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http://www.nature.com/articles/srep20394
- Scientific Reports 6, Article number: 20394 (2016)
- doi:10.1038/srep20394
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Abstract
Novel
therapeutic options are urgently needed to improve global treatment of
virus infections. Herbal products with confirmed clinical safety
features are attractive starting material for the identification of new
antiviral activities. Here we demonstrate that Cistus incanus (Ci) herbal products inhibit human immunodeficiency virus (HIV) infections in vitro.
Ci extract inhibited clinical HIV-1 and HIV-2 isolates, and,
importantly, a virus isolate with multiple drug resistances, confirming
broad anti-HIV activity. Antiviral activity was highly selective for
virus particles, preventing primary attachment of the virus to the cell
surface and viral envelope proteins from binding to heparin.
Bioassay-guided fractionation indicated that Ci extract contains
numerous antiviral compounds and therefore has favorably low propensity
to induce virus resistance. Indeed, no resistant viruses emerged during
24 weeks of continuous propagation of the virus in the presence of Ci
extracts. Finally, Ci extracts also inhibited infection by virus
particles pseudotyped with Ebola and Marburg virus envelope proteins,
indicating that antiviral activity of Ci extract extends to emerging
viral pathogens. These results demonstrate that Ci extracts show potent
and broad in vitro antiviral activity against viruses that cause
life-threatening diseases in humans and are promising sources of agents
that target virus particles.
Introduction
Virus
infections pose serious threats to human health on a global scale. The
human immunodeficiency virus (HIV) causes chronic, life-long infection
that leads to AIDS without antiretroviral treatment. Over 35 million
individuals are living with HIV/AIDS and the pandemic has remained among
the 10 leading global causes of death for over a decade, especially in
low-income countries1.
Emerging viruses like the Ebola virus (EBOV) can cause an acute disease
with symptoms appearing 2–21 days after infection and a high risk of
death (average mortality rate ~50%) (For summary of current knowledge
regarding Ebola virus disease see2).
EBOV can cause sudden outbreaks, like the one that flared up in May
2014 in West Africa (Guinea, Liberia and Sierra Leone). Next to the
death of more than 10 000 individuals, this outbreak placed an
additional heavy burden on countries already weakened by lack of
resources and long periods of conflict and instability and lead to
breakdown of local health care systems.
There is a strong need for the development of novel antiviral agents for treatment of life-threatening viral infections. Despite the availability of a number of approved drugs for treatment of HIV/AIDS (≥253), current anti-HIV therapies would still benefit from various improvements. Limitations include the high risk of emergence of resistant viruses, poor penetration of virus sanctuaries like the central nervous system, adverse effects, especially in the context of long-term therapy, and incomplete access to affordable therapies in resource-limited areas4,5,6,7. Furthermore, the majority of these drugs block post-entry steps of the virus replication cycle and attack only a few viral targets, such as the viral reverse transcriptase, protease or integrase3.
In contrast to HIV/AIDS, no approved drugs are currently available to combat EBOV infections. The lack of targeted antiviral therapies is one of the most frightening aspects of managing EBOV outbreaks.
Plant-derived natural products play a significant role for medical treatments8,9. Herbal extracts represent the primary form of health care for a major proportion of the world’s population10 and are an important source of single-molecule drug leads. A prominent example is the anti-malaria activity of Artimisia annua11 discovered by YouYou Tu, recipient of the 2015 Nobel Prize for Physiology and Medicine12.
Antiviral activities have been reported for numerous medicinal plants9,13. However, their implementation as herbal antiviral medicines requires in-depth research of their efficacy, safety, composition and mechanisms-of-action14. Data for clinical safety and for biological activities are available for a few herbal extracts, some of which are sold as over-the-counter medicines in Europe. We seek to investigate the antiviral activities of these clinically evaluated herbal medicines against major human viral pathogens like HIV-1 as an initial step for the identification of new sources of antiviral agents. This approach is supported by our recent demonstration of anti-HIV-1 activity of extracts of Pelargonium sidoides15, licensed in Germany as the herbal medicine Umckaloabo®.
