Inhibition of HIV-1 entry by extracts derived from traditional Chinese medicinal herbal plants
© Park et al; licensee BioMed Central Ltd. 2009
Received: 19 June 2009
Accepted: 5 August 2009
Published: 5 August 2009
Highly active anti-retroviral therapy (HAART) is the current HIV/AIDS treatment modality. Despite the fact that HAART is very effective in suppressing HIV-1 replication and reducing the mortality of HIV/AIDS patients, it has become increasingly clear that HAART does not offer an ultimate cure to HIV/AIDS. The high cost of the HAART regimen has impeded its delivery to over 90% of the HIV/AIDS population in the world. This reality has urgently called for the need to develop inexpensive alternative anti-HIV/AIDS therapy. This need has further manifested by recent clinical trial failures in anti-HIV-1 vaccines and microbicides. In the current study, we characterized a panel of extracts of traditional Chinese medicinal herbal plants for their activities against HIV-1 replication.
Crude and fractionated extracts were prepared from various parts of nine traditional Chinese medicinal herbal plants in Hainan Island, China. These extracts were first screened for their anti-HIV activity and cytotoxicity in human CD4+ Jurkat cells. Then, a single-round pseudotyped HIV-luciferase reporter virus system (HIV-Luc) was used to identify potential anti-HIV mechanisms of these extracts.
Two extracts, one from Euphorbiaceae, Trigonostema xyphophylloides (TXE) and one from Dipterocarpaceae, Vatica astrotricha (VAD) inhibited HIV-1 replication and syncytia formation in CD4+ Jurkat cells, and had little adverse effects on host cell proliferation and survival. TXE and VAD did not show any direct inhibitory effects on the HIV-1 RT enzymatic activity. Treatment of these two extracts during the infection significantly blocked infection of the reporter virus. However, pre-treatment of the reporter virus with the extracts and treatment of the extracts post-infection had little effects on the infectivity or gene expression of the reporter virus.
These results demonstrate that TXE and VAD inhibit HIV-1 replication likely by blocking HIV-1 interaction with target cells, i.e., the interaction between gp120 and CD4/CCR5 or gp120 and CD4/CXCR4 and point to the potential of developing these two extracts to be HIV-1 entry inhibitors.
Human immunodeficiency virus type 1 (HIV-1) causes acquired immune deficiency syndrome (AIDS) [1, 2]. CD4+ T lymphocytes are the natural target of HIV-1 infection . At the cellular level, HIV-1 life cycle begins with binding of HIV-1 gp120 to cellular receptors CD4 and chemokine receptors CCR5 or CXCR4 that are expressed on the surface of HIV-1 target cells, followed by gp41 conformational change, which in turn leads to virus-cell membrane fusion and entry of the viral core (nucleocapsid) into the cytoplasm [4–6]. The virion core undergoes uncoating, the viral RNA genome is converted into proviral DNA by the virally encoded enzyme reverse transcriptase (RT) . The DNA enters the nucleus and is covalently integrated into the genome of the host cell by the second virally encoded enzyme integrase (IN) [8–10]. The integrated viral DNA serves as the template for viral transcription and synthesis of various components of progeny viruses . Progeny viruses are assembled on and budded through the plasma [11, 12]. As a result, the progeny viruses become encapsulated by a layer of membrane that also harbors the viral envelope glycoproteins . Concomitant with budding, a third virally encoded enzyme protease (PR) processes the core proteins into their final forms, and the virion undergoes a morphologic change known as maturation [7, 13]. This final step primes the progeny viruses for the next round of infection.
