Genetic and Immunologic Heterogeneity among Persons Who Control HIV Infection in the Absence of Therapy

Background. Spontaneous control of human immunodeficiency virus (HIV) infection has been documented in a minority of HIV-infected individuals. The mechanisms behind this outcome remain largely unknown, and a better understanding of them will likely influence future vaccine strategies. Methods. HIV-specific T cell and antibody responses as well as host genetics were examined in untreated HIVinfected patients who maintain comparatively low plasma HIV RNA levels (hereafter, controllers), including those with levels of 50 RNA copies/mL (elite controllers, n 64), those with levels of 50‐2000 copies/mL (viremic controllers,n 60);wealsoexaminedHIV-specificTcellandantibodyresponsesaswellashostgeneticsforpatients with levels of 10,000 copies/mL (chronic progressors, n 30). Results. CD8TcellsfrombothcontrollergroupspreferentiallytargetGagoverotherproteinsinthecontextof diverseHLAclassIalleles,whereasresponsesaremorebroadlydistributedinpersonswithprogressiveinfection.Elite controllers represent a distinct group of individuals who have significantly more CD4 and CD8 T cells that secrete interferon- and interleukin-2 and lower levels of HIV-neutralizing antibodies. Individual responses were quite heterogeneous, and none of the parameters evaluated was uniquely associated with the ability to control viremia. Conclusions. Elite controllers are a distinct group, even when compared to persons with low level viremia, but they exhibit marked genetic and immunologic heterogeneity. Even low-level viremia among HIV controllers was associated with measurable T cell dysfunction, which has implications for current prophylactic vaccine strategies.