- Antiretrovirals have improved the life expectancy for millions living with HIV – human immunodeficiency virus.
- However, some antiretrovirals have been linked to impacts on the function of immune cells.
- Dr Neill Liptrott and Bethany Heaton at the University of Liverpool, UK, reveal a potential mechanism behind this possible inhibition of function.
- They find that the drugs alter energy processes and glucose uptake in cells, leading to decreased immune cell activation.
- These responses now need further investigation, to see if these effects are seen with other antiretrovirals and if there are any clinical impacts.
More than 75 million people worldwide are believed to be living with HIV – human immunodeficiency virus – with a considerable proportion living in low- and middle-income countries. HIV is a retrovirus which incorporates its genome into the host’s genetic makeup to produce more copies of itself. Treatment can be challenging, but antiretroviral therapies have improved the lives of many people living with the virus. HIV infects white blood cells of the immune system such as T-cells and macrophages (which engulf and destroy viruses and bacteria) and replicates within these cells. Antiretroviral drugs stop this group of retroviruses from multiplying and can slow down disease progression and reduce associated deaths. Unfortunately, for a proportion of individuals antiretroviral drugs do not work or are toxic, making further treatment complicated. Dr Neill Liptrott and Bethany Heaton from the University of Liverpool are investigating what’s behind the potential for some antiretrovirals to impact on the function of certain immune cells.
Previous research at the University of Liverpool, developing exceedingly small particles of a drug called solid drug nanoparticles (SDNs), has shown that use of these nanoparticles of antiretroviral drugs may reduce the toxicity associated with the standard way the drugs are administered. Additionally, the development of long-acting formulations of antiretrovirals may make treatment easier because the patient doesn’t need to take the drugs every day, reducing the risk of missed doses leading to the emergence of resistant strains. In their most recent research, Liptrott and Heaton investigate the effects of commonly used antiretroviral drugs lopinavir and efavirenz on glucose uptake in immune cells and discover unintended consequences for immune system activation.
Glucose uptake transporters (GLUTs) help carry glucose across the cell membrane and into the cell where it is needed.
The immune system: going into battle
Our body’s immune system protects us against invasion from foreign molecules and infection. This complex defence system may be thought of as an army going into battle, employing soldiers (white blood cells) and numerous tactics or mechanisms to organise and sustain their actions. These soldiers of the immune system engulf foreign particles or antigens and fight off infection. Messengers called cytokines regulate and control this process, activating more immune cells when needed and providing a method of communication between cells and tissues. Such a large-scale operation requires a lot of energy to support the cells’ function, and this energy comes in the form of a type of sugar, glucose.


Sugar sugar!
It is very difficult to get molecules across the cell membrane, and membrane transporters of various types are responsible for this. Membrane transporters such as glucose uptake transporters, members of the solute carrier (SLC) transporter family, help carry glucose across the cell membrane and into the cell where it is needed. GLUT1, also known as SLC2A1, is one such transporter whose job is to ensure cells have enough glucose for normal functioning. When the immune system is activated and more energy is needed, SLC2A1 moves to the cell surface and a signal is sent to make more SLC2A1 membrane transporters. There are studies that show a link between the activity of these transporters and immune cells responses in people living with HIV, suggesting they are important in the body’s response to infection. As immune cells are fighting against the virus, correct functioning of proteins such as SLC2A1 transporters are vital to ensure the appropriate bioenergetic profile – the way energy is used and processed in cells. Such changes in bioenergetics and glucose uptake into immune cells can impact their function, the immune responses, and the body’s defences.


