The Cuban strain

A collaboration between Cuban researchers, a virologist from KU Leuven and Professor Michel Moutschen from GIGA at the University of Liège has led to the identification of a particularly aggressive strain of HIV in Cuba. In a study published in EBioMedicine, the scientists reveal how the CRF19 strain causes the rapid progression of the infection to AIDS.

HIV. Three small letters that stand for a lot. They have been causing a stir since the 1980s and are still a source of major concern in many parts of the world.  The Human Immunodeficiency Virus (HIV) – and the acquired immunodeficiency syndrome (AIDS) for which it is responsible – remains one of the main public health problems in the world. In 2013, more than 35 million people were living with HIV/AIDS, according to the figures provided by the World Health Organisation (WHO). The vast majority of them live in low-income regions such as Sub-Saharan Africa. HIV is still a step ahead of science and medicine since we have yet to find a cure to eradicate it.  However, even if specialists haven’t yet won the war against this virus, they have nevertheless won a battle. They have succeeded in developing combination antiretroviral therapy which prevents HIV from multiplying in the body. Currently, if the diagnosis is made during the first few years of HIV infection, patient life expectancy is normal providing they have access to treatment and they take it regularly.

From intuition to collaboration

We often talk about the Human Immunodeficiency Virus as if there was only one type. In reality, several well-identified types, groups and subtypes of this virus coexist in the world. Owing to HIV’s great ability to mutate, the number of different strains is increasing. Sometimes, a person can be infected by two separate strains of HIV which then recombine, meaning their genome is “mixed”. Such an event can therefore give rise to a new strain of HIV. “These new strains may have surprises in store for us by developing new properties. That’s why it’s important to monitor the situation”, explains Professor Michel Moutschen, Director of GIGA’s Immunology and Infectious Diseases Research Unit at ULg, and Head of Department at CHU Liège’s Centre de référence SIDA. Within the framework of a collaboration with KU Leuven and Cuban researchers, Michel Moutschen participated in the characterisation of a particularly virulent recombinant HIV strain present in Cuba.  “Since the beginning of the 2000s, Cuban researchers had the intuition that local patients infected by HIV were progressing very rapidly to AIDS”, Michel Moutschen points out.  "Thanks to funding from the Walloon Region, Anne-Mieke Vandamme, an eminent AIDS virologist from KU Leuven, and I were able to welcome a Cuban researcher, Vivian Kouri, and train her in a series of lab techniques used for this study", he explains. This team work helped them to discover the CRF19 strain present in Cuba, which is indeed associated with a rapid progression to the disease in certain patients.  The results of this study were published in the journal EBioMedicine (1) and caused quite a stir at the annual CROI (Conference on Retroviruses and Opportunistic Infections) last February.

HIV, a two-cycle pathogen

In the majority of cases, HIV strains have a tropism that remains limited to the T lymphocytes of the mucous membranes during the first few years of the infection. “When contamination occurs, and during the initial period of infection, the virus is configured in such a way that it can bind to the CD4 T lymphocytes of the mucous membranes and, in particular, the intestinal mucous membranes”, Michel Moutschen elaborates. These lymphocytes present a certain type of receptor on their surface which isn’t the same as those found on other T lymphocytes in the body, for instance in the spleen, in ganglions or in the blood. “Hence, for a certain period of time, the damage linked to the presence of the virus is limited to the T lymphocytes of the mucous membranes and the rest of the immune system is protected”, the specialist continues. “This is what explains the asymptomatic phase of the infection, which can last several years. The virus is present, replicates but the person is in good health and presents only very low concentrations of infected T lymphocytes in the blood”, Michel Moutschen adds. In general the first signs of illness due to HIV only appear after five or six years. “Then the virus mutates and acquires the ability to bind to the T lymphocyte receptors present in the whole body. At this point, the patient’s immunity drops sharply with the onset of AIDS. That’s the usual scenario”, the researcher specifies.

