Antibody responses to envelope glycoproteins in HIV-1 infection

Abstract

Antibody responses to the HIV-1 envelope glycoproteins can be classified into three groups. Binding but non-neutralizing responses are directed to epitopes that are expressed on isolated envelope glycoproteins but not on the native envelope trimer found on the surface of virions and responsible for mediating the entry of virus into target cells. Strain-specific responses and broadly neutralizing responses, in contrast, target epitopes that are expressed on the native trimer, as revealed by recently resolved structures. The past few years have seen the isolation of many broadly neutralizing antibodies of remarkable potency that have shown prophylactic and therapeutic activities in animal models. These antibodies are helping to guide rational vaccine design and therapeutic strategies for HIV-1.

Figure 1

Schematic of some of the forms of Env protein that may be present on infectious HIV-1 and available to elicit Ab responses. Only neutralizing Abs (nAbs) will bind to functional Env trimer spikes, although neutralizing Abs could, in principle, be elicited by other forms of Env protein. A range of non-neutralizing Abs (non-nAbs) and some neutralizing Abs will bind to nonfunctional Env proteins. Non-neutralizing Abs could be elicited by the types of nonfunctional Env protein shown, but also by, for example, monomeric gp120 or Env debris from infected cells. The molecules shown on virions could also be expressed on infected cells. Other forms of Env protein may be expressed on HIV-1 (refs. 1,2,98).

Figure 2

Structure of the HIV-1 Env trimer. Ribbon representation of the viral spike trimer structure (without bound Abs) with three identical gp120 (red) and gp41 (blue) molecules and variable loop regions (V1–V4). Dotted lines indicate loop regions not fully resolved within the crystal structures. The structure of the native cleaved trimeric Env, BG505 SOSIP.664, bound to several neutralizing Abs, has been solved by both cryo-electron microscopy and X-ray crystallography^,. Image adapted from ref. , Nature Publishing Group.

Figure 3

Broadly neutralizing Abs (antigen-binding (Fab) fragments) bound to the HIV-1 Env trimer. Shown are binding locations for prototype Abs to gp41 and gp120 (35O22 (ref. 10), 8ANC195 (ref. 99), PGT151 (refs. 7,8)); to the CD4-binding site (VRC01 (ref. 74)); to high-mannose-patch (PGT122, PGT128, PGT135 (refs. ,,–102)); and to V2 apex (PG9 (refs. 5,103)). The Abs to MPER^,, bind very close to the viral membrane; the MPER is not included in the recombinant trimer structure. Other much-studied broadly neutralizing Abs include b12 (ref. 106) and 3BNC117 (Abs to the CD4-binding site); 10-1074 (Ab to the high-mannose patch); CAP256 (ref. 9), PGT145 (ref. 6) and PGDM1400 (ref. 73) (Abs to the V2 apex). Image courtesy of A. Ward and C. Corbaci.