Liptrott had previously demonstrated that exposure of T-cells and macrophages to these drugs made them less active when the immune system was stimulated. The researchers’ most recent study aimed to try to identify the reasons behind this.
Liptrott and Heaton found there was up to 90% less glucose inside cells that were exposed to these drugs compared to cells that were not.
Antiretrovirals’ unintended consequences
It has been known for some time that antiretrovirals are also transported across cell membranes by SLC transporters; therefore, Liptrott and Heaton aimed to determine if this decreased immune cell activation was due to decreased glucose uptake in the presence of these antiretroviral drugs. Specifically, they wanted to know whether the drug molecules interact with GLUTs binding sites thereby affecting the uptake of glucose, causing subsequent changes in how energy is used and processed in cells. Firstly, their experiments revealed there was up to 90% less glucose inside cells that were exposed to these drugs compared to cells that were not. They also studied binding affinity (approximately how likely one molecule will form bonds with another) – in this case, how strongly a drug molecule is predicted to bind to the SLC2A1 transporter on an immune cell in a theoretical environment. Their findings showed that both lopinavir and efavirenz had strong associations with binding sites for SLC2A1, but efavirenz displayed unexpected findings when it bound differently to SLC2A1 than compared to where glucose would bind to the membrane transporter. If there is a change in the shape of the transporter, or competition between antiretroviral molecules and glucose for binding to the membrane transporter, SLC2A1, then this could displace the glucose, reducing the ability of the transporter to carry it into the cell. Finally, the antiretroviral drugs studied were also shown to change the rate of production of adenosine triphosphate, a molecule that produces energy for cell function.


This work has provided a deeper understanding of the mechanisms induced by these antiretrovirals and how they can lead to altered glucose levels and bioenergetics in immune cells. Ultimately, the result is decreased immune cell activation and changes in immune modulation, the consequences of which need further investigation.
Although efavirenz and lopinavir have been tremendously successful in the fight against HIV, this pioneering lab-based research may shed light on the mechanisms behind some of the possible side effects of these types of antiretrovirals. However, risk and benefit are balanced for all medicines and all medicines have varying degrees of toxicity. Through their work the group seeks to understand the mechanisms underpinning known long-term, and acceptable, risks associated with these drugs. Now, more research is needed to determine if these results translate from the laboratory into humans, and to fully understand the consequences for the immune system, to enable greater insight into the true effects of such medication on the human body.


What made you first suspect that glucose was involved in the negative effect antivirals were having on the immune system?
Our previous work (Liptrott) focused on the activity of membrane transporters in human immune cells, in relation to antiretrovirals. We knew that these drugs can be substrates of SLC transporters and, with GLUTs being members of the SLC family, wondered if the ‘blockage’ of glucose uptake could be affected.
What are the next steps to gain a better understanding of any in vivo immunological effects of these drugs?
First, we need to try to determine if the impact on the bioenergetics is linked to actual functional changes in primary immune cells, thereby confirming our findings. Disentangling immune responses in people living with HIV is tricky, as many have been living with HIV for years and have complicated treatment histories. Our first step would be to repeat the work we have published here, using immune cells from people living with HIV and assess the responses there. Next, it would be necessary to view the treatment history of patients, as our work here also showed that some of the more ‘modern’ antiretrovirals did not have the same effect; knowing if there are changes when patients swap regimens will be a vital step in improving our understanding.
Do you think using solid drug nanoparticles to administer antiretrovirals could reduce their negative impacts on immune cells?
Although we haven’t looked at the impact of SDN formulations of these drugs on glucose uptake, we do know that there was no difference between the impact on immune cells between the formulated and unformulated drugs. Based on that, we suggest that the effect is due to the drug, not the formulation. This is a good thing, as it means that the SDNs have no greater impact on these processes than the drug themselves, and there are decades of safety and efficacy data on those drugs.
Is there any possibility that the current findings could be useful in other areas for therapeutic applications?
It is possible. A number of researchers in fields outside of infectious disease are developing GLUT inhibitors for various applications. Our findings here suggest that these drugs could serve as a ‘template’, from a chemical structure perspective, to develop GLUT inhibitors that have greater specificity for the GLUTs active in specific cell types, thereby providing a basis for new therapeutics. We are currently assessing if this may be possible and trying to determine what it is about these molecules that enables their inhibitory capacity.