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). More than one hundred individuals infected with a characteristic subtype B lineage of HIV-1 were found who experienced double the rate of CD4+ cell count declines than expected. 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. —CA
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 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.The risk posed by viruses evolving to greater virulence—i.e., causing greater damage to their hosts—has been extensively studied in theoretical work despite few population-level examples (1–3). The most notable recent example is the B.1.617.2 lineage (Delta variant) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), for which an increased probability of death has been reported (4–6), as well as increased transmissibility (7, 8). RNA viruses have long been a particular concern, as their error-prone replication results in the greatest known rate of mutation—and thus high potential for adaptation. Greater virulence could benefit a virus if it is not outweighed by reduced opportunity for transmission. These antagonistic selection pressures may result in an intermediate level of virulence being optimal for viral fitness, as observed for HIV (9). Concrete examples of such evolution in action, however, have been elusive. 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 (www.unaids.org).The main (M) group of HIV-1, responsible for the global pandemic, first emerged around 1920 in the area of what is now Kinshasa, Democratic Republic of the Congo (10), and had diversified into subtypes by 1960 (11). The subtypes, and the most common circulating recombinant forms (CRFs) between the subtypes, took different routes for global spread, establishing strong associations with geography (12), ethnicity, and mode of transmission. Differences in virulence between subtypes and CRFs have been reported, though it is challenging to disentangle genotypic effects on virulence from confounding effects while retaining large sample sizes, given the strong associations between viral, host, and epidemiological factors (13). The co-receptor used for cell entry has long been understood to affect virulence (14, 15), and this has been proposed as a mechanism that underlies differences in virulence between subtypes and CRFs (13), as well as one reported difference within a CRF (16).HIV-1 virulence is most commonly measured by viral loads (the concentration of viral particles in blood plasma) and CD4 counts (the concentration of CD4+ T cells in peripheral blood, which tracks immune system damage by the virus). Successful treatment with antiretroviral drugs suppresses viral load and interrupts the decline in CD4 counts that would otherwise lead to AIDS. Both viral load and rate of CD4 cell decline are heritable properties—that is, these properties are causally affected by viral genetics, leading to correlation between an individual and whomever they infect (17–21). It has therefore been expected that viral load and CD4 cell decline could change with the emergence of a new viral variant. We substantiate that expectation with empirical evidence by reporting a subtype-B variant of HIV-1 with exceptionally high virulence that has been circulating within the Netherlands during the past two decades.
Discovery of the highly virulent variant
Within an ongoing study (the BEEHIVE project; www.beehive.ox.ac.uk), we identified a group of 17 individuals with a distinct subtype-B viral variant, whose viral loads in the set-point window of infection (6 to 24 months after a positive test obtained early in the course of infection) were highly elevated (Table 1, middle column). 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.
Replication of the discovery in Dutch ATHENA data
To replicate the finding and to investigate this viral variant in more detail, we then analyzed data from 6706 participants in ATHENA with subtype-B infections (expanding on the subset of 521 participants in ATHENA who were eligible for inclusion in BEEHIVE). We found 92 additional individuals infected with the viral variant, bringing the total to 109 such individuals in either dataset. When replicating the BEEHIVE test with the ATHENA data (Table 1, right column), we again observed a large rise in viral load in individuals with this viral variant: an increase of 0.54 log10 viral copies/ml (i.e., a ~3.5-fold increase). The effect size was the same in a linear model including age at diagnosis and sex as covariates, and persisted in newly diagnosed individuals over time (Fig. 1A). Henceforth, for brevity, we refer to this viral variant as the “VB variant” (for virulent subtype B), to individuals infected with this variant as “VB individuals,” and to individuals infected with a different strain of HIV as “non-VB individuals.”…
