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Review
. 2014 Jun 18:5:289.
doi: 10.3389/fimmu.2014.00289. eCollection 2014.

Which Antibody Functions are Important for an HIV Vaccine?

Bin Su  1 , Christiane Moog  1
Affiliations
Review

Which Antibody Functions are Important for an HIV Vaccine?

Bin Su et al. Front Immunol. .

Abstract

HIV antibody (Ab) functions capable of preventing mucosal cell-free or cell-to-cell HIV transmission are critical for the development of effective prophylactic and therapeutic vaccines. In addition to CD4(+) T cells, other potential HIV-target cell types including antigen-presenting cells (APCs) (dendritic cells, macrophages) residing at mucosal sites are infected. Moreover, the interactions between APCs and HIV lead to HIV cell-to-cell transmission. Recently discovered broadly neutralizing antibodies (NAbs) are able to neutralize a broad spectrum of HIV strains, inhibit cell-to-cell transfer, and efficiently protect from infection in the experimentally challenged macaque model. However, the 31% protection observed in the RV144 vaccine trial in the absence of detectable NAbs in blood samples pointed to the possible role of additional Ab inhibitory functions. Increasing evidence suggests that IgG Fcγ receptor (FcγR)-mediated inhibition of Abs present at the mucosal site may play a role in protection against HIV mucosal transmission. Moreover, mucosal IgA Abs may be determinant in protection against HIV sexual transmission. Therefore, defining Ab inhibitory functions that could lead to protection is critical for further HIV vaccine design. Here, we review different inhibitory properties of HIV-specific Abs and discuss their potential role in protection against HIV sexual transmission.

Keywords: ADCC; FcγR; HIV; antigen-presenting cells; cell-to-cell transfer; mucosal HIV vaccine; neutralizing antibodies; non-neutralizing inhibitory antibodies.

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Figures

Figure 1
Figure 1
Different HIV-1 antibody activities in mucosal tissues. Infectious HIV-1 particles can cross a multi-cellular layer of stratified squamous epithelial cells in genital mucosal tissues. Both cell-free and cell-associated HIV-1 virions infect host cells. Langerhans cells transport the virus into the sub-epithelium and mucosal lesions may provide an accessible pathway for HIV-1. In the sub-epithelium, in addition to target CD4+ T cells, other potential HIV-target cell types including myeloid dendritic cells (DCs) and macrophages are infected either by cell-free virions or by cell-associated virions. Mucosal HIV-specific IgA (IgA, in green) can bind and neutralize cell-free virus at mucosal surfaces. Adaptive immune responses such as HIV-1-specific IgG neutralizing antibodies (NAbs, in red) are important for preventing HIV-1 cell-free infection. Only NAbs are able to inhibit HIV infection of CD4 T lymphocytes while both NAbs and FcγR-mediated inhibitory Abs (in blue) help to inhibit the spread of infection via cell-to-cell transmission route. Prevention of HIV-1 infection and killing of virus-producing cells by Ab-dependent mechanisms, especially antibody-dependent cellular cytotoxicity (ADCC) via binding of Fc receptors presented on the surface of innate immune cells such as natural killer (NK) cells, monocytes, DCs, or macrophages, takes place by inhibiting viral replication and diminishing viral reservoirs in vivo. Moreover, inhibitory NAbs directed to cellular target epitopes, such as CCR5 or other HIV-receptor/co-receptor structures, could provide additional targets for the rational design of novel vaccine candidates.
Figure 2
Figure 2
Model representation of HIV-1 envelope glycoprotein structure and epitopes of broadly neutralizing antibodies. The surface receptor binding subunit gp120 and the fusion-mediating transmembrane subunit gp41 make up the functional HIV-1 envelope glycoproteins. The targets of broadly neutralizing antibodies (bNAbs) can be divided into several groups: (1) IgG anti-CD4-binding site, (2) IgG anti-V1V2 site, (3) IgG anti-N-linked glycan V3 site, and (4) IgG anti-gp41 membrane proximal external region (MPER). The IgG anti-distinct conformational epitope present on the envelope trimer, remains to be determined (adapted from Dr. Béatrice Labrosse).
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