Anti-HIV Effect of Nivolumab: One Possible Mechanism is Via Reversing T-Cell Exhaustion An HIV patient treated with the anti-cancer drug nivolumab had in a major decrease in his HIV reservoirs (these viral reservoirs normally persist in spite of antiretroviral therapy). Article: Cancer drug leads to 'drastic decrease' in HIV infection in lung cancer patient Study: Drastic decrease of the HIV reservoir in a patient treated with nivolumab for lung cancer Nivolumab is a PD-1 inhibitor. PD-1 is also called CD279. See programmed death-1 protein. The function of PD-1 is to down-regulate the immune response, thereby promoting self-tolerance by suppressing T-cell inflammatory activity. So the activation of PD-1 helps prevent autoimmune diseases, but it can also prevent the immune system from destroying cancer cells, and clearing viral infection. Nivolumab blocks PD-1 activation, and thereby increases the immune response to cancers. Other PD-1 inhibitors include pembrolizumab. In the above study, the authors hypothesize that PD-1 inhibitors like nivolumab may target HIV in two ways: (1) by restoring immune function in exhausted T-cells that express the PD-1 receptor, and (2) by promoting HIV gene transcription in the reservoirs. For ME/CFS purposes, it is the reversal of T-cell exhaustion that might conceivably help clear the chronic enterovirus and herpesvirus infections associated with ME/CFS. This paper found evidence for CD8 T-cell exhaustion in ME/CFS patients. PD-1, T-Cell Exhaustion and the Antiviral Response This paper provides an overview of T-cell exhaustion: Persistent viral infections can result in the exhaustion of antiviral T-cells. Excessive and sustained levels of viral antigen drive T-cell exhaustion. Exhausted T-cells are distinct from typical effector and memory subsets. Exhausted T-cells are functionally ineffective and compromise viral clearance. Blocking inhibitory receptors and modifying cytokine levels can alleviate exhaustion. This paper says high antigen levels are the cause of T-cell exhaustion in chronic viral infection. This paper says that sustained expression of the PD-1 receptor on T-cells is a characteristic marker of T-cell exhaustion. Although recent data show that PD-1 is not required for initiating T-cell exhaustion, and that absence of PD-1 even promotes accumulation of exhausted CD8+ T cells in mice. This paper says that T-cell exhaustion due to persistent antigen stimulation is a key feature of chronic viral infections and cancer. PD-1 is a major regulator of T-cell exhaustion, and blocking the PD-1 pathway restores T-cell function and improves pathogen control and tumor eradication. Could Nivolumab be Effective for Chronic Enterovirus Infection in ME/CFS? ME/CFS is linked to chronic non-cytolytic enterovirus infections that reside inside cells. Could nivolumab help clear chronic enterovirus? This study on acute coxsackievirus B3 myocarditis found PD-1 expression was markedly increased in heart myocytes, and that blocking PD-1 increased the myocardial inflammation. The authors suggest that activating PD-1 or PD-L1 will be useful for suppressing myocardial inflammation and myocardial damage in acute infections. But in ME/CFS, the acute stage of the infection has passed, and we are likely dealing with chronic infections, and in the case of enterovirus-associated ME/CFS, chronic non-cytolytic infections. Could blocking PD-1 with nivolumab help clear these chronic enterovirus infections? In the case of Epstein-Barr virus and cytomegalovirus associated ME/CFS, this study found no difference in the expression of the T-cell exhaustion marker PD-1 on EBV- and CMV-specific T-cells between patients and controls. Side Effects of Nivolumab This paper says adverse effects of anti-PD-1 immunotherapy treatment like nivolumab include the precipitation of diabetes (one case of diabetes was reported in 206 subjects treated with nivolumab). Conceivably the risk might be highwe in patients with coxsackievirus B1 or coxsackievirus B4 infections, as these viruses are linked to type 1 diabetes (these viruses can infect the insulin-producing beta cells of the pancreas).