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HIV Sequencing Study in Netherlands Uncovers Virulent Variant Mutations, History

NEW YORK – An international team led by investigators at the University of Oxford characterized the clinical and genetic features found in a particularly virulent version of HIV-1 that appears to have been present in the Netherlands for roughly three decades.

"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," senior and co-corresponding author Christophe Fraser, a researcher affiliated with the University of Oxford Big Data Institute and the Wellcome Centre for Human Genetics, and his colleagues wrote in a paper published in Science on Thursday.

Researchers involved in a "Bridging the Epidemiology and Evolution of HIV in Europe," or BEEHIVE, project initially identified 17 individuals infected with the particularly infectious HIV-1 variant, which falls into the HIV B subtype and was dubbed the "virulent subtype B," or VB, variant. In addition to sequencing isolates from those cases, they assessed data for more than 6,700 individuals enrolled in one of the research cohorts encompassed by BEEHIVE, uncovering 109 individuals infected with the VB variant.

The team noted that the VB variant-infected participants showed enhanced viral loads prior to treatment — at least three-and-a-half times higher than those described for other strains — along with dramatic drops in their CD4-positive T immune cell repertoires compared to individuals infected with other HIV strains in the B subtype.

While the available clinical data suggested that survival and CD4 T-cell recovery patterns were similar for the VB variant-infected individuals and individuals with other subtype B strains, the researchers cautioned that the rapid immune system impairments identified highlight the importance of identifying and treating the infections.

"Our findings emphasize 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," Fraser said in a statement. "This limits the amount of time HIV can damage an individual's immune system and jeopardize their health. It also ensures that HIV is suppressed as quickly as possible, which prevents transmission to other individuals."

To explore the roots of this virulence, the investigators generated 17 whole-genome sequences based on isolates from infected individuals in the Netherlands, Switzerland, and Belgium. Together with available HIV sequences in public databases, the sequence set pointed to more than 500 nucleotide changes and shifts affecting an estimated 250 amino acids in the VB variant.

Based on whole-genome sequence data for the 15 VB variant cases originating in the Netherlands, along with 100 other HIV B subtype sequences reported in the past and partial gene sequences for additional VB variant isolates, the team explored phylogenetic relationships between VB and other HIV subtype B strains. It also traced the most recent common ancestor of the new variant back to at least the early 1990s, and tracked down samples of a VB variant-infected case going back to 1992.

"Phylogenetic analysis suggested that this individual was infected with a virus that had evolved most of the way, but not entirely, toward VB-variant viruses typical of later dates," the authors noted. "This individual was diagnosed in Amsterdam, consistent with the aforementioned ancestral reconstruction of region."

In a related perspectives article, the University of California at San Diego's Joel Wertheim noted that an improved understanding of viral evolution will likely inform research into HIV and other viruses, including SARS-CoV-2, pointing to their potential to become more virulent under some selection conditions.

Even so, Wertheim cautioned that "[o]bserving the emergence of more virulent and transmissible HIV is not a public health crisis."

"Standard public health action — including molecular HIV surveillance, facilitating linkage to care, and partner notification — are still the best options when faced with a rapidly growing cluster of more virulent HIV," he explained.

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