Self antigen prognostic for human immunodeficiency virus disease progression

Abstract

We have recently found that an extracellular protein, alpha(1) proteinase inhibitor (alpha(1)PI; alpha(1) antitrypsin), is required for in vitro human immunodeficiency virus (HIV) infectivity outcome. We show here in a study of HIV-seropositive patients that decreased viral load is significantly correlated with decreased circulating alpha(1)PI. In the asymptomatic category of HIV disease, 100% of patients manifest deficient levels of active alpha(1)PI, a condition known to lead to degenerative lung diseases and a dramatically reduced life span. Further, HIV-associated alpha(1)PI deficiency is correlated with circulating anti-alpha(1)PI immunoglobulin G. These results suggest that preventing HIV-associated alpha(1)PI deficiency may provide a strategic target for preventing HIV-associated pathophysiology.

Figures

FIG. 1

α1PI and α2M concentrations in serum by clinical category of HIV disease. (A) Values were not normally distributed. Category medians are represented by bars and are statistically compared in Table 1. (B) HIV RNA was found to be correlated with total α1PI in asymptomatic patients (P < 0.04) but not in other clinical categories. HIV RNA was not related to CD4 levels in any clinical category. (C) There was no relationship between α2M and α1PI concentrations in asymptomatic and symptomatic pre-AIDS patients; however, in AIDS patients, α2M was correlated with both active α1PI (r2 = 0.73, P < 6 × 10−6) and inactive α1PI (r2 = 0.45, P < 0.04). (D) Schematic representation of CD4 (.....), HIV RNA (—), active α1PI (----), and total α1PI (––––) concentrations in this patient population.

FIG. 2

Autoantibodies reactive with α1PI in HIV disease. (A) Autoantibodies reactive with α1PI were detected by ELISA. Bars represent mA405 per minute and are statistically compared in Table 3. The mean reactivity was significantly lower in AIDS patients than in asymptomatic (P < 0.0005) or symptomatic pre-AIDS (P < 0.02) patients. (B) A monoclonal antibody with specificity for gp120 epitopes near the fusion domain also recognized α1PI (●) but not CD4 (■). Binding of anti-gp120 to α1PI was inhibited in the presence of 8 μM competing gp120 (▴). A monoclonal antibody with specificity for gp120 epitopes near the V3 loop failed to recognize α1PI (▾). (C) Alignment of amino acid sequences for human α1PI and the epitope recognized by anti-HIV gp120 near the fusion domain revealed significant homology. Boxed residues are identical or conservatively substituted. The immunizing peptide for monoclonal anti-gp120 antibody is underlined. The hydrophobic α1PI pentapeptide is depicted in boldface. The proteinase reactive site of α1PI is Met-358. HIV gp120 and gp41 are produced by cleavage near Lys-517 and Arg-518 to reveal the fusion domain.