying the α(1)PI deficiency that attends HIV-1 infection.<h4>Methods and findings</h4>Active α(1)PI 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 α(1)PI, HLE(CS) (+) lymphocytes, and CXCR4(+) lymphocytes (r(2) = 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 α(1)PI (r(2) = 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 α(1)PI. Chimpanzee α(1)PI differs from human α(1)PI by a single amino acid within the 3F5-binding epitope. Unlike human α(1)PI, chimpanzee α(1)PI 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-α(1)PI immune complexes correlated with decreased CD4(+) lymphocytes in HIV-1 subjects.<h4>Conclusions</h4>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.https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22363634/pdf/?tool=EBI |
| spellingShingle | Cynthia L Bristow Mariya A Babayeva Michelle LaBrunda Michael P Mullen Ronald Winston α1Proteinase inhibitor regulates CD4+ lymphocyte levels and is rate limiting in HIV-1 disease. PLoS ONE |
| title | α1Proteinase inhibitor regulates CD4+ lymphocyte levels and is rate limiting in HIV-1 disease. |
| title_full | α1Proteinase inhibitor regulates CD4+ lymphocyte levels and is rate limiting in HIV-1 disease. |
| title_fullStr | α1Proteinase inhibitor regulates CD4+ lymphocyte levels and is rate limiting in HIV-1 disease. |
| title_full_unstemmed | α1Proteinase inhibitor regulates CD4+ lymphocyte levels and is rate limiting in HIV-1 disease. |
| title_short | α1Proteinase inhibitor regulates CD4+ lymphocyte levels and is rate limiting in HIV-1 disease. |
| title_sort | α1proteinase inhibitor regulates cd4 lymphocyte levels and is rate limiting in hiv 1 disease |
| url | https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22363634/pdf/?tool=EBI |
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