HIV-Helminth Co-Infections and Immune Checkpoints: Implications for Cancer Risk in South Africa

South Africa has the highest HIV prevalence globally, often co-occurring with helminth infections in impoverished regions. 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 β = 0.12, <i>p</i> = 0.034) and TIM-3 (adjusted β = 23.15, <i>p</i> = 0.052) levels, with the latter showing a trend toward significance. However, lower CD28 levels (adjusted β = -651.95, <i>p</i> = 0.010) were observed. Helminth-infected individuals had higher TIM-3 levels (adjusted β = 20.98, <i>p</i> = 0.020). The co-infected group had higher PD-1 (unadjusted β = 0.18, <i>p</i> = 0.0046) and PD-L2 (adjusted β = 7.95, <i>p</i> = 0.033) levels. A significant decrease in CD28 profile was observed across all infected groups: HIV-infected (adjusted β = -651.95, <i>p</i> = 0.010), helminth-infected (adjusted β = -674.32, <i>p</i> = 0.001), and co-infected (adjusted β = -671.55, <i>p</i> = 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's 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.