In this study, we investigated antiviral activities of Cistus incanus (Pink Rockrose) against HIV and Filoviruses. Cistus incanus (Ci) is native to Mediterranean regions of Southern Europe and North Africa and belongs to a different taxonomic order (Malvales) than Pelargonium sidoides (Geraniales). Ci extracts have been shown to have anti-inflammatory, anti-oxidant, antimycotic and antibacterial activities16,17,18,19. Ci is rich in polyphenols18,19,20,21,22,23, a chemical class of compounds that includes many representatives with antimicrobial/antiviral activities24,25. Furthermore, Ci extracts were demonstrated to inhibit infection by influenza A virus21,26. Different Ci preparations are commercially available, including a CYSTUS052® decoction, throat lozenges and a herbal tea. Clinical studies performed with patients with upper respiratory tract infections revealed decreased symptoms and less adverse effects in treated patients compared to control patients, indicating clinical efficacy and a favorable safety profile of CYSTUS052®27,28.
We demonstrate that Ci extracts show broad inhibitory activity against different HIV isolates, including a clinical virus isolate with multiple resistances against conventional drugs. Mode-of-action studies demonstrate that Ci extracts target viral envelope proteins, preventing the primary attachment of the virus to host cells. Antiviral activity of Ci extracts was also directed against the Ebola virus envelope protein. Extract deconvolution studies revealed that Ci extracts contain numerous active ingredients against HIV and Ebola virus. Our results demonstrate that Ci extract has potent antiviral activity against HIV and Ebola virus and indicate that Ci extract contains multiple compounds that prevent these viruses from entering host cells for replication.
There is a strong need for the development of novel antiviral agents for treatment of life-threatening viral infections. Despite the availability of a number of approved drugs for treatment of HIV/AIDS (≥253), current anti-HIV therapies would still benefit from various improvements. Limitations include the high risk of emergence of resistant viruses, poor penetration of virus sanctuaries like the central nervous system, adverse effects, especially in the context of long-term therapy, and incomplete access to affordable therapies in resource-limited areas4,5,6,7. Furthermore, the majority of these drugs block post-entry steps of the virus replication cycle and attack only a few viral targets, such as the viral reverse transcriptase, protease or integrase3.
In contrast to HIV/AIDS, no approved drugs are currently available to combat EBOV infections. The lack of targeted antiviral therapies is one of the most frightening aspects of managing EBOV outbreaks.
Plant-derived natural products play a significant role for medical treatments8,9. Herbal extracts represent the primary form of health care for a major proportion of the world’s population10 and are an important source of single-molecule drug leads. A prominent example is the anti-malaria activity of Artimisia annua11 discovered by YouYou Tu, recipient of the 2015 Nobel Prize for Physiology and Medicine12.
Antiviral activities have been reported for numerous medicinal plants9,13. However, their implementation as herbal antiviral medicines requires in-depth research of their efficacy, safety, composition and mechanisms-of-action14. Data for clinical safety and for biological activities are available for a few herbal extracts, some of which are sold as over-the-counter medicines in Europe. We seek to investigate the antiviral activities of these clinically evaluated herbal medicines against major human viral pathogens like HIV-1 as an initial step for the identification of new sources of antiviral agents. This approach is supported by our recent demonstration of anti-HIV-1 activity of extracts of Pelargonium sidoides15, licensed in Germany as the herbal medicine Umckaloabo®.
In this study, we investigated antiviral activities of Cistus incanus (Pink Rockrose) against HIV and Filoviruses. Cistus incanus (Ci) is native to Mediterranean regions of Southern Europe and North Africa and belongs to a different taxonomic order (Malvales) than Pelargonium sidoides (Geraniales). Ci extracts have been shown to have anti-inflammatory, anti-oxidant, antimycotic and antibacterial activities16,17,18,19. Ci is rich in polyphenols18,19,20,21,22,23, a chemical class of compounds that includes many representatives with antimicrobial/antiviral activities24,25. Furthermore, Ci extracts were demonstrated to inhibit infection by influenza A virus21,26. Different Ci preparations are commercially available, including a CYSTUS052® decoction, throat lozenges and a herbal tea. Clinical studies performed with patients with upper respiratory tract infections revealed decreased symptoms and less adverse effects in treated patients compared to control patients, indicating clinical efficacy and a favorable safety profile of CYSTUS052®27,28.
We demonstrate that Ci extracts show broad inhibitory activity against different HIV isolates, including a clinical virus isolate with multiple resistances against conventional drugs. Mode-of-action studies demonstrate that Ci extracts target viral envelope proteins, preventing the primary attachment of the virus to host cells. Antiviral activity of Ci extracts was also directed against the Ebola virus envelope protein. Extract deconvolution studies revealed that Ci extracts contain numerous active ingredients against HIV and Ebola virus. Our results demonstrate that Ci extract has potent antiviral activity against HIV and Ebola virus and indicate that Ci extract contains multiple compounds that prevent these viruses from entering host cells for replication.
