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The coexistence of these infections leads to immunological interactions, potentially enhancing oncogenesis by upregulating immune checkpoint molecules (ICs) among other effects. Notably, most ICs are overexpressed in cancer and correlated with its progression. Helminth infections trigger Th2-type immunity, increasing immunosuppressive M2 macrophages, regulatory T cells, and associated IC molecules. PD-L2 is reported to contribute to Th2-type immunity induced by helminth infections. Similarly, TIM-3, elevated during chronic viral infections, induces a similar immunosuppressive profile. CTLA-4 and PD-1 impact T-cell function by interacting with CD28, crucial for T-cell function. CD28 is downregulated in chronic infections and cancer. This study investigated the impact of HIV-helminth co-infection on co-stimulatory and co-inhibitory molecule profiles associated with antitumor immunity. Using 78 serum samples collected from March 2020 to May 2021, participants were categorized into uninfected control (no HIV and helminth infections), HIV-infected, helminth-infected, and HIV-helminth co-infected groups. Multiplex immune regulatory molecule assay analysis was conducted. The data were analyzed using multivariate regression analysis and adjusted for confounders (age, gender, BMI, ART, supplements, and other chronic diseases). The uninfected control group was used as the baseline reference group for analysis. HIV-infected individuals had higher PD-1 (adjusted \u03b2 = 0.12, p = 0.034) and TIM-3 (adjusted \u03b2 = 23.15, p = 0.052) levels, with the latter showing a trend toward significance. However, lower CD28 levels (adjusted \u03b2 = \u2212651.95, p = 0.010) were observed. Helminth-infected individuals had higher TIM-3 levels (adjusted \u03b2 = 20.98, p = 0.020). The co-infected group had higher PD-1 (unadjusted \u03b2 = 0.18, p = 0.0046) and PD-L2 (adjusted \u03b2 = 7.95, p = 0.033) levels. A significant decrease in CD28 profile was observed across all infected groups: HIV-infected (adjusted \u03b2 = \u2212651.95, p = 0.010), helminth-infected (adjusted \u03b2 = \u2212674.32, p = 0.001), and co-infected (adjusted \u03b2 = \u2212671.55, p = 0.044). The results suggest that HIV-helminth co-infections alter immune checkpoint markers, potentially increasing cancer risk by promoting an immunosuppressive microenvironment that hinders anti-cancer immunity. CD28\u2019s downregulation underscores immune inefficiency in chronic diseases. Addressing these co-infections is crucial for improving HIV care and potentially reducing cancer risks through targeted strategies.<\/jats:p>","DOI":"10.3390\/v17030451","type":"journal-article","created":{"date-parts":[[2025,3,20]],"date-time":"2025-03-20T12:23:11Z","timestamp":1742473391000},"page":"451","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["HIV-Helminth Co-Infections and Immune Checkpoints: Implications for Cancer Risk in South Africa"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3060-5572","authenticated-orcid":false,"given":"Botle Precious","family":"Damane","sequence":"first","affiliation":[{"name":"Department of Surgery, Steve Biko Academic Hospital, University of Pretoria, Hatfield 0028, South Africa"},{"name":"Department of Medical Microbiology, College of Health Sciences, School of Laboratory Medicine & Medical Sciences, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban 4041, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4071-3905","authenticated-orcid":false,"given":"Thanyani Victor","family":"Mulaudzi","sequence":"additional","affiliation":[{"name":"Department of Surgery, Steve Biko Academic Hospital, University of Pretoria, Hatfield 0028, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6216-5703","authenticated-orcid":false,"given":"Sayed Shakeel","family":"Kader","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of KwaZulu Natal, Durban 4001, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8905-5926","authenticated-orcid":false,"given":"Pragalathan","family":"Naidoo","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology, College of Health Sciences, School of Laboratory Medicine & Medical Sciences, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban 4041, South Africa"},{"name":"Division of Research Capacity Development, South African Medical Research Council (SAMRC), Tygerberg, Cape Town 7505, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8012-3646","authenticated-orcid":false,"given":"Zodwa","family":"Dlamini","sequence":"additional","affiliation":[{"name":"SAMRC Precision Oncology Research Unit (PORU), DSTI\/NRF SARChI Chair in Precision Oncology and Cancer Prevention (POCP), Pan Africa Cancer Research Institute (PACRI), University of Pretoria, Hatfield 0028, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0373-9973","authenticated-orcid":false,"given":"Zilungile Lynette","family":"Mkhize-Kwitshana","sequence":"additional","affiliation":[{"name":"Division of Research Capacity Development, South African Medical Research Council (SAMRC), Tygerberg, Cape Town 7505, South Africa"},{"name":"Biomedical Sciences Department; School of Life and Consumer Sciences, College of Agriculture and Environmental Sciences, University of South Africa, Florida Campus, Johannesburg 1710, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1758835921992987","DOI":"10.1177\/1758835921992987","article-title":"Elevated risk of colorectal, liver, and pancreatic cancers among HCV, HBV and\/or HIV (co)infected individuals in a population based cohort in Canada","volume":"13","author":"Darvishian","year":"2021","journal-title":"Ther. 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