The Antibody Response against HIV-1

Abstract

Neutralizing antibodies (NAbs) typically play a key role in controlling viral infections and contribute to the protective effect of many successful vaccines. In the case of HIV-1 infection, there is compelling data in experimental animal models that NAbs can prevent HIV-1 acquisition, although there is no similar data in humans and their role in controlling established infection in humans is also limited. It is clear HIV-specific NAbs drive the evolution of the HIV-1 envelope glycoprotein within an infected individual. The virus's ability to evade immune selection may be the main reason HIV-1 NAbs exert limited control during infection. The extraordinary antigenic diversity of HIV-1 also presents formidable challenges to defining NAbs that could provide broad protection against diverse circulating HIV-1 strains. Several new potent monoclonal antibodies (MAbs) have been identified, and are beginning to yield important clues into the epitopes common to diverse HIV-1 strains. In addition, antibodies can also act in concert with effector cells to kill HIV-infected cells; this could provide another mechanism for antibody-mediated control of HIV-1 replication. Understanding the impact of antibodies on HIV-1 transmission and pathogenesis is critical to helping move forward with rational HIV-1 vaccine design.

Figure 1.

Schematic representation of the mechanism of action of NAbs and antibodies that act through ADCC and ADCVI. (A) Antibody neutralization of cell-free virus. Neutralizing antibodies bind to HIV-1 envelope glycoproteins and block the interaction of viral particles with CD4 and CCR5, essential receptors on target cells required for infection. (B) Antibody-dependent cellular cytotoxicity leads to the killing of infected cells. In the case of ADCC, a complex between the IgG Fab portion of antibody bound to envelope protein on the cell surface and the Fc portion to the Fc receptors on effector cells leads to lysis of the infected cell. (C) Antibody-dependent cell-mediated virus inhibition. ADCVI measures the effects of ADCC-mediated cell killing, which lead to reduced virus production, as well as virus inhibition by antiviral cytokines and other secondary effects of FcR-virus interactions such as phagocytosis.

Figure 2.

Targets of autologous NAbs on HIV-1 subtype B and subtype C envelopes. The figure summarizes data from studies in which the precise targets of autologous NAbs on gp120 have been defined. This includes two studies in HIV-1 subtype B infection (KJ Bar, unpubl.; Tang et al. 2011) and two in HIV-1 subtype C infection (Moore et al. 2009; Rong et al. 2009). The sites targeted are listed in color with the corresponding regions on the gp120 structures in the same color. Sites are highlighted on the crystal structure of HIV-1 JR-FL gp120 core protein containing the third variable region (V3) complexed with CD4 and the X5 antibody (PDB 2B4C) (Huang and Tang 2005).

Figure 3.

Specificity of antibodies in cross-neutralizing samples. Summary of the three most comprehensive mapping studies to date examining the specificities of antibodies mediating neutralization breadth. This includes (A) 19 samples from Walker et al. (2009), (B) seven samples from Gray et al. (2011), and (C) nine samples from Tomaras et al. (2010). PG9/16-like NAbs and an undefined epitope that involves a glycan at position 332 in the outer domain of gp120 were the most common targets in all three studies. Antibodies found to be responsible for breadth in fewer samples included those targeting the MPER (B,C) or CD4bs/CoRbs (A). In all three studies the antibody specificities in some of the broadly cross-neutralizing sera/plasma could not be identified.