Role of Fc-mediated antibody function in protective immunity against HIV-1

Abstract

The importance of Fc-mediated effector function in protective immunity to HIV-1 (hereafter referred to simply as HIV) is becoming increasingly apparent. A large of number of studies in natural infection cohorts, spanning the last 26 years, have associated Fc-mediated effector function, particularly antibody-dependent cellular cytotoxicity, with a favourable clinical course. These studies strongly suggest a role for Fc-mediated effector function in the post-infection control of viraemia. More recently, studies in both humans and non-human primates (NHPs) also implicate Fc-mediated effector function in blocking HIV acquisition. Accordingly, this review will discuss the results supporting a role of Fc-mediated effector function in both blocking acquisition and post-infection control of viraemia. Parallel studies in NHPs and humans will be compared for common themes. Context for this discussion will be provided by summarizing the temporal emergence of key host and virological events over the course of an untreated HIV infection framing where, when and how Fc-mediated effector function might be protective. A hypothesis that Fc-mediated effector function protects primarily in the early stages of both acquisition and post-infection control of viraemia will be developed.

Figure 1

A depiction of the typical course of untreated HIV infection from acquisition to the development of AIDS. General clinical signs and symptoms are shown in addition to key pathological processes leading to failure of lymphocyte homeostasis followed by AIDS and death. This figure is modelled on figures in ref. .

Figure 2

A map of the specific virological and immunological events to Fiebig stages defined in ref. for acute HIV infections. This figure is modelled on figures in ref. .

Figure 3

The early virological events during the eclipse phase of HIV infection. The window of opportunity is shown where immunological or pharmacological interventions block acquisition. The window is widest during the first 24 hr after exposure and decreases thereafter until it closes with establishment of the latent CD4⁺ T-cell viral reservoir.

Figure 4

The A32 epitope region in gp120 C1 that is implicated as a dominant antibody-mediated cellular cytotoxicity (ADCC) target of non-neutralizing antibodies implicated in protection against HIV. (a) The inner (grey) and outer domains (bronze) of gp120 from PDB:3JW0. (b) gp120 rotated to show inner domain mobile layers 1 (yellow), 2 (green) and 3 (cyan). (c) Mobile layers 1, 2 and 3 with the outer domain of gp120 removed for clarity. (d) Point mutations (red) in mobile layers 1 and 2 that alter binding of monoclonal antibody A32 to gp120. (e) Peptides (red) in mobile layers 1 and 2 that are ADCC targets in a Thai HIV cohort. (f) Peptides (red) in mobile layers 1 and 2 that are ADCC targets in an Australian HIV cohort. The purple residues in mobile layer 2 are sites of ADCC escape. (g) Peptide (red) recognized by RV144 IgA antibodies that inhibit ADCC mediated by RV144 IgG antibodies to the A32 epitope region.,,