Abstract Background: Colorectal cancer (CRC) incidence is rising in sub-Saharan Africa, where immune-modulating infections such as HIV and helminths remain prevalent. These chronic infections may disrupt gut microbial ecosystems, including the virome, thereby contributing to cancer risk. However, virome alterations linked to HIV-helminth co-infection and their association with CRC-associated signatures remain poorly characterized in African populations. Methods: We conducted untargeted shotgun metagenomic sequencing of fecal DNA from 62 South African adults across five clinical groups: uninfected controls (n=10), HIV-only (n=14), helminth-only (n=15), HIV-helminth co-infected (n=13), and CRC-confirmed patients (n=10). Sequencing reads were quality filtered, taxonomically profiled, and functionally annotated using Prodigal and DIAMOND. Diversity indices and differential abundance were computed via SQMtools, DESeq2, and vegan in R. Results: Shannon diversity was significantly higher in CRC samples compared to uninfected and helminth-only groups (p0.05). Beta diversity analysis showed strong clustering between CRC and HIV-helminth groups (p2.2×10-16), indicating convergent gut virome restructuring. Among 26 shared viral species, nine were unique to HIV-helminth co-infection and eight to HIV-only. Notably, the HIV-helminth group displayed increased abundance of Myoviridae and Podoviridae, including cyanophages previously implicated in gut inflammation. This taxonomic shift is consistent with studies that showed significant virome alterations in CRC patients, including changes in Siphoviridae and Myoviridae. Functionally, adenine-specific DNA methylase (COG2189), involved in DNA replication and methylation, was significantly enriched in CRC (p=2.98e-06), helminth-only (p=1.30e-07), and HIV-helminth groups (p=6.11e-06), suggesting a shared microbial epigenetic signature potentially linked to CRC oncogenic processes. Conclusion: HIV-helminth co-infection is associated with a distinct virome that mirrors CRC in both diversity and functional gene enrichment. This overlap reinforces the notion that chronic infections shape the virome in ways that may promote tumorigenesis. Functional markers such as adenine-specific DNA methylase may serve as early indicators of CRC risk in co-infections. This study emphasizes the need to integrate virome ecology into cancer surveillance strategies in high-burden, underrepresented regions. Citation Format: Botle Precious. Damane, Thanyani Victor. Mulaudzi, Jonathan Featherston, Sayed Shakeel . Kader, Pragalathan Naidoo, Zodwa Dlamini, Zilungile Lynette. Mkhize-Kwitshana. Gut virome remodeling in HIV–helminth co-infection reflects colorectal cancer–associated signatures in a South African cohort abstract. In: Proceedings of the 18th AACR Conference on the Science of Cancer Health Disparities; 2025 Sep 18-21; Baltimore, MD. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2025;34(9 Suppl):Abstract nr C035.
Damane et al. (Thu,) studied this question.