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

CRISPR/Cas9 Target Regulatory Genes of AIDS Virus

By destroying the regulatory genes of the AIDS virus HIV-1 using the genome editing system CRISPR/Cas9, a Japanese research group has succeeded in blocking the production of HIV-1 by infected cells.

Human immunodeficiency virus-1 (HIV-1) infection is a chronic disease affecting more than 35 million people worldwide. The infection can be controlled by antiretroviral therapy (ART), but there is still no complete cure. It is hard to eradicate cells latently infected with HIV-1 in a patient's body because when the virus proliferates, the viral gene is inserted into the chromosomes in the infected cells.

Genome editing methods cut specific parts of genes, allowing us to remove or add sections of the DNA sequence. The recently developed CRISPR/Cas9 system is a promising tool for deactivating the HIV-1 genes that have been incorporated into the chromosomes of infected individuals.

 

This study targeted two genes that regulate the proliferation of HIV-1, known as tat and rev. Based on genetic information from six major HIV-1 subtypes, the team designed six types of guide RNA (gRNA) that enable specific genome editing using the CRISPR/Cas9 system. They created a lentiviral vector that expresses Cas9 and gRNA. When they introduced this vector to cultured cells that expressed the regulatory gene products Tat and Rev, they succeeded in significantly lowering the expression and functions of both Tat and Rev. The team found no off-target mutations (non-specific genome editing that unintentionally targets the host cell genes), and the expression of Cas9 and gRNA did not affect the survival rate of the cultured cells.

By introducing gRNA and Cas9 to cultured cells with a latent or persistent HIV-1 infection, they were able to markedly suppress cytokine-dependent HIV-1 reactivation in latently infected cells and HIV-1 replication from persistently infected cells. Furthermore, by introducing all six types of gRNA at the same time, they managed to almost completely block virus production from the infected cells.

The research team was led by Associate Professor Masanori Kameoka, Assistant Professor Tomohiro Kotaki (Kobe University Graduate School of Health Sciences) and Youdiil Ophinni (Kobe University Graduate School of Medicine). The findings were published on May 17 in Scientific Reports.

"These results show that the CRISPR/Cas9 system, by targeting the regulatory genes of HIV-1, tat and rev, is a promising method for treating HIV infection" comments Associate Professor Kameoka.

"We now need to investigate how we can selectively introduce a CRISPR/Cas9 system that targets HIV-1 genes into the infected cells of patients. To safely and effectively introduce the CRISPR/Cas9 system the vectors must be improved. We hope this research will provide us with useful information in developing a treatment method that can completely cure the HIV-1 infection."

Source:

https://www.news-medical.net/news/20180518/New-CRISPRCas9-system-targets-regulatory-genes-of-AIDS-virus.aspx

http://www.kobe-u.ac.jp/research_at_kobe_en/NEWS/news/2018_05_18_01.html

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'Molecular Scissors' in the Fight against Diseases including HIV infection

One way to fight diseases including HIV infection and autoimmune disorders could involve changing how a naturally occurring enzyme called SAMHD1 works to influence the immune system, new research suggests.

The study, led by researchers from The Ohio State University, details how the enzyme influences proteins that stimulate the immune response.

SAMHD1 isn't a molecular "good guy" or "bad guy" per se, but there are cases in which blocking its activity might thwart disease progression, said Li Wu, the study's senior author and a professor of veterinary biosciences and microbial infection and immunity in Ohio State's Center for Retrovirus Research.

The research, conducted in human and mouse immune cells, appears online in the journal Proceedings of the National Academy of Sciences. 

"Lacking this enzyme due to SAMHD1 gene mutations can activate the human immune system and increase inflammation, and now we better understand the fundamental biological process behind that," Wu said.

"In a perfect world, SAMHD1 is responsible for balanced regulation of the immune response, but it also could limit HIV or other viral infections and alter the progression and treatment of certain cancers. We need good immune responses, obviously, but we don't want overwhelming immune activation."

Before this study, it was unclear whether and how SAMHD1 regulated immune responses, Wu said. Scientists identified the human gene for this enzyme in 2000, and since then it's been linked to human diseases including autoimmune disorders, HIV infection and cancers.

Unlocking the precise way in which it influences disease progression is one of the goals of Wu's lab. Previous research had established SAMHD1 as a key player in inhibiting HIV replication in human immune cells, piquing his interest.

The new study illuminated the way in which SAMHD1 interacts with several cellular proteins that play a critical role in regulating innate immune responses. Importantly, the enzyme can act as an inhibitor of potentially harmful responses during viral infection.

"The enzyme's job is to break down a DNA building block in our cells- to act as 'molecular scissors,'" Wu said.

"Too much of this building block due to SAMHD1 deficiency caused by genetic mutations can lead to autoimmune diseases and help cancerous tumours grow. If we can find a way to cut off or reduce the supply, the disease might not be viable -- like a car without gas."

This study could open the possibility of finding ways to turn this activity on and off, making way for new therapeutic approaches for hard-to-treat diseases, Wu said.

"Because inflammatory pathways influence nearly all diseases in humans and animals, including HIV infection and cancers, identification of SAMHD1 as an inhibitor of immunity may have far-reaching implications in biomedical research," he said.

Source: https://www.sciencedaily.com/releases/2018/04/180402192705.htm

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