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 log 10 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 millimeter, 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.

Many bacteria and other organisms carry out fermentations forming acetate. These fermentations have broad importance to foods, agriculture, and industry. They also are important to bacteria themselves because they often generate ATP. Here we found a biochemical pathway for forming acetate and synthesizing ATP that was unknown in fermentative bacteria. We found the bacterium Cutibacterium granulosum formed acetate during fermentation of glucose. It did not use phosphotransacetylase or acetate kinase, enzymes found in nearly all acetate-forming bacteria. Instead, it used a pathway involving two different enzymes. The first enzyme, succinyl-CoA:acetate CoA-transferase (SCACT), forms acetate from acetyl-CoA. The second enzyme, succinyl-CoA synthetase (SCS), synthesizes ATP. We identified the genes encoding these enzymes, and they were homologs of SCACT and SCS genes found in other bacteria. The pathway resembles one described in eukaryotes, but it uses bacterial, not eukaryotic, gene homologs. To find other instances of the pathway, we analyzed sequences of all biochemically-characterized homologs of SCACT and SCS (103 enzymes from 64 publications). Homologs with similar enzymatic activity had similar sequences, enabling a large-scale search for them in genomes. We searched nearly 600 genomes of bacteria known to form acetate, and we found 6% encoded homologs with SCACT and SCS activity. This included >30 species belonging to 5 different phyla, showing a diverse range of bacteria encode the SCACT/SCS pathway. This work suggests the SCACT/SCS pathway is important to forming acetate in many branches of the tree of life. Importance Pathways for forming acetate during fermentation have been studied for over 80 years. In that time, several pathways have been described in a range of organisms, from bacteria to animals. However, one pathway (involving succinyl-CoA:acetate CoA-transferase and succinyl-CoA synthetase) has not been reported in prokaryotes. Here we discovered enzymes for this pathway in the fermentative bacterium Cutibacterium granulosum. We also found >30 other fermentative bacteria that encode this pathway, demonstrating it could be common. This pathway represents a new way for bacteria to form acetate from acetyl-CoA and synthesize ATP via substrate-level phosphorylation. It could be a target for controlling yield of acetate during fermentation, with relevance to foods, agriculture, and industry.

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Many bacteria and other organisms form acetate during fermentation. Forming acetate from high energy-precursors (acetyl-CoA or acetyl phosphate) is one of the few ways that fermentative bacteria generate ATP. Here we found a biochemical pathway for forming acetate and synthesizing ATP that was unknown in bacteria. We found the bacterium Cutibacterium granulosum formed acetate during fermentation of glucose. With enzymatic assays, we showed it formed acetate using a pathway involving two enzymes. The first enzyme, succinyl-CoA:acetate CoA-transferase (SCACT), forms acetate from acetyl-CoA. The second enzyme, succinyl-CoA synthetase (SCS), synthesizes ATP. This pathway is common in eukaryotes, but it has not been found in bacteria or other organisms. We found two related bacteria (C. acnes and Acidipropionibacterium acidipropionici) also used this pathway. None used the most common pathway for forming acetate in bacteria (involving acetate kinase and phosphotransacetylase). The SCACT/SCS pathway may be used by many bacteria, not just C. granulosum and relatives. When we searched genomes for bacteria known to form acetate, we found over 1/6 encoded this pathway. These bacteria belong to 104 different species and subspecies in 12 different phyla. With this discovery, all five pathways known to form acetate and ATP during fermentation can be found in bacteria. This discovery is important to manipulating fermentation and to the evolution of biochemical pathways.

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