The human immunodeficiency virus type 1 (HIV-1), which can lead to acquired immune deficiency syndrome (AIDS), remains a leading cause of death and a health threat worldwide, with over 38.4 million people currently living with the virus. Global health sector strategies strive to end HIV-1 epidemics by 2030 (Duncombe et al., 2019). This requires significant investment in resources to treat and prevent the disease, such as reducing the number of people who do not know they are carrying the virus and improving the availability and affordability of effective treatments.
In cities that have scaled up HIV-1 treatment and prevention, it will be crucial to establish whether new HIV-1 infections are due to ongoing local transmission or to infections acquired abroad. This means reconstructing the spread of HIV-1 between individuals through contact tracing: interviewing people recently diagnosed with HIV, and locating and notifying their intimate partners. However, contact tracing is both time-consuming and intrusive (El-Sadr et al., 2022).
A cost-effective alternative to contact tracing is to compare the genomic sequences of HIV-1 samples from different patients, which are often collected to screen for mutations that confer drug resistance. Infections that are genetically similar are more likely to be related through recent transmissions. This is especially true for HIV-1, a rapidly evolving virus that becomes genetically unique within months of an infection (Williamson, 2003).
These genetic sequences can be used to build a tree that represents the shared evolutionary history of the infections and approximates the history of recent transmissions (De Maio et al., 2018; Romero-Severson et al., 2014). Furthermore, the spread of infections from one place to another can be extrapolated by reconstructing locations of ‘ancestral’ infections at deeper nodes of the tree from the known locations at the tips (Faria et al., 2011). The accuracy of these estimates, however, is impeded by the unknown number of people with undiagnosed infections, or with diagnosed infections that have not been sequenced (Didelot et al., 2017). In addition, reconstructing transmission patterns from HIV-1 sequences comes with its own ethical challenges because HIV-1 transmission is criminalized in many countries (Dawson et al., 2020).
Now, in eLife, Oliver Ratmann at the HIV Transmission Elimination Amsterdam Consortium and colleagues – including Alexandra Blenkinsop as first author – report an innovative approach to overcome the disadvantages of sequence analysis (Blenkinsop et al., 2022). Blenkinsop et al. combined different data sources to reconstruct the transmission histories of HIV-1 in Amsterdam, which has the highest concentration of HIV-1 cases in the Netherlands. Amsterdam is also part of the Fast-Track city network, which provides funds to expand effective HIV prevention, testing and treatment services.
Blenkinsop et al. extended the standard approach of reconstructing transmission histories from HIV-1 sequences by incorporating additional information from clinical biomarkers (biological indicators of disease progression or response to treatment) and other patient data (Figure 1). A statistical model was fitted to two biomarkers: the number of HIV-1 particles circulating in the blood (the viral load) and the number of white blood cells targeted by HIV-1. Based on how these biomarkers changed over time, it was possible to estimate the length of time between a person’s HIV-1 infection and diagnosis. These estimates were then used to infer how many cases were transmitted from people with unsequenced infections, adjusting for factors like route of transmission (e.g., injection drug use), age group, and place of birth.
Despite extensive measures to curb the transmission of HIV in Amsterdam, results from Blenkinsop et al. suggest that many HIV-1 infections have remained undiagnosed for a long time, especially among heterosexual residents and recent arrivals from sub-Saharan Africa. Further, they provide evidence of ongoing HIV-1 transmission within the city over the duration of the five-year study. These results suggest that, while Amsterdam has made significant progress in reducing the spread of HIV-1, closing the final gap to end the local epidemic by 2030 remains a challenge.
The study also highlights the importance of linking HIV-1 sequences to both clinical and demographic information to determine which groups have been neglected by the generalized scale-up of public health testing and treatment. This may also be a critical step for other cities in the FastTrack initiative. Furthermore, the work of Blenkinsop et al. mirrors ongoing challenges in tracking and controlling other infectious diseases like COVID-19, which is characterised by an abundance of viral genome sequences but a lack of linked contextual information, including clinical outcomes, travel histories and sampling strategies (Chiara et al., 2021; Chen et al., 2022).
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The association between cardiovascular disease (CVD) and selected psychiatric disorders has frequently been suggested while the potential role of familial factors and comorbidities in such association has rarely been investigated.
