When a study published last year on an HIV variant that has been circulating in the Netherlands for the past 20 years made global headlines, it was a reminder that SARS-CoV-2 is not the only virus out there that is constantly mutating.
Behind the headlines though, the story also offered a reminder of how different HIV is from SARS-CoV-2 with its Betas, Deltas and Omicrons. To appreciate the differences, some basic terms are worth revising, writes Elri Voigt in Spotlight.
“In virology, the terms variants, strains, and subtypes all describe genetic differences between viruses in the same grouping or species. There is a progression of how big the genetic change or differences are, with variants being the smallest difference, strains slightly more, and subtypes a much bigger difference,” says Professor Eftyhia Vardas, a clinical virologist pathologist and the head of virology at Lancet Laboratories.
These genetic differences occur because of mutation in the virus. They occur frequently, says Vardas, because viruses replicate quickly and their replication mechanism – primarily enzymes – makes frequent errors.
Some mutations are more beneficial than others.
Those incompatible with the virus’ survival are immediately selected out and not replicated: those mutations that are beneficial to the virus’ survival are selected and will be replicated. This, depending on how big the genetic difference is, leads to the development of new variants, strains, or even subtypes of a virus.
Highly mutagenic
Professor Francois Venter, executive director of Ezintsha in the faculty of health sciences at the University of the Witwatersrand, says the HIV virus is highly mutagenic. In its stable phase it can generate billions of viruses daily, with at least one mutation present in each virus.
“One virologist told me that within the week of infection, every known HIV patient has every known mutation to every known HIV drug even though they’ve never seen the drug, (it’s) just simply by chance,” he said. “The reason that’s not such a big deal is that when a virus gets a mutation, they are mostly so terrible they just cripple or kill the virus. The virus can’t replicate.”
He likens this to zombies in a movie – that don’t move very quickly and thus aren’t very efficient at spreading the infection.
“Most of these mutations actually have a cost to the virus, so they either die or are not as efficient as the originator virus. But… very occasionally they get better,” Venter said.
This “getting better” is what’s still happening with SARS-CoV-2, he added, where the virus is still mutating in ways that make it more transmissible.
A study conducted in South Africa and published in Nature demonstrated how the Omicron BA.1 and BA.2 subvariants had significantly higher attack rates than the previous Delta variant, infecting more people in a shorter timeframe. This was despite there being previous immunity to SARS-CoV-2 from previous infection or vaccination.
Two types of HIV
HIV might not have the same well-known alphabet soup of variants as SARS-CoV-2, but it has its own interesting virological history.
Venter said there are two types of HIV. The type associated with the general major HIV epidemic is called HIV-1, the other type is HIV-2, and is slowly becoming extinct, as it is much less transmissible than HIV-1.
Vardas said HIV-1 and HIV-2 are distinct species, with HIV-2 having a larger genetic difference from HIV-1. They also emerged from different ancestor viruses.
“HIV-1 (evolved) from the simian immunodeficiency virus in chimpanzees (SIVCPZ) and HIV-2 from SIV from the Sooty mangabey monkey (SIVSM): this significantly affects how they affect humans,” she said. “HIV-2 has decreased virulence and pathogenicity – it doesn’t infect humans as well as HIV-1 does and doesn’t cause such severe disease as HIV-1.”
Subtypes of HIV-1
Whereas we are mostly talking of variants with SARS-CoV-2, with HIV-1 we have already seen differentiation into several sub-types (which as we explained above, indicate larger changes than variants).
“There are four groups of HIV-1 (M, N, O, P),” Vardas said, “(and) with most viruses classified into the ‘M’ or Major group.
“Within the HIV-1 group M, there are nine subtypes (classified alphabetically as) A-K, which differ genetically from each other between 25% to 30% and are found in geographically distinct places. The differences for HIV subtypes are relatively big, not enough to reclassify the viruses into a different species, but enough to affect how well the virus spreads and responds to antiretroviral treatment.”
Explaining genetic difference, Vardas said HIV-1 has all of its genetic material represented on two identical strands of RNA held within the protein core of the virus.
“The virus core is covered by a lipid-protein bilayer with spikes sticking through it and which are used by the virus to attach to and infect host cells. Each bit of the virus is encoded by this RNA genetic material at the centre of the core. The arrangement of the genetic information on this RNA follows the same pattern for all HIV-1 subtypes, with each discrete section coding for each part of the virus when it reproduces within the host,” she said.
