AIDS: HIV also has variants, and some are particularly dangerous

AIDS: HIV also has variants, and some are particularly dangerous

#AIDS #HIV #variants #dangerous

This has been our news for two years. Alpha, Delta, Omicron… We already know 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 mutations present in its genome, but that is not enough: it must also cause a different type of infection (more contagious , more virulent, etc.) or its appearance must have an effect on the epidemic (for example, cause an increase in the number of cases).

What about other infectious diseases besides 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 great viral epidemic: AIDS, caused by HIV (human immunodeficiency virus).

If the official start date of the pandemic is June 5, 1981, the original version of HIV has been evolving with our species for approximately a century: it is estimated that the virus passed from a chimpanzee to humans in the decade 1920, probably in Cameroon The fact that the appearance of HIV is old (compared to that of SARS-CoV-2 or other emerging viruses) could suggest that the virus currently circulating is genetically relatively homogeneous and well adapted to the human species…

Actually, this is not the case.

Not one, but the AIDS viruses.

Unlike us, who have our genetic information in a DNA molecule, HIV is a virus called RNA: its genetic information is encoded in the form of a single strand of RNA (“cousin” molecule of DNA) of about 9700 nucleotides (letters) long. A small genome, but one that encodes all the essential genes for the replication of the virus in human cells.

Due to our difference in the 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 it produces its proteins… and new copies of its genome (which will form as many new viral particles). However, this step is carried out 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 be divided into several “subtypes” that are like “families” of HIV, that is, genetically distinct forms. These subtypes evolved at the very beginning of the epidemic, between the 1920s and 1950s, and can be distinguished by different capacities, in terms of virulence in particular (their pathogenicity, their harmfulness to the host/morbidity and mortality caused to the host).

For example, it has been observed in Uganda, where the two main HIV subtypes are A and D, that people 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 extremely high genetic variability of HIV and its virulence. In particular, Christophe Fraser of the University of Oxford and his team have carried out extensive collaboration with clinicians and virologists to collect thousands of HIV genomes associated 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 established that between 20 and 30% of the variability in virulence was linked 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”, that is, the amount of viral particles present in the blood when individuals are in the asymptomatic phase of infection.

In our new research, we have characterized a highly virulent variant of HIV circulating in the Netherlands which we have named ‘VB’, ‘Virulent Subtype B’ variant. We discovered this variant a posteriori, analyzing these thousands of HIV genomes associated with viral load data in these European patients.

Its exacerbated virulence can be seen on several levels. People infected with the VB variant already have a concentration of virus in their blood that is three to five times higher than people infected with other genotypes.

Another indicator is the rate of decline of a category of immune cells: T lymphocytes that carry on their surface a particular molecule called CD4, an essential intermediary in establishing our response to infections. The number of these cells gradually decreases in people with HIV, because the virus infects and kills them.

In people infected with the VB variant, the number of CD4 cells declines twice as fast as in people infected with the “classic” form of subtype B. The normal number of CD4 cells is 500 to 1,500 per mm of blood. The AIDS stage of HIV infection, ie the stage where the risk of opportunistic infections is high, is declared at 200 cells per mm of blood.

Thus, a more rapid decline results in a more rapid progression to the AIDS stage in the absence of treatment: in theory, just over 2 years after diagnosis for a patient with the BV variant, versus 6 years for a patient carrying the classic form of the 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 its diversity. To do this, we study the mutations it carries and that we know accumulate on a regular basis. This allows us to date the events in the “family” tree that represent the different versions of the virus, such as the one that groups the different main types of HIV presented above.

The common ancestor of these VB variants appears to date from the late 1990s. The VB variant is characterized by 509 mutations that are specific to it, homogeneously distributed throughout the genome. If the rate of mutation accumulation here is consistent with the average rate, it theoretically took years for these mutations to accumulate. Interestingly, we did not find intermediate forms between the VB variant and the classic forms of subtype B.

The recent history of the VB variant is unique as evidenced by its great diversity (VB phylogeny compared to other HIV subtype B).  The colors give the level of viral load, with VB being particularly loaded.

The recent history of the VB variant is unique as evidenced by its great diversity (VB phylogeny compared to other HIV subtype B). The colors give the level of viral load, with VB being particularly loaded.

Wymant et al., Science 2022

A feature reminiscent of what was observed for the Omicron variant of SARS-CoV-2 (although on a shorter time scale for the latter). One possible hypothesis is that these mutations accumulate in a single host with particular characteristics, for example immunocompromised. Or that they have evolved in several individuals forming a transmission chain of several years, but that has never been detected.

How could such a virulent variant be selected in its early expansion phase? We still don’t have a clear answer…

According to an 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 mean level of HIV virulence in Europe is approximately at the level predicted by this theory. But the virulence of BV is stronger than this optimal level. However, we do not understand what factors may have promoted the appearance of the VB variant in the 1990s.

What consequences in terms of public health?

Fortunately, as we show in our study, people infected with the VB variant do not ultimately die faster than other patients. The generalization of antiretroviral treatment as soon as the infection is detected plays an important role in this. These effective treatments now make it possible to control the replication of the virus within the host and prevent the onset of AIDS.

On the other hand, the VB variant, after an expansion phase between 1995 and 2003, appears to have been in decline since 2013. So it is probably not destined to spread worldwide and replace existing strains as they did. certain variants of SARS-CoV-2.

The discovery of this variant has, in our opinion, 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 may have an impact on public health.

For SARS-CoV-2, the possible adaptation of the virus was not at the center of the concerns of epidemiologists until the end of 2020. The appearance of Alpha, Delta, etc. has led to a mass awareness of the ability of the virus to adapt to its host, often resulting in epidemic outbreaks.

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, although in the specific case of the VB variant, the impact on human health has been reduced thanks to 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 people. This highlights the value of genomic screening and monitoring of circulating virus strains, in order to detect any appearance of new variants in the future.

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