In parallel with these progresses made in our understanding of basic HIV-1 virology and pathogenesis is development of anti-HIV-1 therapeutics. The primary targets for anti-HIV-1 therapeutic development have been two virally encoded enzymes: RT and PR. The Food and Drug Administration (FDA) has approved a total of 21 anti-HIV-1 drugs, a majority of these drugs are HIV-1 RT and PR inhibitors. Various combinations of these inhibitors, so-called highly active anti-retroviral therapy (HAART) is very effective in suppressing viral replication and has led to a significant reduction in the mortality rate of the disease, increase in the lifespan of HIV/AIDS patients and improvement of the quality of life of these patients [14–16]. However, issues such as viral reservoirs, drug resistance, high dosages and frequencies, and high cost, have led to a significant crisis in the management of HIV/AIDS patients, particularly in developing nations, where there is the greatest need [17–19]. It has become evident that HAART does not offer a complete solution to the problem. Meanwhile, relatively fewer anti-HIV-1 therapeutics have been developed to target other steps of HIV-1 life cycle including entry, fusion, and integration. On the other hand, recent trials on anti-HIV-1 vaccines and microbicides have shown that some of current vaccine and microbicide strategies not only did not prevent but actually increased HIV-1 infection and transmission risks [20–23]. Therefore, additional and alternative anti-HIV-1 therapeutic strategies are desperately needed to be explored and developed to fight this virus from destroying the immune system of infected individuals and from spreading the virus to others.
In the current study, we investigated a panel of traditional Chinese medicinal herbal extracts obtained from plants in Hainan Island, China, a geographically unique tropical/subtropical region for their activities against HIV-1 replication. We demonstrate that extracts from Euphorbiaceae, Trigonostema xyphophylloides (TXE) and Dipterocarpaceae, Vatica astrotricha (VAD) both block HIV-1 replication at the entry step. These results point to the potential of developing these plant extracts as anti-HIV-1 entry inhibitors.
Preparation of plant extracts
Tropical plants selected to make extracts for anti-HIV screening
Plant (family, species)
Euphorbiaceae, Antidesma ghaesembilla
Euphorbiaceae, Alchoornea rugosa
Euphorbiaceae, Alchoornea rugosa
Euphorbiaceae, Trigonostema xyphophylloides
Euphorbiaceae, Trigonostema xyphophylloides
Euphorbiaceae, Mallotus furetianus
Euphorbiaceae, Mallotus furetianus
Euphorbiaceae, Sapium insigne Benth. Et Hook
Clavicipitaceae, Cordyceps inensis Sacc
TB, cough, sweating
Rubiaceae, Saprosma hainanense Merr
Guttiferae, Calophyllum membranaceum
Dipterocarpaceae, Vatica astrotricha
Dipterocarpaceae, Vatica astrotricha
Cells, HIV-1 HXBc2 viruses and chemicals
Jurkat cells were purchased from American Tissue Culture Collection (ATCC, Manassas, VA) and cultured in RPMI 1640 medium supplemented with 10% fetal bovine serum, 100 units/ml penicillin, and 100 μg/ml streptomycin sulfate. U87.CD4.CXCR4 and U87.CD4.CCR5 cells expressing CD4/CXCR4 and CD4/CCR5 respectively were obtained from the NIH AIDS Reagent Program  and cultured in DMEM medium supplemented with 10% fetal bovine serum, 100 units/ml penicillin, and 100 μg/ml streptomycin sulfate. Proviral DNA of T-tropic HIV-1 strain HXBc2 was transfected into Jurkat cells to generate viral inoculums by the DEAE-Dextran method. HIV-1 HXBc2 expresses HIV-1 Eli strain nef and all other HXB2 genes. Unless stated otherwise, all chemicals were from Sigma (St. Louis, MO).
HIV-1 replication assay
One million Jurkat cells in 1 ml culture medium were infected with HIV-1 corresponding to a 10,000 cpm RT activity. At twenty-four hr post-infection, cells were treated with plant extracts at indicated concentrations or equivalent concentrations of the DMSO solvent. Fresh extracts as well as DMSO were added every other day. Meanwhile, the culture supernatants were collected for the RT activity assay. Briefly, 1 ml of the culture supernatant was collected and cleared to remove any cells and cell debris by centrifugation at 1,000 g for 5 min, followed by filtration of the cleared supernatants through a 0.2 μm syringe filter. Virions in the supernatant were pelleted by centrifugation at 12,000 g for 1 hr and the RT activity was determined as described [25, 26].
