HIV-1 variable loop 2 and its importance in HIV-1 infection and vaccine development

Abstract

A vaccine that can prevent the transmission of HIV-1 at the site of exposure to the host is one of the best hopes to control the HIV-1 pandemic. The trimeric envelope spike consisting of heterodimers, gp120 and gp41, is essential for virus entry and thus has been a key target for HIV-1 vaccine development. However, it has been extremely difficult to identify the types of antibodies required to block the transmission of various HIV-1 strains and the immunogens that can elicit such antibodies due to the high genetic diversity of the HIV-1 envelope. The modest efficacy of the gp120 HIV-1 vaccine used in the RV144 Thai trial, including the studies on the immune correlates of protection, and the discovery of vaccine-induced immune responses to certain signature regions of the envelope have shown that the gp120 variable loop 2 (V2) is an important region. Since there is evidence that the V2 region interacts with the integrin α4β7 receptor of the host cell, and that this interaction might be important for virus capture, induction of antibodies against V2 loop could be postulated as one of the mechanisms to prevent the acquisition of HIV-1. Immunogens that can induce these antibodies should therefore be taken into consideration when designing HIV-1 vaccine formulations.

Figure 1

HIV-1 entry pathway. A. HIV-1 is captured through relatively weak interactions between gp120 V1V2 loop and surface molecules such as α₄β₇ integrin. This leads to high affinity interactions between gp120 and CD4 molecule, the primary receptor on CD4⁺ T cell. The engagement of CD4 receptor causes a conformational change in the envelope glycoprotein exposing the V3 loop-binding site for the chemokine co-receptor, CCR5 or CXCR4 [19, 138]. Further conformational changes occur after co-receptor interaction leading to the opening up of the two long helices HR1 and HR2 of gp41 and insertion of the N-terminal fusion peptide into the host cell membrane [139, 140]. A gp41 prehairpin intermediate [141], a three-stranded coiled coil stabilized by inter-molecular interactions between HR1 helices, is then formed, followed by the disassociation of gp120 subunits from gp41, allowing the HR2 helices to fold back and interact with the HR1 helices. The trimeric HR1 core, the interacting HR2 helices and the intervening loops in between form a hairpin structure of gp41 that is referred to as the six-helix bundle (6HB). This structure brings the host and the viral membranes in close proximity, facilitating membrane fusion and release of the nucleocapsid core into the cytosol [142-144]. B. CryoEM structure of the envelope trimer with the crystal structure of monomeric gp120 (PDB: 3DNN) fitted into the density map (kindly provided by Alan Merk and Sriram Subramaniam, NCI, NIH). The top and side views are shown; gp120 structure is shown in green. The structure lacks V1V2 domain, but the β-strands to which the V1V2 sequence would be linked are shown in red. C. Structural features of the V1V2 domain (PDB: 3U2S). V1 region is shown in cyan and V2 region is shown in magenta. The four β strands are labeled A to D. Disulfide bonds (-S-S-) are shown as sticks. The variable loop region in V1 and V2 are disordered in the structure and shown as dashed lines. The positions of the α₄β₇ binding tripeptide, LDI/V, and of the signature residue K169 in V2 loop are shown. C. Sequence alignment of V1V2 domain. Several founder V1V2 sequences from clades B and C viruses that were obtained from the Los Alamos National Laboratory HIV-1 database are aligned. The amino acids highlighted in black are identical, in magenta have ≥75% identity, and in cyan have ≥50% identity. The positions of β strands A-D are indicated at the bottom of the aligned sequences. The colors of the β strands correspond to the colors shown in the structure in (C).