On the 1st of December, all around the world, people raised money and awareness of HIV and AIDS for World AIDS Day. They also brought news announcing that screening programmes are finding more and more undiagnosed patients infected with the HIV virus – something needs to be done. So much work is already being done to try and find a cure or to slow the progression of the disease, so in this blog I’m going to to focus on a particularly nifty bit of research.
Human Immunodeficiency Virus type 1, more commonly known as HIV, is a viral particle. This is a tiny infectious agent that consists of a small amount of genetic material surrounded by a protein coat. These particles can’t replicate on their own genome, so they must first invade a host (in this case human cells). HIV particles specifically invade CD4+ T lymphocytes; this is just the fancy name for a cell of the immune system that has a CD4 molecule on their cell surface to which the virus can bind. Once inside these T cells, the virus hijacks the host’s cellular mechanisms and uses them to produce a whole brood of new HIV viral particles; a process which I could spend hours explaining, but for now you’ll just have to take my word for it. The new viruses burst out the host cell in a process called lysis which is simply just breaking the cell apart in order for them to escape and go on to invade other T cells. If this continues to happen the virus can kill many CD4+ T cells. The loss of these cells has a major effect on the immune system as they are essential for antibody production and the activation of cytotoxic T cells, both of which are used to recognise and remove potential harmful pathogens. The eventual progression of the loss of CD4+ T cells lead to AIDS (Acquired Immunodeficiency Syndrome), where the host is left incapable of fighting off other infections, resulting in common infections becoming life-threatening. The patient is also left very susceptible to serious infections such as TB.
RNA Interference (RNAi)
The central dogma of biology is that genetic information is taken from DNA, transcribed into RNA and then translated into proteins. So if reducing the amount of protein within a cell would aid in fighting a disease, degrading the RNA would stop the protein being produced – this is the principle of RNA interference.
RNA interference is a cellular mechanism that can be adapted and used as a gene therapy treatment. Small RNA molecules are designed to bind specifically to the messenger RNA (mRNA) transcripts of genes and destroy them. The perfect base pairing between the small RNA and the mRNA results in the cleavage of the latter and it is therefore not translated and no protein is produced from it.
To get these small RNAi molecules into the cell a gene therapy approach is used in which a non-pathogenic virus is used to insert the gene that codes for the RNAi into the DNA of the cells which the HIV virus will attack, such as CD4+ T cells.
RNAi and HIV
There are a few types of RNAs which can perform RNA interference- in this study Knoepfel’s group look into using small hairpin RNA’s (shRNA’s) which is so named due to its loop like structure. Over a 7 year period the group tested over 135 shRNA’s for their anti-viral effects along with other strict parameters that gave them 3 ‘potent and safe’ shRNA’s against mRNAs that are specifically produced when the HIV virus enters the host cell. By targeting the mRNA of proteins that are required for HIV viral replication or cell recognition but not proteins that are essential for T cells it will stop the virus while preventing the death of the host T cell.
RNAi is now in clinical trials for HIV type 1 treatment to test their therapeutic against the current HIV treatments, and it may not be too long until it’s rolled out to patients. New treatments for this devastating disease will aim to help the 34 million people living with HIV or AIDS worldwide.
With enough research one day we will find a cure.
von Eije KJ, & Berkhout B (2009). RNA-interference-based gene therapy approaches to HIV type-1 treatment: tackling the hurdles from bench to bedside. Antiviral chemistry & chemotherapy, 19 (6), 221-33 PMID: 19641231
Knoepfel SA, Centlivre M, Liu YP, Boutimah F, & Berkhout B (2012). Selection of RNAi-based inhibitors for anti-HIV gene therapy. World journal of virology, 1 (3), 79-90 PMID: 24175213