Antibodies to Tat and Vpr in the GRIV cohort: differential association with maintenance of long-term non-progression status in HIV-1 infection

Abstract

The HIV-1 regulatory protein Tat and the accessory protein Vpr are thought to stimulate viral replication and contribute to viral pathogenesis as extracellular proteins. Humoral immune responses to these early viral proteins may therefore be beneficial. We examined serum anti-Tat and anti-Vpr IgG by ELISA in the GRIV cohort of HIV-1 seropositive slow/non-progressors (NP) and fast-progressors (FP), and in seronegative controls. Based on information obtained during a brief follow-up period (median = 20 months), NPs were sub-grouped as those maintaining non-progression status and therefore stable (NP-S), and those showing signs of disease progression (NP-P). As the primary comparison, initial serum anti-Tat and anti-Vpr IgG (prior to follow-up) were analyzed in the NP sub-groups and in FPs. Anti-Tat IgG was significantly higher in stable NP-S compared to unstable NP-P ( P = 0.047) and FPs ( P < 0.0005); the predictive value of higher anti-Tat IgG for maintenance of non-progression status was 92% ( P = 0.029). In contrast, no-difference was observed in anti-Vpr IgG between NP-S and NP-P, although both were significantly higher than FPs ( P ≤ 0.001). Serum anti-Tat IgG mapped to linear epitopes within the amino-terminus, the basic domain and the carboxy-terminal region of Tat in stable NP-S. Similar epitopes were identified in patients immunized with the Tat-toxoid in a Phase I study in Milan. High titer serum anti-Tat IgG from both GRIV and Milan cohorts cross-reacted in ELISA with Tat from diverse viral isolates, including HIV-1 subtype-E (CMU08) and SIVmac251 Tat; a correlation was observed between anti-Tat IgG titers and cross-reactivity. These results demonstrate that higher levels of serum anti-Tat IgG, but not anti-Vpr IgG, are associated with maintenance of non-progression status in HIV-1 infection. Evidence that vaccination with the Tat toxoid induces humoral immune responses to Tat similar to those observed in stable non-progressors is encouraging for vaccine strategies targeting Tat.