Cytotoxicity and syncytia formation
The cytotoxicity of the plant extracts was determined using the trypan blue exclusion method. Briefly, Jurkat cells that were exposed to plant extracts in the presence or absence of HIV-1 infection for various lengths of time were stained in 0.2% trypan blue dye and then counted for viable cells under a light microscope. HIV-1-infected Jurkat cells were scored for syncytia formation from 4 random fields from each of the triplicate samples over the course of HIV-1 infection by a light microscope.
Preparation and infection of HIV-1 pseudotyped viruses
HIV-1 viruses pseudotyped with different envelope proteins were prepared as previously described [27, 28]. Briefly, 293T cells (2 × 106 cells per 10-cm plate) were transfected with 20 μg of HIV-Luc plasmid and 4 μg of pHXB2-env, p89.6-env, pVSV-G, or pcDNA3 by the calcium phosphate precipitation method. Cell culture supernatants were collected 48 hr after medium change, filtered, and saved as virus stocks. For infection, pseudotyped viruses corresponding to a 2,000 cpm RT activity were used to infect target cells. Following 2 hr infection, the cells were removed of remaining viruses by multiple washes with fresh medium. The cells were continued to incubate for 48 hr and then harvested for the Luc activity assay as described [27, 28].
Fractionation of crude extracts of TXE and VAD
TXE and VAD extracts obtained above were suspended in 1.5 L H2O and partitioned successively with petroleum ether (PE) (4 × 1.5 L), chloroform (CF) (5 × 1.5 L), ethyl acetate (EA) (5 × 1.5 L), and n-butanol (BT) (5 × 1.5 L) to obtain respective subfractions. The excessive solvents were removed from these subfractions under a reduced pressure to generate ointments. The ointments were lyophilized to the powder form. These subfractions were dissolved in DMSO at a concentration of 100 mg/ml by overnight shaking on a shaker, and the undissolved materials were removed by low speed centrifugation followed by filtration through syringe filter, as described above.
All values expressed as mean ± SEM, or representative of at least three independent experiments. Comparisons among groups were made using two-tailed Student's t-test. A p value of < 0.05 was considered statistically significant (*), and p < 0.01 highly significant (**).
Anti-HIV-1 activity of extracts of traditional Chinese medicinal herbal plants
Cytotoxicity of the extracts
Inhibition of HIV-1-induced syncytia formation by the extracts
No inhibition of HIV-1 RT activity by the extracts
Block of HIV-1 entry by these extracts
No effects of the extracts on HIV-1 itself and HIV-1 post-entry
Effect of TXE or VAD on entry of primary HIV-1 isolate 89.6 into cells
Identification of anti-HIV components of TXE and VAD
Using a well-established HIV-1 replication system, we screened extracts of traditional Chinese medicinal herbal plants for their anti-HIV activities (Table 1). We showed that extracts from the stem of Euphorbiaceae, Trigonostema xyphophylloides (TXE) and the stem of Dipterocarpaceae, Vatica astrotricha (VAD) inhibited HIV-1 replication without apparent effects on cell proliferation and cell survival (Figure 1 and Figure 2). The inhibitory effects of these two extracts were further corroborated by the finding that these extracts prevented HIV-infected cells from forming syncytia (Figure 3). Nevertheless, we did not detect any effects of these extracts on HIV-1 RT enzymatic activity (Figure 4). Instead, we showed that these extracts potently blocked HIV-1 from entering its target cells (Figure 5). Furthermore, we showed that these extracts had little effects on post-entry HIV-1 gene expression (Figure 6). We obtained similar results with the primary isolate, HIV-1 89.6 which displays dual tropism, using both CXCR4 and CCR5 for entry into cells (Figure 7). Taken together, these studies revealed the anti-HIV activities of these two plant extracts and suggest that their anti-HIV activity results from interfering with HIV-1 entry.
