Antibodies for Human Immunodeficiency Virus-1 Cure Strategies

Abstract

Human immunodeficiency virus (HIV) infection leads to the establishment of a long-lived latent cellular reservoir. One strategy to eliminate quiescent reservoir cells is to reactivate virus replication to induce HIV envelope glycoprotein (Env) expression on the cell surface exposing them to subsequent antibody targeting. Via the interactions between the antibody Fc domain and Fc-γ receptors (FcγRs) that are expressed on innate effector cells, such as natural killer cells, monocytes, and neutrophils, antibodies can mediate the elimination of infected cells. Over the last decade, a multitude of human monoclonal antibodies that are broadly neutralizing across many HIV-1 subtypes have been identified and are currently being explored for HIV eradication strategies. Antibody development also includes novel Fc engineering approaches to increase engagement of effector cells and optimize antireservoir efficacy. In this review, we discuss the usefulness of antibodies for HIV eradication approaches specifically focusing on antibody-mediated strategies to target latently infected cells and options to increase antibody efficacy.

Keywords: Fc function; HIV cure; HIV reservoir; Infected cell recognition; monoclonal antibodies.

Figure 1.

Distribution of human immunodeficiency virus (HIV) envelope glycoprotein (Env) on the cell surface. Env is distributed (red) on the surface of an HIV NLAD8-infected (p24⁺; green) lymphocyte and is detected by the fluorescently labeled broadly neutralizing antibody 2G12 (red). Bright puncta of p24⁺ and Env⁺ suggest virions budding from the plasma membrane. The image is a projection of confocal sections through the entire thickness of the cell. Nuclear morphological characteristics are shown by 4′,6-diamidino-2-phenylindole (DAPI) staining (blue).

Figure 2.

Fc-mediated antibody effector functions, depicting innate effector recognition of immune complexes of antibodies and infected cells. Antibody-opsonized cells display the Fc in a conformation recognized by innate effectors, such as monocytes, natural killer (NK) cells, and neutrophils, which are capable of responses that vary by effector type. Abbreviation: NO, Nitric Oxide.

Figure 3.

Time-lapse confocal microscopy of a live human immunodeficiency virus (HIV)–infected (green) cell and antibody-dependent cellular cytotoxicity (ADCC) by natural killer (NK) cells. Purified primary NK cells (smaller cells) were coincubated with HIV-1 JR-CSF–infected CEM cells that express green fluorescent protein (GFP) when infected. Envelope glycoprotein recognition was mediated by a mix of AF647-conjugated 2G12 and unlabeled 2G12 (1:5 ratio). NK cells appear to be associated with the yellow envelope patch (first panel), the cell blebs (second panel), show diminished GFP expression (third panel), and are ultimately destroyed by NK cells (fourth panel). Numbers indicate time in minutes after coculture of effectors and targets; scale bar represents 10 μm.