A Little Help From the Follicles: Understanding the Germinal Center Response to Human Immunodeficiency Virus 1 Infection and Prophylactic Vaccines

Abstract

Human immunodeficiency virus 1 (HIV-1) is the causative agent of AIDS. There are currently more than 35 million people living with HIV infection worldwide, and more than 2 million new infections occur each year. The global pandemic caused by HIV-1 is the subject of numerous research projects, with the development of a prophylactic vaccine and a therapeutic cure being the ultimate goals. The classic paradigms of vaccinology have proven incapable of producing a viable vaccine due to the complexity of the virus' replication cycle, its genetic diversity, and a lack of understanding of the immune correlates of protection. Here, we briefly discuss recent vaccine approaches and the immune correlates of protection from HIV-1 infection with a focus on the role of the germinal center as a reservoir of replication-competent virus and its role in the development of broadly neutralizing antibodies in response to vaccination.

Keywords: Germinal center; HIV-1; TFH; broadly neutralizing antibody; vaccines.

Figure 1.

Mucosal pathogenesis of human immunodeficiency virus 1 (HIV-1). Most of the HIV-1 infections occur at mucosal sites via sexual transmission. On gaining access to tissue-resident CD4⁺ T cells or when taken up by tissue-resident dendritic cells (DC), infected cells may be phagocytosed by granulocytes, such as macrophages (Mϕ), and the virus is carried to the draining lymph nodes (DLNs) where these antigen-presenting cells may directly infect CD4⁺ T cells. Replication-competent viruses multiply and establish latency. In this way, the DLNs become the largest tissue reservoir during chronic infection.

Figure 2.

Role of antibodies in HIV-1 infection. Affinity-matured, class-switched, highly-mutated, long-lived plasma cells can secrete anti–HIV-neutralizing antibodies that are capable of neutralizing free virus to prevent infection of target cells (left) as well as mediating ADCC or ADCP (middle) by natural killer cells. Quiescent cells that are latently infected remain immune to anti-HIV responses (right). ADCC indicates antibody-dependent cell-mediated cytotoxicity; ADCP, antibody-dependent cellular phagocytosis; HIV-1, human immunodeficiency virus 1; NK, natural killer.

Figure 3.

The germinal center reaction. On antigen presentation in the context of the proper cytokine milieu, naïve CD4⁺ T cells differentiate into follicular helper T (T_FH) cells and migrate to germinal centers where they select germinal center B cells (GC B) which are responsive to the appropriate antigen via presentation of the antigen on major histocompatibility complex (MHC I). Both T_FH and GC B cells traffic to the germinal center by virtue of their expression of the receptor CXCR5, following a chemokine gradient of the CXCR5 ligand CXCL13. T_FH cells and GC B cells make physical connection between costimulatory molecules, B7 and CD28, CD40 and CD40L, inducible costimulator (ICOS) and ICOS ligand (ICOSL), as well as PD-1 and PD-1L. This interaction is also cytokine based with the T_FH cell secreting interleukin (IL)-21 which is recognized by the IL-12R on GC B cells and mediates STAT3 support of affinity maturation, somatic hypermutation, and class switching of antibodies. T_FH cells also secrete IL-4 which is recognized by the IL-4 receptor on GC B cells and supports STAT3 expression. Antigen-specific dendritic cells which also present antigen to T_FH secrete IL-6 which promotes Bcl-6 expression in T_FH and GC B supporting the GC phenotype. Finally, this reaction is subject to regulation by T follicular regulatory (T_FR) cells which secrete IL-10 and inhibit both T_FH and GC B function.