Plant compound 'much more effective' than traditional anti-HIV drug

Azidothymidine, the first drug that was approved in the fight against AIDS in the 1980s, is still a main component in the medication mix commonly prescribed to HIV patients today. But new research may have found a plant-derived chemical compound that is much more effective than azidothymidine.

In the United States, the Centers for Disease Control and Prevention (CDC) estimate that around 1.1 million people have HIV, and 1 in 7 of them are not aware that they have it.

Due to awareness campaigns and efforts to prevent HIV, the number of new infections dropped by 19 percent between 2005 and 2014. The number of HIV-related deaths has also been falling since the mid-1990s, largely due to advances in HIV treatment.

Although there is yet no cure for HIV, antiretroviral therapy significantly slows down the progression of the virus. The first drug to have been approved in the fight against AIDS is azidothymidine (AZT).

Since 1987, however - the year in which AZT was approved by the U.S. Food and Drug Administration (FDA) - the virus has adapted to the drug. Today, HIV patients are given a combination of various drugs, of which AZT is often still the main component.

AZT works by inhibiting an enzyme that the HIV virus needs to replicate inside a host cell. This enzyme is called reverse transcriptase.

New research, published in the Journal of Natural Products, has found a plant compound that may be more effective at inhibiting this enzyme than AZT.

The chemical compound is called "patentiflorin A" and is derived from a medicinal plant found in East Asia: Justicia gendarussa.

The discovery is the result of a research effort extending over several years, carried out by an international team of scientists from the University of Illinois at Chicago (UIC), the Hong Kong Baptist University in Kowloon Tong, and the Vietnam Academy of Science and Technology in Hanoi.

The team was led by Lijun Rong, a professor of microbiology and immunology at the UIC College of Medicine, who has special expertise in identifying antiviral agents.

Patentiflorin A inhibits HIV 'much more effectively' than AZT

Prof. Rong and colleagues selected Justicia from a pool of more than 4,500 plants.

After separating the extracts of the stems and roots of this plant using bioassay-guided isolation - which is the most common procedure for separating extracted compounds based on their biological activity - the researchers found the "anti-HIV arylnaphthalene lignan glycoside" that is patentiflorin A.

Then, Prof. Rong and team assessed the effect of the compound against the M-tropic and T-tropic HIV isolates. "Tropism" refers to the type of cells that the virus can invade. M-tropism refers to the virus' ability to invade macrophages, while T-tropism refers to its ability to invade T cells, which are both white blood cells with key roles in immunity.

The tropism tests showed that patentiflorin A had "a significantly higher inhibition effect than the clinically used anti-HIV drug AZT."

"Patentiflorin A was able to inhibit the action of reverse transcriptase much more effectively than AZT and was able to do this both in the earliest stages of HIV infection when the virus enters macrophage cells and alter infection when it is present in T cells of the immune system," Prof. Rong explains.

He also notes that his team managed to synthesize the compound de novo, or "from scratch." He says:

"If we can make the drug in the lab, we don't need to establish farms to grow and harvest the plant, which requires significant financial investment, not to mention it has an environmental impact."

He concludes, "Patentiflorin A represents a novel anti-HIV agent that can be added to the current anti-HIV drug cocktail regimens to increase suppression of the virus and prevention of AIDS."

Source: https://www.medicalnewstoday.com/articles/317966.php

Scientists Figure Out Why HIV-1C Subtype Replicates Faster

A team of scientists from India and America have figured out why HIV-1C subtype is more prevalent than other subtypes of the virus.

The human immunodeficiency virus consists of two types HIV 1 and 2 and each one of them has many subtypes. Of them, HIV-1C alone causes half of all the HIV infections globally and nearly all in India.

Researchers have found that HIV-1C can efficiently duplicate an important region of its genome to replicate faster unlike other subtypes. HIV-1C duplicates a region of its Gag protein called PTAP domain to make two copies of this domain.

The study was conducted in a group of HIV positive persons in India. It was found that viral strains of HIV-1C containing two PTAP domains could dominate viral strains containing only one PTAP domain in the blood of eight persons during follow up.

“This molecular trick may have given HIV-1C a big replication advantage over others. Given the dynamic nature of viral evolution, this trick may be transmitted to other slow-witted cousins through ‘viral recombination’ and may make this new molecular trick a universal problem,” explained Dr. Udaykumar Ranga, a scientist at Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR), Bangalore, who led the study.

Dr. Shahid Jameel, a virologist and CEO of Wellcome Trust DBT India Alliance, who was not associated with this study, pointed out that “HIV shows high degree of sequence variation, making it both an interesting virus to study and a difficult one to control through vaccines and drugs.” 

Dr. Akhil C. Banerjea, Emeritus Professor at the National Institute of Immunology commented that “the researchers have found a new motif in HIV that may explain why subtype C can multiply at a faster rate. This study will also allow targeting this motif to control viral replication.”

The research team included Shilpee Sharma, P.S. Arunachalam, Malini Menon, J. Jebaraj, Shambhu G., Chaitra Rao, Sreshtha Pal and Udaykumar Ranga (JNCASR); V. Ragupathy, I. Hewlett (Center for Biologics Evaluation and Research, USA); Ravi Vijaya Satya (GRAIL Inc, USA); S. Saravanan, K. G Murugavel, P. Balakrishnan and (late) S. Solomon (Y.R. Gaitonde Centre for AIDS Research and Education, Chennai). 

