This has been our news for two years. Alpha, Delta, Omicron… We now know the term “variant” in viruses, in this case SARS-CoV-2.
A new viral “variant of concern” as defined by the World Health Organization (WHO) is characterized by the mutations present in its genome, but that is not enough: it must also cause a specific type of infection (more contagious, more virulent, etc. ) or their occurrence must have an impact on the epidemic (e.g. lead to an increase in the number of cases).
What about infectious diseases other than Covid? Do other viruses also have their “variants”? How are these variants selected? And what are the consequences for human health? These questions interest us in another major virus epidemic: AIDS, caused by HIV (Human Immunodeficiency Virus).
If the official start date of the pandemic is June 5, 1981, the version of HIV at its origin has evolved with our species for about a century: it is estimated that the virus passed from a chimpanzee to humans in the 1920s in Cameroon. The fact that the emergence of HIV is old (compared to SARS-CoV-2 or other emerging viruses) may indicate that the currently circulating virus is genetically relatively homogeneous and well adapted to the human species…
In fact, this is not the case.
Not one, but AIDS viruses
Unlike us, who have our genetic information on a DNA molecule, HIV is a so-called RNA virus: its genetic information is in the form of a single strand of RNA (molecule “cousin” of DNA) of about 9700 nucleotides (letters) long. A small genome, but it encodes all the genes essential for the virus to replicate in human cells.
Because of our difference in genetic molecules, an essential step in this replication is the “reverse transcription” of its RNA into DNA: this allows it to integrate its genetic material, now in the form of DNA, with that of its host so that the latter can produce its proteins to do it… and make new copies of its genome (which will make as many new virus particles). However, this step is performed by an enzyme that makes many mistakes. As a result, HIV has a high mutation rate, hence the existence of many groups and subgroups.
The form of HIV that caused the pandemic is HIV-1 group M. Group M can itself be divided into several “subtypes” which are like “families” of HIV, ie genetically distinct forms. These subtypes evolved at the very beginning of the epidemic, in the 1920s to 1950s, and can be distinguished by different capacities – particularly in terms of virulence (their pathogenicity, their harmfulness to the host/morbidity and mortality in the host).
For example, in Uganda, where the two main HIV subtypes are A and D, it has been observed that individuals infected with subtype D report AIDS and die faster: subtype D appears to be more virulent.
A particularly virulent variant
For several years we have been interested in quantifying and characterizing the relationship between the very large genetic variability of HIV and its virulence. In particular, Christophe Fraser of the University of Oxford and his team have undertaken an extensive collaboration with clinicians and virologists to bring together thousands of HIV genomes in conjunction with clinical data from infected patients across Europe from 1985 to the present.
Until recently, we thought that the severity of the infection was mainly due to the human host… However, since 2014, several studies have found that 20-30% of the variability in virulence is actually related to the genotype of the virus itself. They also showed that a trait involved in virulence was heritable from one infection to another: ‘viral load’, which is the amount of virus particles present in the blood when people are in the asymptomatic phase of the disease.
In our new research, we have characterized a highly virulent HIV variant circulating in the Netherlands, which we have named “VB” for “virulent subtype B” variant. We discovered this variant retrospectively by analyzing thousands of HIV genomes associated with viral load data in these European patients.
Its enhanced virulence can be seen on multiple levels. Already, people infected with the VB variant have a three to five times higher virus concentration in their blood than people infected with other genotypes.
Another indicator is the rate of decline in a category of immune cells: T-lymphocytes, which carry a particular molecule called CD4 on their surface, a key mediator in establishing our response to infection. The number of these cells gradually decreases in people with HIV as the virus infects and kills these cells.
In people infected with the VB variant, the amount of CD4 cells decreases twice as fast as in people infected with the “classic” form of subtype B. The normal amount of CD4 cells is 500 to 1,500 per mm of blood. The AIDS stage of HIV infection, that is, the stage at which the risk of opportunistic infections is high, is given as 200 cells per mm of blood.
Faster regression therefore leads to faster progression towards AIDS without treatment: theoretically little more than 2 years after diagnosis for a patient with the VB variant, versus 6 years for a patient with the classic form of subtype B.
An atypical development for “VB”
To better understand its specifics, we decided to retrace the history of the VB variant by analyzing its genome and the diversity it exhibits. To do this, we study the mutations it carries that we know accumulate regularly. This allows us to date the events on the “family tree” that represents the different versions of the virus, such as: B. the one that summarizes the different main types of HIV presented above.
The common ancestor of these VB variants turned out to date back to the late 1990s. The VB variant is characterized by 509 mutations specific to it and homogeneously distributed in the genome. In theory, if the rate of accumulation of mutations here matches the average rate, it has taken years for those mutations to accumulate. Curiously, we did not find any intermediate forms between the VB variant and the classic forms of the B subtype.
A feature reminiscent of what was observed in the Omicron variant of SARS-CoV-2 (albeit on a shorter timescale for the latter). One possible hypothesis is that these mutations have accumulated in a single host with certain characteristics, such as being immunocompromised. Or that they evolved in multiple individuals, forming a chain of transmission that spans several years but has never been discovered.
How could such a virulent variant be selected in its initial expansion phase? We don’t have a clear answer yet…
According to an evolutionary theory, an intermediate level of virulence is optimal for HIV. In fact, a virus that causes a high viral load is transmitted better per unit time but for less time because infected people develop AIDS and die faster. The average level of HIV virulence in Europe is around the level predicted by this theory. But the virulence of VB is stronger than this optimal level. It is not clear to us what factors might nevertheless have promoted the emergence of the VB variant in the 1990s.
What consequences for public health?
Fortunately, as we show in our study, individuals infected with the VB variant ultimately die no faster than other patients. Generalization of treatment with antiretroviral drugs as soon as the infection is detected plays an important role. These effective treatments now make it possible to control viral replication in the host and prevent the onset of AIDS.
On the other hand, the VB variant seems to have been in decline since 2013, after a period of expansion between 1995 and 2003. It is therefore unlikely destined to spread globally and replace existing strains as certain variants of SARS-CoV-2 did.
The discovery of this variant has, in our view, two main implications. First, it shows once again that the evolution of viruses can have profound consequences: it can impair the virulence of these pathogenic organisms, making them more dangerous; and therefore it may have public health implications.
In the case of SARS-CoV-2, the possible adaptation of the virus was not the focus of epidemiologists’ concerns until the end of 2020. The emergence of Alpha, Delta & Co. has led to massive awareness of the virus’ ability to adapt to its host, often resulting in renewed epidemics.
In HIV, the mechanism and risks are similar. Therefore, from the point of view of evolutionary theory, it is important to strengthen research programs interested in virulence – even if in the specific case of the VB variant, the impact on human health has been reduced thanks to the immediate availability of effective treatments.
Second implication: The possible development of new virulent HIV variants is an additional argument for public health policies to promptly identify and treat infected individuals. This underscores the value of screening and genomic monitoring of viral strains in circulation to detect any emergence of new variants in the future.