The native HIV-1 Env trimer complex is meta-stable and readily acquires lower energy forms that are highly immunogenic [reviewed in Ref. those in healthy hosts. So far, broadly neutralizing antibody responses were not induced by vaccination in primates Rabbit polyclonal to Anillin or small animals with natural B cell repertoires. An increased focus on the development vaccine-induced responses BPTES in healthy subjects is therefore needed to delineate how the immune system recognizes different forms of HIV-1 Env and to optimize approaches to stimulate antibody responses against relevant neutralizing antibody epitopes. In this review, we describe aspects of Env-directed antibody responses that differ between chronic HIV-1 infection and subunit vaccination for an increased appreciation of these differences; and we highlight the need for an improved understanding of vaccine-induced B cell responses to complex glycoproteins such as Env, in healthy subjects. Keywords: B cells, HIV-1, neutralizing antibodies, vaccine, HIV-1 Infection B Cell Subsets in Normal Physiology The human adaptive immune system relies on several B-lymphocyte BPTES subsets with distinct roles. Circulating B cells can be classified as antigen-inexperienced or antigen-experienced cells. Among the former are the immature, transitional B cells and the mature naive B cells. Human transitional B cells are divided into T1 (CD10+CD21loCD27-) and T2/3 (CD10+CD21hiCD27?) B cells, while the mature naive B cells are defined as CD10-CD20hiCD27? cells. Transitional B cells and mature naive B cells express germline-encoded immunoglobulin (Ig) genes of the IgD and/or IgM isotypes. In contrast, memory B cells, plasmablasts, and plasma cells are antigen-experienced cells that in most cases originate from germinal center reactions. Most antigen-experienced B cells have undergone somatic hypermutation (SHM) and class switch recombination to IgG, IgA, or IgE BPTES (1), but non-switched memory B cells also exist (2). Resting memory B cells persist by self-renewal, which proliferate and differentiate into plasma cells upon antigen re-exposure. To maintain the lineage following activation, some daughter cells remain as slowly dividing memory B cells, while others become terminally differentiated antibody-secreting cells (ASCs). Whether this is a stochastic process (3) or mediated by directed asymmetric cell division (4) remains a question of debate. Peripheral ASCs, often referred to as plasmablasts, are short-lived and distinct from the long-lived plasma cells found in bone marrow (BM) or other anatomical niches that support their survival (5, 6). BPTES During late-stage B cell development, immature/transitional B cells exit the BM to enter the circulation where they are subjected to peripheral selection. This is at least in part regulated by B cell-activating factor (BAFF), which is present in limited quantities, thereby setting a competitive threshold for B cell survival (7, 8). The surviving mature naive B cells migrate to secondary lymphoid organs, i.e., the spleen, lymph nodes, and mucosa-associated lymphoid tissue. Upon antigen encounter, extrafollicular plasma cell responses resulting in the production of antibodies that have not undergone SHM may occur. However, most B cell responses against protein antigens are T cell dependent and products of germinal center reactions. Here, antigen-specific B cells undergo hypermutation of the encoded antibody sequences BPTES to diversify the antigen-specific repertoire and the resulting B cells interact closely with follicular dendritic cells and follicular helper T (Tfh) cells for selection of high affinity B cell clones. The signals that dictate B cell differentiation into memory B cells or plasma cells in the germinal center reaction are only beginning to be understood (9), including the important roles of Tfh cells (10C12). These processes are of high relevance for vaccine research as both memory B cells and plasma cells are needed for sustained humoral immunity. B Cell Dysfunction in HIV-1-Infected Individuals During chronic HIV-1 infection, several imbalances in B cell subsets develop (Figure ?(Figure1),1), affecting the capacity of chronically infected individuals to respond to vaccination and handle co-infections (13C17). Hypergammaglobulinemia and loss of B cell memory are hallmarks of these humoral immunity alterations (18, 19). Dysregulation of B cells is apparent relatively early after HIV-1 infection and worsens during disease.