This work was supported by Department of Science and Technology (DST). The researchers have published their findings in the Journal of Biological Chemistry.

Journal Reference: PTAP motif duplication in the p6 Gag protein confers a replication advantage on HIV-1 subtype C 

Source: https://www.scisoup.com/2018/06/scientists-figure-out-why-hiv-1c.html

Experimental HIV Vaccine Elicits Antibodies that Neutralize Dozen of HIV Strains

An experimental vaccine regimen based on the structure of a vulnerable site on HIV elicited antibodies in mice, guinea pigs and monkeys that neutralize dozens of HIV strains from around the world. The findings were reported today in the journal Nature Medicine by researchers at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, and their colleagues.

Peter D. Kwong, Ph.D., and John R. Mascola, M.D., led the study. Dr. Kwong is chief of the Structural Biology Section at the NIAID Vaccine Research Center, and Dr. Mascola is the center director.

“NIH scientists have used their detailed knowledge of the structure of HIV to find an unusual site of vulnerability on the virus and design a novel and potentially powerful vaccine,” said NIAID Director Anthony S. Fauci, M.D. “This elegant study is a potentially important step forward in the ongoing quest to develop a safe and effective HIV vaccine.”

A preliminary human trial of the new vaccine regimen is anticipated to begin in the second half of 2019.

Today’s report reflects one of two broad, complementary approaches NIAID is pursuing to develop an HIV vaccine. In one approach, scientists first identify powerful HIV antibodies that can neutralize many strains of the virus, and then try to elicit those antibodies with a vaccine based on the structure of the HIV surface protein where the antibodies bind. In other words, scientists start with the most promising part of the immune response and work to develop a vaccine that will induce it. This method was used to design the vaccine described today.

The other, empiric approach to HIV vaccine development begins by evaluating the most encouraging vaccine candidates for efficacy in people through clinical trials. Then scientists try to build on successful trial results by, for example, examining blood and other clinical specimens from study participants who received the vaccine to identify the most promising parts of the immune response. Researchers subsequently use this information to improve vaccination approaches for future trials. This method was used to develop the HIV vaccine regimen tested in the RV144 clinical trial and the HIV vaccine regimens currently under study in the HVTN 702 and Imbokodo clinical trials.

Over the past several years, HIV researchers have discovered many powerful, naturally occurring antibodies that can prevent multiple HIV strains from infecting human cells in the laboratory. About half of people living with HIV make these so-called “broadly neutralizing” antibodies but usually only after several years of infection — long after the virus has established a foothold in the body. Scientists have identified and characterized the sites, or epitopes, on HIV where each known broadly neutralizing antibody binds. Many laboratories around the world are developing HIV vaccine candidates based on the structure of these epitopes with the goal of coaxing the immune systems of HIV-negative people to make protective antibodies after vaccination.

The experimental vaccine described in today’s report is based on an epitope called the HIV fusion peptide, identified by NIAID scientists in 2016. The fusion peptide, a short string of amino acids, is part of the spike on the surface of HIV that the virus uses to enter human cells. According to the scientists, the fusion peptide epitope is particularly promising for use as a vaccine because its structure is the same across most strains of HIV, and because the immune system clearly “sees” it and makes a strong immune response to it. The fusion peptide lacks sugars that obscure the immune system’s view of other HIV epitopes.  

To make the vaccine, the researchers engineered many different immunogens — proteins designed to activate an immune response. These were designed using the known structure of the fusion peptide. The scientists first assessed the immunogens using a collection of antibodies that target the fusion peptide epitope, and then tested in mice which immunogens most effectively elicited HIV-neutralizing antibodies to the fusion peptide. The best immunogen consisted of eight amino acids of the fusion peptide bonded to a carrier that evoked a strong immune response. To improve their results, the scientists paired this immunogen with a replica of the HIV spike.

The researchers then tested different combinations of injections of the protein plus HIV spike in mice and analyzed the antibodies that the vaccine regimens generated. The antibodies attached to the HIV fusion peptide and neutralized up to 31 percent of viruses from a globally representative panel of 208 HIV strains.

Based on their analyses, the scientists adjusted the vaccine regimen and tested it in guinea pigs and monkeys. These tests also yielded antibodies that neutralized a substantial fraction of HIV strains, providing initial evidence that the vaccine regimen may work in multiple species. 

The scientists are now working to improve the vaccine regimen, including making it more potent and able to achieve more consistent outcomes with fewer injections. The researchers also are isolating additional broadly neutralizing antibodies generated by the vaccine in monkeys, and they will assess these antibodies for their ability to protect the animals from a monkey version of HIV. The NIAID scientists will use their findings to optimize the vaccine and then manufacture a version of it suitable for safety testing in human volunteers in a carefully designed and monitored clinical trial.

Source: https://www.nih.gov/news-events/news-releases/hiv-vaccine-elicits-antibodies-animals-neutralize-dozens-hiv-strains?utm_source=social&utm_campaign=https%3A%2F%2Fgoo.gl%2Fyba4t2

Abstract submission for STD 2018 are welcome, submit your abstract here: https://std-hiv-aids.cmesociety.com/call-for-abstracts/