HIV-1 controllers possess a unique CD8+ T-cell activation phenotype and loss of control is associated with increased expression of exhaustion markers

Abstract

HIV-1 controllers are a rare population of individuals that exhibit spontaneous control of HIV-1 infection without antiretroviral therapy. These controllers can be categorized based on the level and mechanism of control. Understanding the mechanisms by which controllers maintain and eventually lose this ability would be highly valuable in HIV-1 cure or vaccine research. We explored whether CD8+ T cell exhaustion plays a role in the maintenance and loss of control by examining immune characteristics of HIV-1 controllers and controllers who lost control within the duration of the study. Previous work revealed the ability of CD8+ T-cells isolated from HIV-1 controllers to suppress HIV-1 replication in matched CD4+ T-cells ex vivo. Using flow cytometry, we analyzed exhaustion marker expression on CD8+ T-cells from these controllers and determined that they maintain a unique exhaustion profile as compared to HIV-negative individuals and standard progressors. The low level of T-cell exhaustion seen in controllers was reversed when these individuals lost control and showed increased viral loads. Immune checkpoint blockade targeting exhaustion markers was able to restore ex vivo control by CD8+ T-cells from former controllers. These results suggest that CD8+ T cell exhaustion compromises the ability to control viral replication in HIV-1 controllers. AUTHOR SUMMARYDespite the use of antiretroviral therapy, HIV continues to be a major public health issue that affects the lives of millions of people. Some infected people can control viral infection without therapy. The mechanism by which some people can control HIV infection at low, but detectable levels is unknown. In this study we examined the state of cytotoxic CD8+ T-cells in a group of HIV controllers and found that controllers maintain low levels of markers for a chronic state of activation called exhaustion. Loss of control correlated with increase in exhausted T-cells and for individuals who had recently lost control of infection we could restore protection in the cell culture dish by using immune checkpoint blockade drugs that affect exhaustion.