This has been our news for two years now. Alpha, Delta, Omicron… We are now familiar with the notion of “variant” in viruses, in this case for SARS-CoV-2.
A new viral ‘variant of concern’, as defined by the World Health Organization (WHO), is distinguished by the mutations present in its genome, but that is not enough: it must also cause a distinct type of infection ( more contagious, more virulent, etc.) or its appearance must have an effect on the epidemic (for example lead to an increase in the number of cases).
What about other infectious diseases than Covid? Do other viruses also have their “variants”? How are these variants selected? And what consequences do they have for human health? We are interested in these questions for another major viral epidemic: AIDS, caused by HIV (human immunodeficiency virus).
While the official start date of the pandemic is June 5, 1981, the version of HIV that caused it has been evolving with our species for about a century: it is estimated that the virus jumped from chimpanzees to humans in the 1920s, probably in Cameroon. The fact that the emergence of HIV is old (compared to that of SARS-CoV-2 or other emerging viruses) could suggest that the currently circulating virus is genetically relatively homogeneous and well adapted to the human species…
This is actually 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 encoded in the form of a single strand of RNA (molecule “cousin” of that of DNA) about 9700 nucleotides (letters) long. A small genome, but which codes for all the genes essential for the replication of the virus in human cells.
Because of our difference in genetic molecule, an essential step in this replication is the “reverse transcription” of its RNA into DNA: this is what will allow it to integrate its genetic material, now in the form of DNA, into that of its host, so that the latter produces its proteins for it… and new copies of its genome (which will form as many new viral particles). However, this step is carried out by an enzyme which makes many errors. As a result, HIV has a high mutation rate, hence the existence of many groups and subgroups.
The form of HIV that generated 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 abilities – in terms of virulence in particular (its pathogenicity, harm to the host / morbidity and mortality caused to the host).
For example, it has been observed in Uganda, where the two major HIV subtypes are A and D, that individuals infected with subtype D will declare AIDS and die more quickly: subtype D seems more virulent.
A particularly virulent variant
For several years, we have been interested in quantifying and characterizing the link between the very great genetic variability of HIV and its virulence. In particular, Christophe Fraser at the University of Oxford and his team have carried out an extensive collaboration with clinicians and virologists to bring together thousands of HIV genomes associated with clinical data from infected patients across Europe from 1985 to today. today.
Until recently, we thought that the severity of the infection was mainly due to the human host… However, since 2014, several studies have established that 20-30% of the variability in virulence was actually related to the genotype of the virus itself. They also revealed that a trait involved in virulence was heritable from one infection to another: the “viral load”, i.e. the quantity of viral particles present in the blood when individuals are in the asymptomatic phase of the disease. ‘infection.
In our new research, we have characterized a highly virulent variant of HIV circulating in the Netherlands that we have called “VB”, for variant “Virulent subtype B”. We discovered this variant a posteriori, by analyzing these thousands of HIV genomes associated with viral load data in these European patients.
Its exacerbated virulence can be seen on several levels. Already, individuals infected with the VB variant have a concentration of virus in the blood three to five times higher than those infected with other genotypes.
Another indicator is the rate of decline of a category of immune cell: T lymphocytes carrying on their surface a particular molecule called CD4, an essential intermediary in the establishment of our response to infections. The number of these cells declines gradually in people with HIV, because these cells are infected and killed by the virus.
In people infected with the VB variant, the amount of CD4 cells declines twice as fast as in people infected with the “classic” form of subtype B. The normal amount of CD4 cells is 500 to 1500 per mm3 of blood. The AIDS stage of HIV infection, i.e. the stage where the risk of opportunistic infections is high, occurs at 200 cells per mm3 de sang.
A more rapid decline therefore results in a more rapid progression towards the AIDS stage in the absence of treatment: in theory barely more than 2 years after diagnosis for a patient carrying the VB variant, against 6 years for a patient carrying the classic form of subtype B.
An atypical development for “VB”
To better understand its specificities, we decided to retrace the history of the VB variant by analyzing its genome and the diversity it presents. To do this, we study the mutations it carries that we know accumulate on a regular basis. This allows us to date the events on the “family” tree representing the different versions of the virus, such as the one that groups together the different main types of HIV presented above.
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It appeared that the common ancestor of these VB variants dates from the end of the 1990s. The VB variant is characterized by 509 mutations which are specific to it, homogeneously distributed in the genome. If the rate of accumulation of mutations here is consistent with the average rate, it theoretically took years for these 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 that recalls what was observed for the Omicron variant of SARS-CoV-2 (although on a shorter time scale for the latter). A possible hypothesis is that these mutations accumulated in a single host with particular characteristics, for example immunocompromised. Or that they have evolved in several individuals forming a chain of transmission spanning several years, but which has never been detected.
How could such a virulent variant be selected in its initial phase of expansion? We don’t have a clear answer yet…
According to one evolutionary theory, an intermediate level of virulence is optimal for HIV. Indeed, a virus that causes a high viral load is transmitted better per unit of time, but for less time, because infected people develop AIDS and die more quickly. The average level of HIV virulence in Europe is roughly at the level predicted by this theory. But the virulence of VB is stronger than this optimal level. We do not understand what factors may have nevertheless promoted the emergence of the VB variant in the 1990s.
What consequences in terms of public health?
Fortunately, as we show in our study, individuals infected with the VB variant ultimately die no faster than other patients. The generalization of treatment with antiretrovirals as soon as the infection is detected plays a major role in this. These effective treatments now make it possible to control intra-host virus replication and prevent the onset of AIDS.
On the other hand, the VB variant, after an expansion phase between 1995 and 2003, seems to have been declining since 2013. It is therefore probably not destined to spread worldwide and replace existing strains as did certain variants of SARS-CoV-2.
The discovery of this variant has, in our view, two main implications. First, it demonstrates once again that the evolution of viruses can have profound consequences: it can affect the virulence of these pathogenic organisms, making them more dangerous; and, therefore, it can have an impact on public health.
For SARS-CoV-2, the possible adaptation of the virus was not at the heart of epidemiologists’ concerns until the end of 2020. The appearance of Alpha, Delta, etc. has led to a massive awareness of the ability of the virus to adapt to its host, often resulting in epidemic rebounds.
For HIV, the mechanism and risks are similar. Hence the importance of strengthening research programs interested in virulence from the point of view of evolutionary theory – 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 evolution of new virulent variants of HIV is an additional argument in favor of public health policies for the rapid detection and treatment of infected individuals. This highlights the value of screening and genomic monitoring of virus strains in circulation, in order to be able to detect any appearance of new variants in the future.
The original version of this article was published on The conversationa non-profit news site dedicated to sharing ideas between academic experts and the general public.
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