The typical course of HIV infection for a majority of untreated individuals is persistent viral replication and a gradual loss of CD4 + T cells. One of the consequences of ongoing HIV replication is increased immune activation, aff ecting all major cell populations of the immune system ( 1 -3 ). Within the B cell population, HIV infection has been associated with numerous perturbations ( 4 ), many of which have been attributed to changes in the distribution of B cell subpopulations found in the peripheral blood. These changes include increased frequencies of activated and terminally diff erentiated B cells expressing low levels of CD21 that have been associated with ongoing viral replication ( 5, 6 ), a decreased frequency of memory B cells that is not reversed by antiretroviral therapy ( 7 ), and an increased frequency of immature/transitional B cells that has been associated with CD4 + T cell lymphopenia ( 8, 9 ).The eff ects of immune activation in persistent viral infections have recently been shown to include virus-specifi c T cell exhaustion. After the original description in chronic lymphocyte choriomeningitis virus (LCMV) infection in mice ( 10 ), observations of virus-specifi c CD4 + and CD8 + T cell exhaustion have recently been extended to 12 ). Although PD-1 was the fi rst inhibitory receptor associated with virus-specifi c T cell exhaustion, recent fi ndings suggest that exhaustion may result