Abstract
Chemodietary agents are emerging as promising adjuvant therapies in treating various disease conditions. However, there are no adjuvant therapies available to minimize the neurotoxicity of currently existing antiretroviral drugs (ARVs). In this study, we investigated the anti-HIV effect of a chemodietary agent, Cucurbitacin-D (Cur-D), in HIV-infected macrophages using an in-vitro blood–brain barrier (BBB) model. Since tobacco smoking is prevalent in the HIV population, and it exacerbates HIV replication, we also tested the effect of Cur-D against cigarette smoke condensate (CSC)-induced HIV replication. Our results showed that Cur-D treatment reduces the viral load in a dose-dependent (0–1 μM) manner without causing significant toxicity at <1 μM concentration. Further, a daily dose of Cur-D (0.1 μM) not only reduced p24 in control conditions, but also reduced CSC (10 μg/mL)-induced p24 in U1 cells. Similarly, Cur-D (single dose of 0.4 μM) significantly reduced the CSC (single dose of 40 μg/mL)-induced HIV replication across the BBB model. In addition, treatment with Cur-D reduced the level of pro-inflammatory cytokine IL-1β. Therefore, Cur-D, as an adjuvant therapy, may be used not only to suppress HIV in the brain, but also to reduce the CNS toxicity of currently existing ARVs.
Highlights
The prevalence of HIV-associated neurocognitive disorders (HAND) is increasing despite the successful implementation of antiretroviral therapy (ART) [1,2]
There is an evidence of transmigration of CD14+ CD16+ monocytes in the central nervous system (CNS), which perpetuates the neuropathogenesis of HIV [3]
The human immunodeficiency virus type 1 (HIV-1) p24 antigen level in the supernatant collected from U1 cells was measured using an HIV-1 p24 Antigen ELISA kit (Zeptometrix Corporation, Buffalo, NY, USA)
Summary
The prevalence of HIV-associated neurocognitive disorders (HAND) is increasing despite the successful implementation of antiretroviral therapy (ART) [1,2]. Cigarette smoking is prevalent among HIV-positive subjects [8] and it has been reported to increase HIV replication and its associated conditions by various mechanisms, including oxidative stress [9,10,11]. FDA has approved the first long-acting drug combo for HIV, monthly shots which are beneficial for people who are more likely to have a reduced compliance to the treatment, including people who smoke cigarette [16]. Relatively high costs of the monthly shots may limit their use among the HIV population This drug formulation does not solve the problem of ineffective treatment of HIV in the brain. There is a need to constantly develop new drugs or drug-like compounds that can, alone or in the presence of current ART drugs, effectively suppress HIV, as well as smoking-exacerbated HIV replication and its associated complications, including HAND. We show, for the first time, the potential anti-HIV activity of Cur-D across the in-vitro BBB model in the absence and presence of tobacco constituents
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