Induction of immunity to human immunodeficiency virus type-1 by vaccination

Abstract

Recent findings have brought optimism that development of a successful human immunodeficiency virus type-1 (HIV-1) vaccine lies within reach. Studies of early events in HIV-1 infection have revealed when and where HIV-1 is potentially vulnerable to vaccine-targeted immune responses. With technical advances in human antibody production, clues about how antibodies recognize HIV-1 envelope proteins have uncovered new targets for immunogen design. A recent vaccine regimen has shown modest efficacy against HIV-1 acquisition. However, inducing long-term T and B cell memory and coping with HIV-1 diversity remain high priorities. Mediators of innate immunity may play pivotal roles in blocking infection and shaping immunity; vaccine strategies to capture these activities are under investigation. Challenges remain in integrating basic, preclinical and clinical research to improve predictions of types of immunity associated with vaccine efficacy, to apply these insights to immunogen design, and to accelerate evaluation of vaccine efficacy in persons at-risk for infection.

Figure 1. Unliganded Model of the HIV-1 Envelope Trimer

All glycans on gp160 are shown. Glycans are light blue and white, core gp120 is red, 2G12 epitopes are white (arrow), B12 and VRC01 epitopes are yellow (arrow), and the location of the quarternary epitope involving V2 and V3 loops of mAbs PG9 and PG16 is indicated. Image courtesy of Dr. William Schief, University of Washington, Seattle, WA, adapted with permission from (Schief et al., 2009).

Figure 2. Steps in mucosal HIV-1 transmission potentially amenable to intervention by vaccination

Steps are keyed to assays listed in Table S1. Antibodies that score positive in in vitro assays and protect against SHIV acquisition in in vivo passive protection trials in non-human primates are candidates for correlates of protective immunity in the RV144 vaccine trial. Free virions or virions from infected cells can be aggregated by antibodies (1) and their movement through the mucus layer inhibited (2). Possible sites of transmission are female vagina and cervix (squamous epithelium), endocervix and rectum (columnar epithelium) as well as male rectum (columnar epithelium and forskin (squamous epithelium). Transcytosis through either squamous or columnar epithelium may be blocked by antibodies (3), as can the transfer of DC-bound virions to CD4⁺ T cells (4). Various assays measure the ability of antibody to block CD4⁺ T cell and monocyte-macrophage (not shown) infection such as inhibition of gp120 binding to α4β7 (5), pseudovirus infection inhibition (not shown) (6), PBMC infection inhibition (not shown) (7), syncytium inhibition (not shown) (8), and cell-to-cell infection inhibition (4 and implied in 9). ADCVI and ADCC, as well as phagocytosis assays of opsonized virions, can measure Fc receptor mediated anti-HIV activities. Antibody and/or immune complexes bound to IgG FcR-bearing immune cells such as NK cells and/or monocyte macrophages can also release anti-HIV-1 chemokines and other factors.