title: CD4 T Follicular Helper and Regulatory Cell Dynamics and Function in HIV Infection.
abstract: T follicular helper cells (TFH) are a specialized subset of CD4 T cells that reside in B cell follicles and promote B cell maturation into plasma cells and long-lived memory B cells. During chronic infection prior to the development of AIDS, HIV-1 (HIV) replication is largely concentrated in TFH. Paradoxically, TFHnumbers are increased in early and midstages of disease, thereby promoting HIV replication and disease progression. Despite increased TFHnumbers, numerous defects in humoral immunity are detected in HIV-infected individuals, including dysregulation of B cell maturation, impaired somatic hypermutation, and low quality of antibody production despite hypergammaglobulinemia. Clinically, these defects are manifested by increased vulnerability to bacterial infections and impaired vaccine responses, neither of which is fully reversed by antiretroviral therapy (ART). Deficits in TFHfunction, including reduced HIV-specific IL-21 production and low levels of co-stimulatory receptor expression, have been linked to these immune impairments. Impairments in TFHlikely contribute as well to the ability of HIV to persist and evade humoral immunity, particularly the inability to develop broadly neutralizing antibodies. In addition to direct infection of TFH, other mechanisms that have been linked to TFHdeficits in HIV infection include upregulation of PD-L1 on germinal center B cells and augmented follicular regulatory T cell responses. Challenges to development of strategies to enhance TFHfunction in HIV infection include lack of an established phenotype for memory TFHas well as limited understanding of the relationship between peripheral TFHand lymphoid tissue TFH. Interventions to augment TFHfunction in HIV-infected individuals could enhance immune reconstitution during ART and potentially augment cure strategies.
authors.affiliation: Division of Infectious Diseases, University of Colorado Denver , Aurora, CO , USA.
authors.forename: Brodie
authors.initials: B
authors.lastname: Miles
authors.affiliation: Department of Immunology, University of Colorado Denver , Aurora, CO , USA.
authors.forename: Shannon M
authors.initials: SM
authors.lastname: Miller
authors.affiliation: Division of Infectious Diseases, Department of Medicine, University of Arizona , Tucson, AZ , USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Connick
keywords: HIV; broadly neutralizing antibodies; follicular T helper cells; follicular T regulatory cells; germinal center