20th International AIDS Conference - Melbourne, Australia

Abstract

WEPE001 Poster Exhibition


BIT225 therapy reduces HIV-1 burden in monocyte cells and decreases immune activation

Presented by John Wilkinson (Australia).

J. Wilkinson1, C. Witherington1, C. Luscombe1, G. Ewart1, K. McBride1, N. Tanliang2, W. Ratanasuwan2, R. Murphy3, M. Miller1


1Biotron Limited, Sydney, Australia, 2Siriraj Hospital, Bangkok, Thailand, 3Northwestern University, Chicago, United States

Background: BIT225 is a first in class antiviral drug that blocks Vpu ion channel activity resulting in disrupted HIV-1 assembly within the host cell. In a phase 1b/2a randomized study of the safety, pharmacokinetics and antiviral activity of BIT225 in 21 HIV-1+, antiretroviral therapy naïve subjects receiving BIT225 at 400 mg BID or placebo treatment for 10 days (randomized 2:1), we have previously reported the ability of BIT225 to significantly reduce the viral burden within the monocyte reservoir. Here, we evaluate BIT225 therapy on patient immune activation in these treated individuals.
Methods: CD14+ monocytes isolated from the peripheral blood on days 0, 5, 10 and 20 of treatment were cocultured ex vivo with MT4 T cells. De novo HIV-1 replication was measured by p24 activity of virus released into the culture supernatant out to day 25 of coculture. Additionally, the activation markers sCD163 and neopterin levels were quantitated in patient plasma at each of these treatment time points by ELISA
Results: BIT225 treatment significantly reduced the viral burden in patients'' monocyte cells, with a greater effect seen in individuals with higher viral loads. High plasma levels of sCD163 significantly correlated with higher HIV-1 viral loads at baseline and throughout BIT225 therapy (p=0.0001, r=0.53). Treatment with BIT225 resulted in a significant (p=0.04) decrease in sCD163 levels, 3.98 ±0.37 ng/mL at baseline to 3.6 ±0.37 ng/mL at day 5, that normalised at day 10. At day 20, 10 days after BIT225 cessation, sCD163 levels were significantly (p=0.04) elevated from baseline, 4.37 ±0.41 ng/mL, suggesting the resumption of HIV-1 replication within this myeloid population. No changes were observed in the levels of neopterin, a monocyte activation marker driven by IFN-γ from activated T cells, indicative of ongoing viral replication within the T cells.
Conclusions: Even during a short duration of treatment, BIT225 significantly reduces the viral burden in the monocyte compartment in HIV-1 infected patients and transiently reduces immune activation in these patients as measured by sCD163 levels. BIT225 is a first in class antiviral that is capable of inhibiting viral production in the myeloid cells of HIV-1 infected individuals.

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