HIV-1 early diagnosis of men having sex with men in Hong Kong and discovery of novel agents for HIV-1 treatment from traditional Chinese herbal medicine

Abstract

Over the 30 years since it was first identified, the HIV/AIDS epidemic has had historically unprecedented severity and impact. There are approximately 33.4 million people living with HIV-1/AIDS which urges to seek novel approaches for HIV-1 diagnosis and HIV-1 therapy. Men who have sex with men (MSM) are severely affected by HIV-1 and constitute a large proportion of HIV-infected individuals. In Hong Kong, the transmission route of homosexual and bisexual contacts accounted for nearly 50% of incidence in 2012. To investigate HIV-1 prevalence among MSM in Hong Kong, the combination of fast antibody test (FAT) and real-time dried-blood-spot-based quantitative polymerase chain reaction (DBS-qPCR) was employed for 474 participants chosen randomly from community testing sites of MSM within a one-year period which showed a 4.01% (19/474) rate of HIV-1 prevalence among MSM in Hong Kong with three cases at the acute phase among the newly infected participants. The new survey demonstrated that the risk factors of MSM are mostly correlated with the receptive role during anal sex and syphilis infection. In this study, two traditional Chinese herbal medicines (TCHM), Sanguisorba officinalis (SO) and Spatholobus suberectus (SS), inhibited the infection of model cell lines expressing HIV-1 targets by HIV-1 pseudoviruses, while the anti-HIV-1 properties of SO were demonstrated for the first time. Both SO and SS were able to block not only infection by pseudoviral HIV-1 CCR5-tropic and CXCR4-tropic strains, but also RT and PI drug-resistant strains. Mechanistic studies revealed that SO and SS interact with the viral envelope to prevent the infection of target cells by HIV-1. Two compounds derived from SO and SS, named Gallic acid (GA) and Jiazhi (JZ), retained anti-HIV-1 properties and blocked HIV-1 infection by acting on the viral envelope. Small molecules derived from TCHM were also investigated for their capacity to activate HIV-1 from latency. A small molecule derived from SS, Daidzein (DDZ), demonstrated the potentials to trigger HIV-1 reactivation in latently infected cell lines. DDZ enhanced gene expression from HIV-1 LTR in which the Sp1 binding site plays an important role. The Akt pathway is also involved in the initiation of DDZ-induced activation. Phosflow analysis revealed that DDZ activated the Akt pathway in various subpopulations of T cells, including memory CD4+ T cells which are considered to be a major reservoir for HIV-1. The structure-activity relationships (SARs) study demonstrated the 4'-hydroxyisoflavone as bio-functional core structure. Addition of a hydroxyl group on C-5 position significantly decreases its biological function of HIV-1 latency activation. In summary, this study investigates HIV prevalence and incidence using an assay for early HIV-1 diagnosis and performs an analysis of risk factors of behavior which contributes to the effective control of HIV transmission in Hong Kong and its neighbors in Asia. It also demonstrates a drug research sourced from traditional Chinese herbal medicines that which sheds lights on drug discovery from traditional herbal medicines and facilitates mechanistic drug design for HIV-1 eradication.