The antiviral compound BIT225 inhibits HIV-1 replication in myeloid dendritic cells

Abstract

Background: Previous studies with BIT225 (N-carbamimidoyl-5-(1-methyl-1H-pyrazol-4-yl)-2-naphthamide) have demonstrated a unique antiviral activity that blocks the release of HIV-1 from monocyte-derived macrophages (MDM). Antagonising the ion channel formed by HIV-1 Vpu, BIT225 preferentially targets de novo intracellular virus produced in 'virus-containing compartments' of MDM. In primary infections, dendritic cells (DC) are one of the first cells infected by HIV-1 and can transfer virus to more permissive CD4(+) T cells, making these cells an important target for novel antiviral therapies. To extend previous findings with BIT225, we aimed to further characterise the antiviral activity of BIT225 on HIV-1 replication in monocyte-derived DC (MDDC).

Results: The anti-HIV-1 activity of BIT225 was evaluated in vitro within MDDC alone and in co-cultures with activated CD4(+) T cells to examine the effect of the drug on HIV-1 transfer. Antiviral activity was determined by measuring HIV-1 reverse transcriptase activity in the culture supernatant of BIT225 treated and DMSO control cultures. A single dose of BIT225 resulted in a mean (SE) peak inhibition of HIV-1 release from MDDC by 74.5 % (±0.6) following 14 days of culture and a 6-fold reduction of HIV-1 transfer to activated uninfected CD4(+) T cells in co-culture.

Conclusions: HIV-1 release from MDDC was inhibited by BIT225. This data broadens the drug's antiviral activity profile within cells of the myeloid lineage. These findings suggest a potential role for BIT225 in reducing HIV-1 production and preventing viral dissemination in early and chronic infection and may assist in limiting virus spread with any ongoing viral replication during antiretroviral therapy.

Keywords: Antiviral; Dendritic cells; HIV-1; Myeloid; Viral transfer.

Fig. 1

BIT225 inhibits HIV-1 replication in MDDC. MDDC were infected with HIV-1_BaL in the presence of 20 µM BIT225 (open triangles) or with equivalent DMSO solvent control (full circles). a HIV-1 replication was measured using a reverse transcriptase (RT) activity assay in three separate donors and combined as (b) mean (±SE) percentage viral inhibition

Fig. 2

BIT225 reduces the transfer of HIV-1 from MDDC to more permissive uninfected CD4⁺ T cells. MDDC were infected with HIV-1_BaL in the presence of 20 µM BIT225 (open triangles) or with DMSO solvent control (full circles) and co-cultured with activated CD4⁺ T cells at various times post-infection to measure viral transfer. a HIV-1 replication was measured using a reverse transcriptase (RT) activity assay in three donors and data was also represented as b mean (±SE) percentage viral inhibition