Background & AimsHIV-seropositivity shortens survival in patients with hepatocellular carcinoma (HCC). Although risk factors for HCC including HCV infection can influence T cell phenotype, it is unknown whether HIV can influence functional characteristics of the T cell infiltrate.MethodsFrom the Liver Cancer in HIV biorepository, we derived 129 samples of transplanted (76%) or resected (20%) HCC in eight European and North American centres. We profiled intra- and peritumoural tissue to evaluate regulatory CD4+/FOXP3+ and immune-exhausted CD8+/PD1+ T cells in HIV+ (n = 66) and HIV- (n = 63) samples. We performed targeted transcriptomics and T-cell receptor sequencing in a restricted subset of samples evaluated in relationship with HIV status. We correlated immunopathologic features with patients’ characteristics including markers of HIV infection.ResultsOf the 66 HIV+ patients, 83% were HCV coinfected with an undetectable HIV viral load (51%) and a median blood CD4+ cell count of 430 cells/mm3(range 15–908). Patients who were HIV+ were compared with HIV- controls with similar staging characteristics including Barcelona Clinic Liver Cancer (BCLC) stage A–B (86%vs.83%,p= 0.16), <3 nodules (90%vs.83%,p= 0.3) and median alpha-foetoprotein values (10.9vs.12.8 ng/ml,p= 0.72). HIV+ samples had higher PD-L1 expression rates in tumour tissue (51%vs.8%p<0.0001) and displayed denser intratumoural CD4+/FOXP3+ (p<0.0001), CD8+/PD1+ (p<0.0001), with lower total peritumoural CD4+ (p<0.0001) and higher peritumoural CD8+/PD1+ (p<0.0001). Gene set analysis revealed HIV+ cases to have evidence of dysregulated adaptive and innate immunity. Tumour-infiltrating lymphocyte clonality was not influenced by HIV status.ConclusionsHIV-associated HCC harbours a profoundly immune-exhausted tumour microenvironment, warranting prospective testing of immunotherapy in this treatment-deprived patient population.Impact and ImplicationsHepatocellular carcinoma is a non-AIDS defining malignancy characterised by poor survival. The programmed cell death (PD-1) pathway governs antiviral and anticancer immune exhaustion and is a therapeutic target in HCC. This study highlights how HIV infection is associated with significantly higher PD-L1 expression in HCC cells and in the surrounding microenvironment, leading to changes in cytotoxic and regulatory T cell function and dysregulation of proinflammatory pathways. Taken together, our results suggest dysfunctional T cell immunity as a mechanism of worse outcome in these patients and suggest clinical testing of checkpoint inhibitors in HIV-associated HCC.