As the ongoing coronavirus pandemic has demonstrated, new mutations in viral genetic sequences can impact significantly on viral transmissibility and damage to the host. This potential has long been a concern for HIV-1. A research team headed by scientists at University of Oxford’s Big Data Institute has now discovered a new, highly virulent HIV strain that has been circulating in the Netherlands for the last few decades. According to their newly reported study, a cluster of more than 100 individuals infected with the VB (virulent subtype B) variant showed exceptionally high viral loads, rapid CD4 T cell decline, and increased infectivity.
The study results suggest that after starting treatment, individuals infected with VB variant show similar immune system recovery and survival compared with individuals with other (non-VB) HIV variants. However, the researchers stressed that because the VB variant causes a more rapid decline in immune system strength, it will be critical to diagnose individuals early and start treatment as soon as possible. And while the findings show that the HIV lineage likely arose de novo around the turn of the millennium, extensive changes in its genome make it hard to discern the mechanisms that underlie elevated virulence.
Lead author Chris Wymant, PhD, from the University of Oxford’s Big Data Institute and Nuffield Department of Medicine, said, “Before this study, the genetics of the HIV virus were 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.”
Wymant and colleagues reported their findings in Science, in a paper titled “A highly virulent variant of HIV-1 circulating in the Netherlands.”
The risk posed by viruses evolving to greater virulence has been extensively studied in theoretical work, yet, as the authors acknowledged, there have been just a few population-level examples. One example of note, they pointed out in their new paper, is the Delta variant of SARS-CoV-2, which demonstrates increased transmissibility, as well as a reported increase in probability of death. However, outside of recent studies on SARS-CoV-2 variants, an understanding of the evolution of virulence in viruses beyond theoretical analyses is lacking.
RNA viruses have long been a particular concern, the investigators continued, as error-prone replication results in the greatest known rate of mutation—and thus high potential for adaptation. For many years there have been concerns that such mutations may arise in HIV-1. “Continued monitoring of HIV virulence is important for global health: 38 million people currently live with the virus, and it has caused an estimated 33 million deaths,” the authors stated, citing data from UNAIDS.
The newly characterized VB variant of HIV-1 was first identified by the team in 17 HIV-1-positive individuals from the BEEHIVE ((Bridging the Epidemiology and Evolution of HIV in Europe) project, an ongoing study which collects samples from across Europe and Uganda. These individuals demonstrated highly elevated viral loads. And since 15 of the 17 people were part of the ATHENA study in the Netherlands, the researchers then analysed data from a cohort of over 6,700 HIV-positive individuals in the ATHENA study. They identified an additional 92 individuals with the VB variant, all from Netherlands, bringing the total number of people infected with the VB subtype to 109.
The team’s analyses of the data indicated that individuals with the VB variant had a viral load of between 3.5 times and 5.5 times higher than individuals with a non-VB variant. “When replicating the BEEHIVE test with the ATHENA data, we again observed a large rise in viral load in individuals with this viral variant …” In addition, the rate of CD4 cell decline, which represents a hallmark of immune system damage by HIV, occurred twice as fast in individuals with the VB variant, placing them at risk of developing AIDS much more rapidly. Individuals with the VB variant also showed an increased risk of transmitting the virus to others.
Reassuringly, after starting treatment, individuals with the VB variant did show similar immune system recovery and survival to those with other HIV variants. However, the team estimated that, without treatment, males diagnosed with the VB variant at the age of 30-39 years would progress to advanced HIV—CD4 cell counts below 350 cells per cubic millimetre with long-term clinical consequences—within only 9 months from the time of diagnosis, compared with 36 months for individuals diagnosed with non-VB variants. “Advanced HIV is reached even more quickly in older age groups, and there is considerable variation between individuals around these expected values,” the scientists noted. “Many individuals could therefore progress to advanced HIV by the time they are diagnosed, with a poorer prognosis expected thereafter in spite of treatment.”
And, in practice, there is still considerable variation in the delay between initial infection, to the start of therapy, which makes the VB variant a particular concern “ … even in the high-awareness and highly monitored context of the Dutch HIV-1 epidemic,” the investigators stated. “In contexts with less awareness and monitoring, in which diagnosis often occurs later in infection, the probability of reaching advanced HIV before diagnosis would be even greater.”
The VB variant is characterized by many mutations spread throughout the genome, meaning that a single genetic cause cannot be identified at this stage. By analysing the patterns of genetic variation among the samples, the researchers estimate that the VB variant first arose during the late 1980s and 1990s in the Netherlands. “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.” It spread more quickly than other HIV variants during the 2000s, but its spread has been declining since around 2010.
The research team believes that the VB variant arose in spite of widespread treatment in the Netherlands, not because of it, since effective treatment can suppress transmission. The individuals identified with the VB variant showed typical characteristics for people living with HIV in the Netherlands, including age, sex, and suspected mode of transmission. This indicates that the increased transmissibility of the VB variant is due to a property of the virus itself, rather than a characteristic of people with the virus. “The increased virulence is a property of the virus rather than a confounding property of individuals in this transmission cluster,” the team stated.
Further research to understand the mechanism that causes increased transmissibility of the VB variant and faster damage to the immune system could reveal new targets for next-generation antiretroviral drugs. Senior study author Christophe Fraser, PhD, from the University of Oxford’s Big Data Institute and Nuffield Department of Medicine, commented, “Our findings emphasise the importance of World Health Organization guidance that individuals at risk of acquiring HIV have access to regular testing to allow early diagnosis, followed by immediate treatment. This limits the amount of time HIV can damage an individual’s immune system and jeopardise their health. It also ensures that HIV is suppressed as quickly as possible, which prevents transmission to other individuals.”
