Vpu is a HIV-1 encoded membrane protein with multiple regulatory functions that enhance HIV-1 replication fitness and promote innate immune evasion in multiple cell types including monocytes. BIT225 inhibits HIV-1 replication in myeloid cells in vitro. BIT225 has been studied in patients with chronic HIV-1 infection receiving antiretroviral therapy (ART).
A randomized, placebo controlled, double-blind, Phase 2 study of BIT225 in individuals with HIV-1 commencing ART (males and females, aged 18 to 65 years, viral load >5,000 copies/mL; CD4+count >100 cells/mm3, ART naïve). HIV-1 infected individuals recruited from two sites in Thailand were treated with either BIT225 or placebo in addition to ART (Atripla) for 12 weeks.Individuals were randomized 2:1 (BIT225: placebo). Markers of viral replication and immune functions were investigated.
Thirty-six patients were enrolled. Plasma HIV-1 RNA levels declined with similar viral decay kinetics in both cohorts over the 12 week study period. In contrast, significant changes were observed for multiple immune markers between the 2 cohorts. Levels of the monocyte activation marker sCD163 showed significantly greater reduction from baseline (P<0.05, general linear model, two-way ANOVA) in the BIT225 treated cohort compared to ART alone over the 12 week treatment period. There was a statistically significant increase in activated CD8+, CD4+ cells, and NK cells in the BIT225 cohort. There was a transient statistically significant increase in plasma IL-21 production in the first 3 weeks of BIT225 therapy. There were no significant changes to plasma IL-6, TNF-alfa, and interferon-gamma in either cohort over the treatment period.
The addition of BIT225 to ART resulted in unique stimulation of multiple arms of the innate immune system. The increased numbers of CD8+, CD4+ and NK cells are consistent with enhanced recognition of HIV-1 infected cells. Vpu has been associated with reducing cell surface expression/function of numerous cellular proteins/receptors involved in viral antigen presentation to CD4+, CD8+ T cells and NK cells. The production of IL-21 by Tfh, Th17, and/or NK cells is a unique immunological consequence of addition of BIT225 to ART and offers the potential for treatment targeting different HIV-1 compartments during standard therapy.