Inhibition of HIV-1 entry by antibodies: potential viral and cellular targets

Abstract

Vaccine-induced antibodies that interfere with viral entry are the protective correlate of most existing prophylactic vaccines. However, for highly variable viruses such as HIV-1, the ability to elicit broadly neutralizing antibody responses through vaccination has proven to be extremely difficult. The major targets for HIV-1 neutralizing antibodies are the viral envelope glycoprotein trimers on the surface of the virus that mediate receptor binding and entry. HIV-1 has evolved many mechanisms on the surface of envelope glycoproteins to evade antibody-mediated neutralization, including the masking of conserved regions by glycan, quaternary protein interactions and the presence of immunodominant variable elements. The primary challenge in the development of an HIV-1 vaccine that elicits broadly neutralizing antibodies therefore lies in the design of suitable envelope glycoprotein immunogens that circumvent these barriers. Here, we describe neutralizing determinants on the viral envelope glycoproteins that are defined by their function in receptor binding or by rare neutralizing antibodies isolated from HIV-infected individuals. We also describe the nonvariable cellular receptors involved in the HIV-1 entry process, or other cellular proteins, and ongoing studies to determine if antibodies against these proteins have efficacy as therapeutic reagents or, in some cases, as vaccine targets to interfere with HIV-1 entry.

Fig. 1

Schematic of HIV-1 and the cellular receptors involved in viral entry. The HIV-1 envelope glycoprotein, gp120 (blue), associated with the transmembrane protein gp41 (brown), are exposed on the outside of the virus particles. HIV-1 binds to the primary receptor, CD4 (red) and, following conformational changes, the gp120–CD4 complexes bind the coreceptor, CCR5 (green), which activates gp41 to mediate fusion of the viral membrane to the target cell membrane, leading to viral entry. The exterior viral envelope glycoproteins, gp120 and gp41 are both targets for neutralizing antibodies as are also, potentially, the cellular receptors CD4 and CCR5. Known neutralizing targets are highlighted with a schematic representation of antibodies that are colour-matched with their target proteins.

Fig. 2

Schematic representation of the functional spike and the binding sites of broadly neutralizing antibodies on the viral envelope glycoproteins. The exterior envelope glyco-protein, gp120 (blue), and the transmembrane glycoprotein, gp41 (brown) are shown as noncovalently associated trimers on the surface of the virus (below) and expanded to reveal more details of the spike (above). The membrane proximal epitopes for the two broadly neutralizing gp41 antibodies; 4E10 (orange) and 2F5 (red) are shown on the trimeric stalk of gp41 external to the viral membrane. The two broadly neutralizing gp120 antibodies are 2G12 and IgGb12. 2G12 recognizes a carbohydrate cluster (encircled in white dashes) on the N-linked glycans (magenta) of gp120, which are shown on one gp120 monomer. The antibody IgGb12 recognizes a discontinuous epitope that overlaps with the recessed CD4-binding site on gp120 (grey area) and is shown on one monomer.

Fig. 3

Schematic representation of the HIV-1 particle and its protein and genomic RNA contents. Two copies of the viral positive strand RNA genome are packaged into the particle. Viral enzymes; reverse transcriptase (RT), integrase (IN), protease (Pr) and structural proteins; capsid (CA), nucleocapsid (NC), matrix (MA) and p6 are inside the particle together with the viral regulatory protein Vpr and the cellular protein cyclophilin. The virus is enveloped by a host cell-derived lipid membrane into which trimers of the viral transmembrane glycoprotein gp41 is inserted. Three monomers of the exterior envelope glycoprotein gp120 are noncovalently associated with gp41. Several cellular proteins are also incorporated into the viral membrane with relative abundance, including MHC class I and II molecules and intracellular adhesion molecule-1 shown here.