VIRUSES can be very wily microorganisms.
Take the human immunodeficiency virus (HIV) for example.
Firstly, it attacks the body’s immune cells, specifically the CD4 T lymphocytes (a type of white blood cell), and uses them to create more copies of itself.
As the CD4 cells are responsible for stimulating other immune cells to fight off infection, this also means that HIV is preventing the body from effectively mounting a defence against it.
There is also a third component to this virus’ craftiness.
While most CD4 cells are destroyed after HIV has used up all its resources to replicate itself, some of these HIV-infected cells go into a resting or latent state.
This means that they are not actively producing more HIV; however, the virus is actually using them as camouflage.
Explains Universiti Malaya (UM) senior pharmacy lecturer Dr Reena Rajasuriar: “When you are on treatment, your viral load – that is, the HIV in your blood circulation – becomes undetectable because the treatment does a very good job in suppressing replication of the virus.
“But there is a small proportion of the virus that gets into the human DNA (of the immune cells) and it remains there dormant and silent – the immune system doesn’t recognise them because they are essentially not active.
“This becomes the barrier for cure, because when you stop taking your HIV medication, these viruses reactivate and they start replicating, which then leads to disease progression.”
In fact, this problem is so crucial that it is currently the main focus of those trying to find a cure for HIV and the Acquired Immune Deficiency Syndrome (AIDS), the UM Immunotherapeutics Laboratory head says.
Another important factor is that T lymphocytes, including the CD4 subset, also function as memory cells for the immune system.
The role of these memory cells is to remember the characteristics of the foreign microorganisms that have previously infected our body.
This ability allows our immune system to mount a more rapid response to defend our body the next time the same microorganism attacks us.
During such a repeat attack, the responsible memory cells – a memory cell can only “remember” one type of microorganism – will rapidly reproduce themselves in order to organise the body’s defence on a large scale.
So, imagine what would happen if a latent HIV-infected T memory cell gets activated when the microorganism it “remembers” invades our body.
Says Dr Reena: “When these cells expand because they are fighting off that particular infection, if those particular cells have HIV in them, it will likely expand as well, so your HIV reservoir becomes bigger.”
Different types of HIV
As people living in low- and medium-income countries (LMIC) tend to have greater exposure to different infections, compared to those living in high-income countries, Dr Reena says that this might impact the size of the HIV reservoir in countries like ours.
She gives the example of the herpes virus, which is present in as much as 90% of HIV patients in LMIC, versus around 60% in high-income countries.
Other common infections in LMIC include dengue, tuberculosis and parasitic infections, which are uncommon in high-income countries.
At the moment, the influence of different infections on the HIV reservoir remains a theory, but the clinical pharmacist-turned-immunology researcher hopes to confirm or debunk this hypothesis with her current research.
“What we are trying to look at is how exposure to different antigens (foreign substances harmful to the body that provoke an immune response) or different infections impact the viral reservoir – the burden of the dormant virus in cells,” she explains.
Another important element to her research is the focus on comparing the differences between HIV infection in LMIC and high-income or developed countries.
“Ninety percent of the epidemic is in LMIC, but to date, the majority of the research towards a cure has largely been in developed countries, which only make up probably 10% of the HIV epidemic.
“Understanding where and why these viruses hide is going to be different if you are infected with HIV in a high-income country versus in a low- or medium-income country.
“There are many reasons for that. One is that even the virus subtypes are different.
“Those who live in developed nations have subtype B, which only makes up 12% of the whole HIV epidemic, while in lower income countries, it’s mainly subtype C, which is largely what Africa and India have.
“We (Malaysia) have quite a bit of a strain known as CRF_AE.
“Because the virus subtypes are different, if a lot of the studies are focused in populations where subtype B is predominant, the strategies that might work for a potential cure in such populations might not work as well in populations where the subtype is different,” says Dr Reena.
To this end, she is collaborating with colleagues in three other institutions: the University of California, San Francisco (UCSF), in the United States, the University of Melbourne in Australia and the Agency for Science, Technology and Research (A*Star) in Singapore.
She explains: “So we have a group of patients in UCSF and we have a group of patients in Malaysia, who have been matched for quite a number of characteristics like their age, their gender, how advanced their HIV infection was when they started treatment, how long they’ve been infected and so on.
“We are going to look at the viral reservoir in the Malaysian patients and compare that to patients in the US, so the low- and medium-income country versus the high-income country.
“This will allow us to understand, first of all, if living in LMIC has an impact on the size of your persistent viral reservoir.
“Secondly, whether the size of the reservoir is related to the number of different types of previous infections you’ve had.
“And the third thing that we’re trying to do is trying to see what happens with the viral reservoir when you grow older.
“Because if you think about this, the longer you live, the more experience of exposure to different infections you’ll have had, compared to somebody who is much younger.
“So, if the viral reservoir size depends on your previous encounters with different infections, then the older you are, the bigger the viral reservoir is likely to be.
“We’re doing this in the Malaysian patients – we’re looking at young and old patients to see whether there are differences in size of viral reservoir by age.”
She adds: “I think, for Malaysia, this will be the first investigation of what viral persistence looks like – the size of the reservoir in our setting.
“And I think it will be exciting because it will really allow us to do cure research in this country.”
Doing research naturally requires funds, and Dr Reena has been fortunate to be awarded a US$49,659 (about K159,061.50) grant from the international non-profit organisation amfAR, The Foundation for AIDS Research.
This two-year grant, one of eight awarded this year to a total of US$828,000 (about K2,652,146.06) enabled her to kick start her current research.
Comments amfAR Research associate director Dr Marcella Flores: “Dr Reena’s research will provide much needed insight into how the virus persists in people living in Malaysia versus those living in the US.
“She draws from her passion for HIV care in Asia and is adapting it to ask the important questions for the ultimate treatment – a cure.
“Her work is part of the puzzle that amfAR is aiming to solve, to ensure that a cure for HIV will be effective in all people living with HIV.”
Interestingly, amfAR TREAT Asia vice-president and director Annette Sohn shares that Dr Reena’s mentor, UM Faculty of Medicine dean and infectious diseases consultant Professor Datuk Dr Adeeba Kamarulzaman, was one of the founding investigators of TREAT Asia, a collaborative network of civil society and medical and research institutions, that works to ensure the safe and effective delivery of HIV treatments to adults and children across the Asia-Pacific region.
Dr Reena estimates, however, that the grant only covers about a quarter of her study expenses.
Fortunately, a large part of the research expenses are defrayed by her foreign collaborators through their (volunteered) time and funds to run machines for tests and analysis that are unavailable in Malaysia.
“We’re hoping that by July (2019) or so, we will get results of what the size of the reservoir looks like in the two populations (American and Malaysian).
“That will then give us a bit of idea of what our subsequent steps are going to be and how we can delve further to understand why there are differences.
“Or we might find that there are no differences at all,” she says.
She adds: “It’s never been done before, so it is really going to be interesting to see what the outcome is.
“The second year of research is really going to be about going down and understanding the immunology, and trying to understand which cells in particular contain the latent virus.”
Although she does not expect to come up with a potential cure for HIV with this research, Dr Reena hopes that the results will give some clues as to what HIV cure researchers should be looking at next. – star2