Inflammatory Fingerprints Diverge Across the HIV Risk, Infection and Treatment Journey in Young People

Adolescents and young adults living with HIV, or at elevated risk of acquiring it, carry measurable signatures of immune disruption in their blood, and those signatures change in characteristic ways as individuals move from risk to infection to long-term treatment. That is the central finding of a new study published in Nature Communications, in which researchers performed detailed plasma proteomic profiling of young people spanning the entire HIV spectrum. By measuring 49 circulating inflammatory biomarkers in 262 participants with a mean age of 21.9 years, the team uncovered distinct immune landscapes associated with each stage of HIV exposure, infection and antiretroviral therapy, offering a molecular map that could guide tailored prevention and therapeutic strategies for a population that remains disproportionately affected by the epidemic.

The study design divided participants into four clinically defined groups. Healthy controls served as the immunological baseline. A second group comprised high-risk youth without HIV, referred to in the study as HRY, young people whose behaviors or circumstances place them at elevated risk of acquisition but who remain uninfected. The third group consisted of newly diagnosed youth living with HIV, sampled at the time of diagnosis before or shortly after initiating treatment. The fourth group included previously diagnosed young people who had been on antiretroviral therapy, or ART, for more than 24 months. This cross-sectional architecture allowed the investigators to compare circulating protein profiles across the natural history of the disease and its treatment, rather than studying a single snapshot in isolation.

Technically, the team relied on Luminex multiplex assays, a bead-based platform that permits simultaneous quantification of dozens of proteins from small plasma volumes. The 49 biomarkers spanned key inflammatory axes: interferon-driven chemokines and cytokines, pro-inflammatory interleukins, tumor necrosis factor family members, growth factors and markers of immune activation and regulation. Multiplex profiling of this kind generates high-dimensional datasets, and the researchers applied statistical and bioinformatic approaches to identify which proteins were dysregulated in each group, which alterations were shared across groups, and which transcriptional regulators could plausibly explain the observed circulating patterns. The result is not merely a list of altered proteins but an integrated view of the inflammatory circuitry operating at each stage.

One of the most striking findings concerned the high-risk youth without HIV. Contrary to the expectation that uninfected individuals would display essentially normal inflammatory profiles, the HRY group exhibited dysregulation of circulating interferon-driven inflammation. Interferons are signaling proteins released in response to viral threat, and their pathways orchestrate the expression of chemokines such as those monitored in this study. Persistent or inappropriate activation of interferon signaling in the absence of detectable infection suggests that young people at high HIV risk may already carry a primed or perturbed immune state. The authors identify this as a distinct immune landscape specific to the risk stage, and it raises the possibility that the inflammatory milieu preceding infection could influence susceptibility or early disease course.

Among newly diagnosed youth, the picture was one of overt systemic inflammation. At the time of diagnosis, these young people displayed pronounced elevations across inflammatory markers, consistent with the active viral replication and widespread immune activation that characterize untreated HIV infection. The proteomic signature of this group was the most dramatically altered of any in the study, reflecting the acute immunological battle underway. Importantly, the researchers found that this systemic inflammation partially resolves after the initiation of antiretroviral therapy but does not fully normalize within 24 months of treatment. In other words, even young people who achieve viral suppression on modern regimens continue to circulate inflammatory proteins at levels that differ from healthy controls, a phenomenon long recognized in adult HIV cohorts and now documented in detail in adolescents and young adults.

The group with the longest treatment exposure, previously diagnosed youth on ART for more than 24 months, showed largely normalized immune profiles. This is an encouraging result, indicating that sustained viral suppression in young people can restore much of the circulating proteome toward baseline. However, normalization was not complete. The treated group retained circulating signatures consistent with residual immune checkpoint activation, a state in which inhibitory pathways that normally restrain immune responses remain engaged. Immune checkpoint molecules regulate the balance between immune activation and tolerance, and their persistent elevation suggests a subtle but measurable imprint of past infection that survives two years of effective therapy. Whether this residual checkpoint signature has functional consequences for long-term health remains an open question, but its detection provides a concrete molecular target for future investigation.

Beyond the group-level comparisons, the study identified both conserved and stage-specific circulating inflammatory modulators. Conserved modulators are proteins whose dysregulation appears across multiple stages of the HIV spectrum, potentially representing core features of the host response to the virus or to the risk environment. Stage-specific modulators, by contrast, distinguish one phase from another: the interferon-driven dysregulation of high-risk youth, the systemic inflammatory surge at diagnosis, the partial resolution under early treatment and the checkpoint activation signature of long-term treated individuals. The researchers also pinpointed key transcriptional regulators, upstream molecular switches inferred from the protein data, that plausibly govern these circulating patterns. Together, these elements delineate the molecular choreography of HIV susceptibility, progression and long-term treatment response in a young population.

The clinical implications are significant. Adolescents and young adults represent a critical demographic in the global HIV epidemic, with acquisition rates that remain unacceptably high in many regions, and their immune systems differ from those of adults in ways that could alter both disease trajectory and treatment response. Demonstrating that high-risk uninfected youth already show interferon pathway dysregulation suggests that prevention strategies might one day incorporate inflammatory biomarkers to identify individuals whose immune state warrants closer monitoring. The finding that inflammation persists incompletely resolved during the first two years of therapy supports the rationale for studies of adjunctive anti-inflammatory interventions in youth, and the residual checkpoint activation signature in long-term treated patients may inform research into immune restoration strategies aimed at full normalization.

Methodologically, the study demonstrates the value of applying high-throughput proteomics to pediatric and adolescent HIV research, a field historically constrained by small sample sizes and limited biospecimen availability. The enrollment of 262 participants through the Adolescent Trials Network, with support from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and supplemental funding from the National Institute of Mental Health and the National Institute on Drug Abuse, provided the statistical power needed to resolve group differences across the spectrum. The collaboration spanned institutions including the University of California, Los Angeles, the A*STAR Infectious Diseases Labs in Singapore and Cleveland Clinic, combining clinical expertise in pediatric infectious diseases with computational immunology.

The authors caution that the study is cross-sectional, capturing different individuals at each stage rather than following the same people over time, and that the published version was shared early to accelerate access to peer-reviewed findings. Even so, the work delivers a clear message: the immune perturbations associated with HIV in young people are not a single phenomenon but a sequence of distinct molecular states, each with its own biomarker fingerprint. Mapping that sequence, from the interferon dysregulation seen before infection to the checkpoint activation that lingers after years of successful treatment, provides researchers and clinicians with a framework for developing precisely tailored prevention and enhanced therapeutic strategies for the generation most likely to benefit from them.

Subject of Research: Inflammatory biomarker profiles across the HIV risk, infection and treatment spectrum in adolescents and young adults

Article Title: Distinct inflammatory marker profiles of adolescents and young adults among the HIV risk, infection, and treatment spectrum

Article References: Distinct inflammatory marker profiles of adolescents and young adults among the HIV risk, infection, and treatment spectrum. (n.d.). https://doi.org/10.1038/s41467-026-78034-6

Image Credits: AI Generated

DOI: 10.1038/s41467-026-78034-6

Keywords: HIV, adolescents, inflammation, biomarkers, proteomics, antiretroviral therapy, interferon, immune activation, immune checkpoints, Luminex assay, plasma cytokines, Nature Communications