To return to Cuba, the work in which Professor Moutschen participated shows that the CRF19 strain is capable of using the receptors of the non-mucous membrane T lymphocytes present in the whole body, very early on in the infection. Hence the very short asymptomatic phase and a rapid progression to acquired immunodeficiency syndrome.

When a Cuban strain goes up a gear

CRF19 is the result of the genetic recombination of two other strains of HIV. And, of course, considering its virulence, it is characterised by a particularly high replication speed.  What’s even more surprising is that CRF19 causes a rapid deterioration of the immune status particularly in patients with a high blood concentration of a chemokine known as RANTES. “And yet, RANTES, a product of the inflammation, naturally binds to mucous membrane T lymphocyte receptors which are precisely those used by HIV”, Michel Moutschen explains. “In these patients, since RANTES is already occupying the receptors essential for the replication of HIV in mucous membrane T lymphocytes, considerable selective pressure occurs allowing the short-term use of the receptors of the other T lymphocytes in the body”, the scientist continues. The reason why these Cuban patients show high levels of RANTES in the blood remains unknown. However, according to scientists, these people may have been subject to a systemic inflammation which is itself linked to the presence of CRF19 in their body. “The mere presence of the HIV strain may have stimulated the inflammation and thus provoked the production of RANTES. This scenario, which is counterproductive for the virus in the beginning, ultimately opens the way for it to infect the whole body rapidly. It's a sort of vicious circle”, Michel Moutschen sums up.

While cases of the disease’s rapid progression have been observed in other parts of the world, the specialists are generally unaware of the reasons behind this progression. It can be linked to the viral strain and/or the host. “The genetics of individuals play a major role in the way the virus progresses in the body. According to their genetic make-up, an individual may be more vulnerable or more resistant to HIV. The virus’ strain isn’t the only factor to enter into the equation”, Michel Moutschen indicates. “For the first time, the present study has enabled us to relate virological properties to a rapid clinical progression of the disease. Out of the 50 Cuban patients studied presenting a rapid progression of the HIV infection, ten of them were infected by the CRF19 strain. This is statistically highly significant and sufficient to attribute particular properties to this strain. However, the 40 other patients show that other factors must be present”.

Early treatment of the infection to stall the virus

According to Michel Moutschen, the main message to remember following the results of this study is that anyone infected by HIV must be treated as soon as possible. “Currently, in Belgium and in many other countries, we don’t start treating patients until their concentration of CD4 T lymphocytes falls below a certain threshold. Before that, the treatment isn’t reimbursed”, the professor explains. “This decision is based on the fact that we presume that the speed of progression to AIDS is known and constant. So we wait a while, perhaps to make savings or to prevent the patient from getting tired of taking their medication...”. In Cuba, following the conclusions of the present study, the authorities have decided to significantly raise the threshold determining when HIV-infected patients should be treated.

The Cuban example proves that things can deteriorate much faster than previously thought and that new more aggressive strains can appear at any time. Hence the interest of providing treatment as soon as the infection is detected. “The good news is that the CRF19 strain identified in Cuban patients isn’t, in principle, resistant to the antiretroviral drugs used to slow down HIV infection”, Michel Moutschen adds. HIV strains mutate and always try to find new target cells. It is therefore vital to keep an eye on them because they may still have some surprises in store for us. All the more so since the majority of knowledge acquired until now on HIV particularly concerns subtype B, which is found in Europe, rather than the strains present on the other continents.

(1) Vivian Kouri, Ricardo Khouri, Yoan Alemán, Yeissel Abrahantes, Jurgen Vercauteren, Andrea-Clemencia Pineda-Peña, Kristof Theys, Sarah Megens, Michel Moutschen, Nico Pfeifer, Johan Van Weyenbergh, Ana B. Pérez, Jorge Pérez, Lissette Pérez, Kristel Van Laethem, Anne-Mieke Vandamme. CRF19_cpx is an Evolutionary fit HIV-1 Variant Strongly Associated With Rapid Progression to AIDS in Cuba. EBioMedicine. http://dx.doi.org/10.1016/j.ebiom.2015.01.015