“So, the genetic differences among the subtypes are measured on the structural proteins of the virus envelope and the protein sticking out of the envelope (this is gp120). There may also be smaller differences between subtypes in the non-structural (or regulatory proteins) but these are not used as much for classification of the subtypes.”
Within the nine subtypes from group M, subtype C is the most predominant one globally, including in Southern Africa. Someone could also be “superinfected” with more than one HIV subtype, which could impact the efficacy of treatment.
“There are also overlap subtypes or recombinants of viral subtypes circulating in certain populations, for example, recombinants of AD may occur in some countries. These are hybrid viruses containing the genetic material of both subtypes in a patchwork and are known as circulating recombinant forms (CRF). About 98 CRFs have been sequenced globally and they are found predominantly in Africa and Asia,” she said.
HIV variants and drug resistance
In practice, today’s antiretroviral medicines are so effective that much of this viral complexity hardly matters. Generally, if people take the treatment consistently, HIV becomes suppressed in the body and people can live long and healthy lives.
Vardas said HIV variants are not currently monitored in individuals on a large scale, only when treatment fails and resistance mutations are being sought.
“It is too difficult, very expensive and the virus changes too quickly to monitor variants routinely in infected people,” she said. “We do monitor subtype or CRF changes in populations – those that may affect disease virulence, pathology, and response to treatment.”
Asked how HIV variants tie into the development of drug resistance, Vardas said that drug-resistant variants are created by mutations caused by suboptimal therapy. Things like “limited drug classes, pill burden, toxic effects, late initiation of therapy, and treatment non-compliance along with continuing transmission in high-risk communities”.
“There are specific mutations in circulating viruses that confer drug resistance, and drug resistance mutations are transmissible from one individual to the next. So, the overall population burden of resistance is contributed to both by the emergence of resistance in treated individuals and by the transmission of resistance,” she added.
According to Venter, in the event that the HIV mutations are actually efficient, the class of anti-retroviral drugs (ARVs) currently used worldwide are so potent the mutations won’t get a chance to spread.
In South Africa, the recommended first-line treatment is a three-in-one combination tablet containing the drugs dolutegravir, tenofovir and lamivudine. “It’s almost impossible for this virus to have even the faintest chance (to mutate): whenever the virus raises its head to actually develop the mutations, these three drugs just climb in and kill it immediately,” Venter said.
On the effect late initiation of treatment might have on the potential for HIV to mutate into drug-resistant variants, he said so far, this has not had an effect. Even when people initiate treatment very late, clinicians can still suppress the virus.
But this doesn’t mean no one is monitoring the situation.
“We’re sitting on our laurels. Everyone’s looking and is nervous that at some stage something’s going to crop up (with) a resistant virus, but we haven’t seen it yet,” said Venter.
On the likelihood of new HIV variants developing, Vardas said these “develop all the time and affect the effectiveness of treatment, (but) new subtypes that may impact virulence and pathogenicity are very rare”.
The ‘VB variant’
A prime example of an HIV variant was described in a 2022 study, which identified a variant that had been circulating in the Netherlands for more than two decades. Though publication of the study led to some sensationalist headlines, the variant isn’t really something to worry about.
Though the variant of HIV-1 Sub-type B, known as the “VB” variant, was described as “highly virulent”, it had nothing like the dramatic impact we’ve seen from new SARS-CoV-2 variants. The context was also different in that HIV is sexually transmitted and can be treated with highly effective ARV therapy.
By highly virulent, said Professor Christophe Fraser, Moh Family Foundation Professor of Infectious Disease Epidemiology at the Nuffield Department of Medicine at the University of Oxford, they mean this variant has a more damaging health impact than is normal for HIV.
He is also the principal investigator of the BEEHIVE project. The study found 109 individuals (107 of whom were in the Netherlands) with this variant, which emerged in the late 1980s and 1990.
The VB variant spread more quickly then other HIV variants during the 2000s, but has declined since about 2010.
What was different about this variant was that before treatment, those with the VB variant showed a faster progression to “advanced HIV” than those with other HIV variants. Those with the VB variant had a viral load of 3.5 to 5.5 times higher, had a CD4 decline that was twice as fast, and an increased risk of transmitting the virus to others, making it more virulent than the others it was compared to in the study.
However, said Fraser, after treatment, those with the VB variant responded similarly to those with other variants. “The VB variant does not have mutations that prevent successful treatment,” he says.
“Before this study, the genetics of the HIV virus was known to be relevant for virulence, implying that the evolution of a new variant could change its impact on health. Discovery of the VB variant demonstrated this, providing a rare example of the risk posed by viral virulence evolution. Studying exactly how this variant causes more immune system damage than other variants could reveal new targets for next-generation drugs.”