All currently FDA-approved anti-HIV drugs are chemically synthesized [32, 33]. Development of these drugs involves an extremely long cycle of research, design and optimization, thus these drugs are very expensive. Besides, as many of these drugs are structural analogs of host metabolic components, use of these drugs is often limited by side-effects and non-adherence issues. In contrast, medicines of natural origins such as herbs have a much short development cycle and relatively inexpensive. Importantly, the toxicity of nature-derived medications is rarely an issue. A recent study has shown that more than two third of those who are on anti-HIV medications are also taking alternative therapy, including nearly 25% on those derived from botanicals and Chinese herbs [34, 35]. There is clearly a need to further investigate and develop this alternative anti-HIV therapy, as it likely makes the anti-HIV therapy ultimately affordable and available to all HIV/AIDS-affected individuals including those in developing and under-developed countries.
Some efforts have been made to identify natural remedies to combat HIV/AIDS in clinical settings. A number of natural products have been shown to possess anti-HIV-1 activities, including those derived from microorganisms, marine organisms, and plants, and these natural products inhibit HIV-1 replication at various steps of HIV-1 life cycle . Currently, more than 150 natural products have been isolated from marine organisms to show promising anti-HIV-1 activity [37, 38]. One of the outstanding examples is cyanovirin-N, an 11 KDa anti-HIV-1 protein that was initially isolated from the cyanobacterium (bluegreen alga) Nostoc ellipsosporum . Cyanovirin-N inhibits HIV-1 replication through its vivid binding to HIV-1 gp120 and as a result, inactivates the viruses and blocks the fusion of viruses to the cell membrane [40, 41]. The protein is now in Phase II clinical trial to be used as an anti-HIV-1 microbicide.
Traditional Chinese Medicines (TCMs) have a very long history. They have been used to treat various human diseases and regarded as the state cultural treasure by the Chinese government. Development and standardization of TCMs have recently been proposed as the top biomedical research priority for the next 5–10 years in P. R. China. Studies on the anti-HIV activities and mechanisms of TCMs are very limited and are expected to accelerate. Currently, HIV-1-inhibitory TCMs are reported to include Scutellaria baicalensis Georgi, Prunella vulgaris, Paeonia Suffruticosa, Rhizoma Polygoni Cuspidati, Radix Notoginseng, Ramulus Visci, and Ajuga Decumbens Thumb [42–47]. Our studies added Euphorbiaceae, Trigonostema xyphophylloides (TXE) and Dipterocarpaceae, Vatica astrotricha (VAD) onto this soon-to-be-rapidly-expanding list. Studies are under way to further fractionate these extracts for identification of the active anti-HIV-1 entry constituents in these extracts and for better characterization of their effects on the interaction between HIV-1 gp120 and CD4/chomine receptors CCR5 and CXCR4.
TXE and VAD extracts possess potent inhibitory activities against HIV-1 replication and entry of both T and M tropic HIV-1 isolates. These results suggest that TXE and VAD are potential biosources for further identification and isolation of active anti-HIV-1 constituents. Identification of these active constituents will help establish the precise mechanisms of this entry inhibition as well as standardize the extracts for potential clinical translation.
List of abbreviations
extract from Euphorbiaceae, Trigonostema xyphophylloides
A HIV-1-based reporter virus containing inactive nef and env genes and having the luciferase (Luc) gene inserted at the 5' end nef gene
envelope from HIV-1 isolate 89.6
envelope from HIV-1 isolate HXB2
vascular stomatitis virus envelope glycoprotein
This work was supported in part by a grant award #20562004 from the National Natural Science Foundation of China (to C. Han and G. Chen) and grants R21DA022986 and R21DA025487 (to JJH) from the National Institutes of Health.
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