Alpha-1-proteinase inhibitor regulates CD4 lymphocyte levels and is rate limiting in HIV-1 disease

Introduction

Adult stem cell migration through human hematopoietic tissue requires the chemokine CXCL12 and its receptor CXCR4. 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 α1proteinase inhibitor (α₁PI, α1antitrypsin). Binding of α₁PI to HLECS forms a motogenic complex. We previously demonstrated that α₁PI deficiency attends HIV-1 disease. Here we investigate the mechanism and therapeutically address the α₁PI deficiency of HIV-1 infection.

Materials and methods

Blood was collected from 30 HIV-1 uninfected and 39 HIV-1 infected adults. Residual sera was obtained from 20 HIV-1 uninfected chimpanzees, 2 chimpanzees pre- and 42 months post-HIV-1 challenge, 12 HIV-1-immunized macaques, and 3 SHIV-infected macaques. Three HIV-1 infected individuals received α₁PI augmentation therapy.

Results

In HIV-1 uninfected individuals, CD4⁺ lymphocytes were correlated with the combined factors α₁PI, HLECS+ lymphocytes, and CXCR4+ lymphocytes (r² = 0.91, p < 0.001, n = 30), but not CXCL12. In contrast, in HIV-1 individuals with >220 CD4 cells/µl, CD4+ lymphocytes were correlated solely with active α1PI (r² = 0.93, p < 0.0001, n = 26). The monoclonal anti-HIV-1 antibody 3F5 present in HIV-1 patient blood bound and inactivated human α₁PI. Chimpanzee α₁PI differs from human α₁PI by a single amino acid which lies within the 3F5-binding epitope. Unlike human α₁PI, neither chimpanzee nor macaque α₁PI bound to 3F5, nor was α₁PI depleted following HIV-1 challenge, consistent with the normal CD4⁺ lymphocyte numbers of HIV-1 infected chimpanzees. The presence of IgG- α₁PI immune complexes correlated with decreased CD4⁺ lymphocytes in HIV-1 individuals, and α1PI augmentation quadrupled the number of immunocompetent CD4⁺ lymphocytes with no untoward effects.

Conclusions

An autoimmune component of HIV-1 disease was identified and was overcome therapeutically. 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.