Chris Wymant, a senior researcher in Statistical Genetics and Pathogen Dynamics at the University of Oxford and one of the study authors, said people should not be alarmed about these findings, that the discovery highlights the importance of existing guidance needed by those at risk of acquiring HIV – and access to regular testing to allow for early detection and immediate initiation of treatment.
Monitoring efforts
This raises the question of whether we should more actively be monitoring for new variants, like the VB variant.
Vardas said there was room for improvement in efforts to monitor drug resistance in different HIV variants in South Africa and on a global scale.
“Resistance testing is very expensive, and more available and implemented more frequently in the private sector than in the public sector. Some research projects look specifically at sequencing HIV-1 in subgroups of patients, for example, men who have sex with men or sex workers, but population-based HIV molecular epidemiological monitoring is not something that is available all the time,” she said.
Regarding the monitoring of HIV subtypes in South Africa, she added: “Molecular epidemiological studies for HIV-1 are ongoing to track and characterise HIV-1 subtypes and their characteristics. However, the scientific attention and funding given to the tracking of these viruses is no way near as intense as it has been for SARS-CoV-2.”
Venter is more optimistic.
“We (in South Africa have) got some of the best virologists and virology researchers in the world… they monitor this stuff all the time. To my mind, the reason I don’t worry about it as a clinician is that I kill the virus. My drugs do the job… We should still worry as virologists, and we watch it but it’s not really of clinical concern at the moment as it is with Covid-19,” he says. “It might change and we obviously don’t take it for granted, but there’s no concern yet from my side.”
He said SA was monitoring for the emergence of new HIV variants or variants that are drug-resistant and that the country’s monitoring for diseases through the NICD, in general, was excellent.
Study 1 details
A highly virulent variant of HIV-1 circulating in the Netherlands
Chris Wymant, Daniela Bezemer, François Blanquart, Luca Ferretti, et al., and The Beehive Collaboration.
Published in Science on 3 February 2022
Abstract
We discovered a highly virulent variant of subtype-B HIV-1 in the Netherlands. One hundred nine individuals with this variant had a 0.54 to 0.74 log10 increase (i.e., a ~3.5-fold to 5.5-fold increase) in viral load compared with, and exhibited CD4 cell decline twice as fast as, 6604 individuals with other subtype-B strains. Without treatment, advanced HIV—CD4 cell counts below 350 cells per cubic millimetre, with long-term clinical consequences—is expected to be reached, on average, 9 months after diagnosis for individuals in their thirties with this variant. Age, sex, suspected mode of transmission, and place of birth for the aforementioned 109 individuals were typical for HIV-positive people in the Netherlands, which suggests that the increased virulence is attributable to the viral strain. Genetic sequence analysis suggests that this variant arose in the 1990s from de novo mutation, not recombination, with increased transmissibility and an unfamiliar molecular mechanism of virulence.
Study 2 details
Rapidly shifting immunologic landscape and severity of SARS-CoV-2 in the Omicron era in South Africa
Kaiyuan Sun, Stefano Tempia, Jackie Kleynhans, Anne von Gottberg, Meredith McMorrow, Nicole Wolter, Jinal Bhiman, Cheryl Cohen & the PHIRST-C group
Published in Nature on 16 January 2023
Abstract
South Africa was among the first countries to detect the SARS-CoV-2 Omicron variant. However, the size of its Omicron BA.1 and BA.2 subvariants (BA.1/2) wave remains poorly understood. We analysed sequential serum samples collected through a prospective cohort study before, during, and after the Omicron BA.1/2 wave to infer infection rates and monitor changes in the immune histories of participants over time. We found that the Omicron BA.1/2 wave infected more than half of the cohort population, with reinfections and vaccine breakthroughs accounting for > 60% of all infections in both rural and urban sites. After the Omicron BA.1/2 wave, we found few (< 6%) remained naïve to SARS-CoV-2 and the population immunologic landscape is fragmented with diverse infection/immunisation histories. Prior infection with the ancestral strain, Beta, and Delta variants provided 13%, 34%, and 51% protection against Omicron BA.1/2 infection, respectively. Hybrid immunity and repeated prior infections reduced the risks of Omicron BA.1/2 infection by 60% and 85% respectively. Our study sheds light on a rapidly shifting landscape of population immunity in the Omicron era and provides context for anticipating the long-term circulation of SARS-CoV-2 in populations no longer naïve to the virus.
Science article – A highly virulent variant of HIV-1 circulating in the Netherlands (Open access)
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