The HIV-1 Envelope Glycoproteins: Fusogens, Antigens, and Immunogens

Abstract

The human immunodeficiency virus-type 1 (HIV-1) envelope glycoproteins interact with receptors on the target cell and mediate virus entry by fusing the viral and cell membranes. The structure of the envelope glycoproteins has evolved to fulfill these functions while evading the neutralizing antibody response. An understanding of the viral strategies for immune evasion should guide attempts to improve the immunogenicity of the HIV-1 envelope glycoproteins and, ultimately, aid in HIV-1 vaccine development.

Immunogenicity of recombinant human immunodeficiency virus type 1-like particles expressing gp41 derivatives in a pre-fusion state

“…This may be explained by the fact that the non-covalent interaction of gp120 with gp41 is labile and CD4 binding to gp120 stimulates further shedding of gp120 from the functional envelope spike. Upon dissociation from gp120, gp41 assumes a post-fusion state [70] with concomitant exposure to the immune system of gp41 surfaces that are occluded in the context of the functional trimer, favoring antibody response to irrelevant epitopes [50,71,72].…”

Polymeric Anti‐HIV Therapeutics

“…After extensive work and the elucidation of the trimer-of-hairpin structure through X-ray crystallography, [12,34] T-20 was found to work as a competitive inhibitor that binds to the HR1 coiled coil trimer region of gp41 in an anti-parallel manner. [18,35] Despite the effectiveness of T-20 as a peptide drug, [36] the main side effects are that the drug has to be administered subcutaneously twice daily, is very expensive and is only administered to individuals for whom no other therapeutic options are available. [28] In addition, one of the consequences of high and frequent administration is the emergence of T-20 resistant strains of HIV.…”

“…[9,107] From the neutralizing antibody IgG b12, a peptide domain known as CDR H3 was identified to be involved in binding to the gp120 on HIV-1 and thereby blocking the interaction with CD4 receptor on the host cell and causing neutralization of the virus. [108] Using a consecutive ester-amide/thiol-ene postpolymerization modification strategy, [109] a library of polymer conjugates was prepared that presented multiple copies of the CDR H3 peptide via thioether side chains (35). HIV-1 inhibitory properties with HIV-1 HXB2 on HOS CCR5 cells revealed that midsized polymer conjugates displayed the highest antiviral efficacy (IC 50 ¼ 2-3 Â 10 À6 M total peptide content) while lower efficacies were determined for the copolymers with high and low molecular weight (IC 50 % 10 Â 10 À6 M total peptide content).…”

The good and evil of complement activation in HIV-1 infection

“…34 The HIV-1-specific nAbs described to date interfere with viral attachment to the cellular receptor CD4, binding to the coreceptor (most commonly CCR5 or CXCR4), or postreceptor engagement in the actual fusion process. [35][36][37][38][39][40][41][42][43][44][45] When a host is infected with a virus, Abs are produced against many epitopes on multiple viral proteins. These Abs consist of a mixture of nAbs and non-nAbs, which can contribute to antiviral immunity in four ways: 34 (i) nAbs directly neutralize free virus particles; (ii) both nAbs and non-nAbs trigger complement-mediated lysis of free virus particles and infected cells via specific Ab-antigen binding events and complement activation; (iii) both nAbs and non-nAbs bind to and coat viruses to mediate opsonization and phagocytosis by macrophages and other cells; and (iv) both nAbs and non-nAbs trigger destruction of viruses by stimulating other immune responses such as Ab-dependent cellular cytotoxicity (ADCC).…”

“…Studies suggest that HIV-1 can permanently escape nAb responses by: (i) masking or shedding putative neutralizing epitopes with extensive glycosylation and rapid rearrangement of the glycan shield, (ii) rapid mutation and recombination of the viral genome, particularly the Env gene, or (iii) displaying monomeric gp120 and gp41 stumps, not the typical wild-type gp120-gp41 trimers on the viral surface, which may not be properly recognized by the induced nAbs. 39,45,[73][74][75][76][77][78][79][80][81][82][83] Therefore, the nAb responses of the host are chasing a rapidly evolving HIV-1 virus. Eventually, these nAbs lose their neutralizing capability and become non-nAbs.…”