The new variant replicates faster causing high viral loads, attacks and depletes the CD4 cells more aggressively and rapidly, and was found to be more transmissible.
The study findings on the discovery of the new HIV variant were published in the peer reviewed journal: Science. https://www.science.org/doi/10.1126/science.abk1688
Evolving virulence in HIV
Changes in viral load and CD4+ T cell decline are expected signals of HIV evolution. By examining data from well-characterized European cohorts, Wymant et al. report an exceptionally virulent subtype of HIV that has been circulating in the Netherlands for several years (see the Perspective by Wertheim).
By the time they were diagnosed, these individuals were vulnerable to developing AIDS within 2 to 3 years. This virus lineage, which has apparently arisen de novo since around the millennium, shows extensive change across the genome affecting almost 300 amino acids, which makes it hard to discern the mechanism for elevated virulence.
Discovery of the highly virulent variant
BEEHIVE is a study of individuals enrolled in eight cohorts across Europe and Uganda, who were selected because they have well-characterized dates of infection and samples available from early infection, for whom whole viral genomes were sequenced.
The 17 individuals with the distinct viral variant comprised 15 participants in the ATHENA study in the Netherlands, 1 from Switzerland, and 1 from Belgium. See materials and methods for details on the initial discovery.
| Test | Discovery [BEEHIVE dataset (Europe)] | Replication [ATHENA dataset (Netherlands), excluding overlap with BEEHIVE] |
|---|---|---|
| Viral load measurements compared | Set-point viral loads for N = 15 VB individuals and N = 2446 individuals with any other HIV-1 strain | Mean pretreatment viral loads for N = 91 VB individuals and N = 5272 individuals with any other subtype-B HIV-1 strain |
| Mean and IQR of viral load in non-VB individuals, in log10 copies per milliliter | 5.10 (IQR: 4.69 to 5.58) | 4.79 (IQR: 4.34 to 5.27) |
| Mean and IQR of viral load in VB individuals, in log10 copies per milliliter | 5.84 (IQR: 5.57 to 6.09) | 5.33 (IQR: 4.94 to 5.75) |
| Viral load increase in VB individuals | 0.74 log10 viral copies/ml | 0.54 log10 viral copies/ml |
| P value for increase | 5 × 10−6 (two-tailed t test, significant at a level of 5 × 10−5 when Bonferroni-corrected for performing 50 such tests) | 1 × 10−12 (one-tailed t test) |
TABLE 1. Comparison of viral loads between individuals infected with the VB viral variant and other individuals.When analyzing the viral loads of individuals in the ATHENA study, we first excluded individuals who were in BEEHIVE, so that the test would be independent of the initial finding within the BEEHIVE study. After our statistical tests of viral load, we did not exclude BEEHIVE individuals from the ATHENA data for subsequent analyses. N, number of individuals after those without viral load measurements before treatment were excluded; IQR, interquartile range.
More-rapid CD4 cell decline
At the time of diagnosis, CD4 counts for VB individuals were already lower than for non-VB individuals by 73 cells/mm3 [95% confidence interval (CI): 12 to 134]. These counts subsequently declined faster, by a further 49 cells/mm3 per year (CI: 20 to 79), in addition to the decline for comparable non-VB individuals [49 cells/mm3 per year (CI: 46 to 51) for men diagnosed at the age of 30 to 39 years]. The VB variant is therefore associated with a doubling in the rate of CD4 cell decline.
These values are averages estimated by using a linear mixed model adjusted for sex and age at diagnosis. Figure 1B illustrates the CD4 count decline that would be expected if disease progression were to continue linearly in the absence of treatment. Initiating treatment at a CD4 count of 350 cells/mm3, instead of immediately, was previously shown to substantially increase the subsequent hazard for serious adverse events (25).
As seen in Fig. 1B, this stage of CD4 cell decline is expected to be reached in 9 months (CI: 2 to 17) from the time of diagnosis for VB individuals, as opposed to 36 months (CI: 33 to 39) for non-VB individuals, in males diagnosed at the age of 30 to 39 years. It is reached even more quickly in older age groups, for which we found progressively lower CD4 counts at time of diagnosis (table S1).
At a CD4 count of 200 cells/mm3, there is a high risk of immediate AIDS-related complications; without treatment this stage of decline would be reached, on average, between 2 and 3 years after diagnosis for VB individuals and between 6 and 7 years after diagnosis for comparable non-VB individuals [the latter being similar to previous reports in Europe (26)].
The effect of the VB variant on CD4 cell decline remained after we adjusted for the effect of higher viral load. With this adjustment, VB individuals have a CD4 count at diagnosis as would be expected given their high viral loads, but their subsequent decline in CD4 counts is again twice as fast as for as comparable non-VB individuals with high viral loads—their rate of decline is accelerated by 44 cells/mm3 per year (CI: 16 to 72).
Comparison of this additional decline with that expected from a +1 increase in log10 viral load, 15 cells/mm3 per year (CI: 11 to 18), shows that the variant’s effect on CD4 count decline is equivalent to that expected from a +3.0 increase in log10 viral load. The same analysis of measurements of CD4 percentages (the percentage of all T cells that express CD4) showed that these also declined twice as fast for VB individuals, and again this doubling in speed of decline remained when we adjusted for the higher viral load of the variant (table S2 and fig. S1).
Characteristics of individuals infected with the VB variant
VB individuals were mostly (82%) men who have sex with men, similar to non-VB individuals (76%). Age at diagnosis was also similar for VB and non-VB individuals (fig. S4). Neither ethnicity nor host genotype data were available, but the place of birth was mostly recorded as Western Europe for both groups (71% for non-VB individuals, 86% for VB individuals).
VB individuals were present in all regions of the Netherlands, but with a different distribution relative to that of non-VB individuals (N = 102 versus 6604 individuals, P < 10−7, simulated Fisher’s exact test): VB individuals were more common in the south (25% of VB individuals versus 6% of non-VB individuals) and less common in Amsterdam (20% versus 51%), as shown in table S5. Table S6 lists the hospitals included in each region. The average time from infection to diagnosis, for men who have sex with men in this cohort diagnosed in the late 2000s, was previously estimated to be 3.6 years (CI: 3.3 to 4.0) (27).