We identified 869,056 patients newly diagnosed with CVD from 1987 to 2016 in Sweden with no history of psychiatric disorders, and 910,178 full siblings of these patients as well as 10 individually age- and sex-matched unrelated population controls (N = 8,690,560). Adjusting for multiple comorbid conditions, we used flexible parametric models and Cox models to estimate the association of CVD with risk of all subsequent psychiatric disorders, comparing rates of first incident psychiatric disorder among CVD patients with rates among unaffected full siblings and population controls.
The median age at diagnosis was 60 years for patients with CVD and 59.2% were male. During up to 30 years of follow-up, the crude incidence rates of psychiatric disorder were 7.1, 4.6, and 4.0 per 1000 person-years for patients with CVD, their siblings and population controls. In the sibling comparison, we observed an increased risk of psychiatric disorder during the first year after CVD diagnosis (hazard ratio [HR], 2.74; 95% confidence interval [CI], 2.62–2.87) and thereafter (1.45; 95% CI, 1.42–1.48). Increased risks were observed for all types of psychiatric disorders and among all diagnoses of CVD. We observed similar associations in the population comparison. CVD patients who developed a comorbid psychiatric disorder during the first year after diagnosis were at elevated risk of subsequent CVD death compared to patients without such comorbidity (HR, 1.55; 95% CI, 1.44–1.67).
Patients diagnosed with CVD are at an elevated risk for subsequent psychiatric disorders independent of shared familial factors and comorbid conditions. Comorbid psychiatric disorders in patients with CVD are associated with higher risk of cardiovascular mortality suggesting that surveillance and treatment of psychiatric comorbidities should be considered as an integral part of clinical management of newly diagnosed CVD patients.
This work was supported by the EU Horizon 2020 Research and Innovation Action Grant (CoMorMent, grant no. 847776 to UV, PFS, and FF), Grant of Excellence, Icelandic Research Fund (grant no. 163362-051 to UV), ERC Consolidator Grant (StressGene, grant no. 726413 to UV), Swedish Research Council (grant no. D0886501 to PFS), and US NIMH R01 MH123724 (to PFS).
Background: Over a life-course, human adaptive immunity to antigenically mutable pathogens exhibits competitive and facilitative interactions. We hypothesize that such interactions may lead to cyclic dynamics in immune responses over a lifetime.
Methods: To investigate the cyclic behavior, we analyzed hemagglutination inhibition titers against 21 historical influenza A(H3N2) strains spanning 47 years from a cohort in Guangzhou, China and applied Fourier spectrum analysis. To investigate possible biological mechanisms, we simulated individual antibody profiles encompassing known feedbacks and interactions due to generally recognized immunological mechanisms.
Results: We demonstrated a long-term periodicity (about 24 years) in individual antibody responses. The reported cycles were robust to analytic and sampling approaches. Simulations suggested that individual-level cross-reaction between antigenically similar strains likely explain the reported cycle. We showed that the reported cycles are predictable at both individual and birth-cohort level and that cohorts show a diversity of phases of these cycles. Phase of cycle was associated with the risk of seroconversion to circulating strains, after accounting for age and pre-existing titers of the circulating strains.
Conclusions: Our findings reveal the existence of long-term periodicities in individual antibody responses to A(H3N2). We hypothesize that these cycles are driven by pre-existing antibody responses blunting responses to antigenically similar pathogens (by preventing infection and/or robust antibody responses upon infection), leading to reductions in antigen specific responses over time until individual's increasing risk leads to an infection with an antigenically distant enough virus to generate a robust immune response. These findings could help disentangle cohort-effects from individual-level exposure histories, improve our understanding of observed heterogeneous antibody responses to immunizations, and inform targeted vaccine strategy.
Funding: This study was supported by grants from the NIH R56AG048075 (D.A.T.C., J.L.), NIH R01AI114703 (D.A.T.C., B.Y.), the Wellcome Trust 200861/Z/16/Z (S.R.) and 200187/Z/15/Z (S.R.). This work was also supported by research grants from Guangdong Government HZQB-KCZYZ-2021014 and 2019B121205009 (Y.G. and H.Z.). D.A.T.C., J.M.R. and S.R. acknowledge support from the National Institutes of Health Fogarty Institute (R01TW0008246). J.M.R. acknowledges support from the Medical Research Council (MR/S004793/1) and the Engineering and Physical Sciences Research Council (EP/N014499/1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.