Harnessing innate immunity to cure HIV

Using a single drug derivative of vitamin A, researchers are now beginning to harness our innate immune system in order to force it to recognise, find and kill any cells infected by the human immunodeficiency virus (HIV), giving hope of a cure in the future. 

HIV particles (yellow) on the surface of a T cell, NIAID/NIH

Why we need a cure

Two of the major goals of HIV research are to develop a vaccine to prevent new infections, and develop a way to cure all the millions of people currently infected. Yet both goals have not been reached. According to the World Health Organisation (WHO), 36.7 million people are infected currently with HIV-1 (the most common type of the virus in man) and less than half of those infected are being treated with antiviral drugs. Unfortunately, the number of new people infected each year is dropping as dramatically as we would like, suggesting that we are not yet winning the war against this pandemic.

The fight against HIV has myriad weapons at its disposal, such as: global education strategies, cheap and accurate diagnostics, and antiviral drugs used to suppress virus replication, stop disease and onward transmission. But one thing that has proven to be very difficult is how can we cure all those people infected who are unable to eliminate the virus? The difficulty here is that HIV is expert in hiding from us. 

HIV - hiding in plain sight

Curing somebody from an HIV infection is challenging because of the fundamental biology of the virus (see this for an excellent review of this) HIV is a retrovirus, which means that it replicates by inserting a DNA copy of its entire genome (which is composed of RNA) into the genome of the cell that has just infected. From this DNA copy new RNA genomes are made. Once that copy is there then it cannot be removed.  One of the only ways that the DNA copy may be removed from our body naturally would be through the death of that infected cell but that might not be so simple. 

HIV can infect a kind of immune cell (specifically a T cell) that has the 'CD4' glycoprotein on its surface (CD4+ve 'helper' T cells). These cells from a part of our natural immune response where they interact with other immune cells and can promote an effective response. T cells are a part of the adaptive 'memory' immune system and as a consequence can live for a very long time. As HIV infects these cells, the inserted DNA copy also survives for years, still capable of producing new viruses. The long-lived 'resting' cells however, don't produce a lot of HIV, yet during some conditions these cells can become 'activated', causing them to divide, inducing the production of new HIV genomes, viruses and sustaining the infection.

Shock and kill

HIV antivirals stop these genomes producing viruses and infecting new cells but cannot touch the DNA copy residing in long-lived cells. A complete cure would have to eliminate any traces of HIV DNA from our cells. One strategy would be to activate HIV genome production at once in combination with a way to kill or block new infections, which is known as 'shock and kill'.

Shock and kill has a long history with many attempts focusing on using antivirals (or this), neutralizing antibodies or by promoting our own immune cells to kill the newly activated cells. This approach is challenging because of the need to balance viral activation without producing lots of activated and readily-infectable T cells and effective combination with an additional therapeutic, such as antivirals or antibodies that only block onward infection. However, a recent paper suggests that we could achieve HIV activation, kill those activated cells  and block onward infection using a  single drug by exploiting our own bodies' antiviral response. 

Innate immunity to the rescue

Li et al., reporting in Nature Medicine, show that by administration of a drug Acitretin - a derivative of retinoic acid, which is itself a metabolite of vitamin A - to human cells in the lab infected with HIV, they can kill cells that are infected with HIV.

The secret to how this is achieved is via the simultaneous induction of HIV RNA production and a human gene called DDX58, otherwise known as 'retinoic acid-inducible protein-I' (RIG-I) (which is known to be induced by retinoic acid and its derivatives). 

RIG-I is a very important antiviral protein that can detect viral RNA within the cytoplasm of a cell and kick-start an antiviral response, which can be characterised by cell death (apoptosis) and secretion of antiviral signalling proteins called interferons. In the case of Li et al., their anti-HIV affect following Acitretin treatment was dependent on RIG-I and associated with apoptosis and interferon production; apoptosis would destroy infected cells and the interferon may protect nearby cells (and help induce apoptosis) that are not infected yet, thus preventing the spread of infection. 

Is this a cure?

The simple answer is no. Or at least, not yet. While this study is a neat idea with potential, the work was carried out only in cells in the lab, although it included primary cells from patients with HIV. There are concerns whether these cells isolated from the bloodstream are representative of the long-lived T cells infected with HIV found in the organs of patients. Additional studies in appropriate animal models could clarify this. Other questions would be whether systemic treatment with Acitretin would reach all the infected cells? And how would your body react if all cells reactivated their infection, inducing apoptosis and interferon production, simultaneously? Might there be unwanted side-effects related to reactivation? Or even from Acitretin itself?

In conclusion, while a cure is a long way off, it would be an incredible tool in the response to the HIV pandemic and it is great to such diverse options such as described in this study, especially ones seeking to exploit our own innate immune system. I believe that by studying the interactions between viruses and the innate immune system at the level of the cell we will come up with new ways to make better, safer antivirals and vaccines for all viruses.