The V1, V2, and V3 Regions of the Human Immunodeficiency Virus Type 1 Envelope Differentially Affect the Viral Phenotype in an Isolate-Dependent Manner

Abstract

It is well documented that removal of the V1V2 region or of the V2 loop alone from the envelope glycoprotein of human immunodeficiency virus type 1 (HIV-1) or simian immunodeficiency virus (SIV) increases the susceptibility of these viruses to neutralization by antibodies. The specific role of the V1 loop in defining the neutralization susceptibility of HIV is, however, not well documented. Our current studies indicate that although the V1V2 region is a global modulator of the HIV-1 neutralization susceptibility, the individual roles the V1 and V2 loops have in defining the neutralization susceptibility profile of HIV-1 differ and in some cases are opposite. While deletion of the V2 loop renders the virus more susceptible to neutralization by antibodies that recognize diverse epitopes, in particular certain ones located in the CD4 binding site and the V3 loop, deletion of the V1 loop renders the virus refractory to neutralization, especially by antibodies that recognize CD4-induced epitopes and certain CD4-site binding antibodies. Our current studies also indicate that the relative involvement of the V2 loop of the HIV-1 envelope during virus-cell entry appears to be envelope background dependent. As a result, although deletion of the V2 loop from the clade B, R5-tropic SF162 HIV-1 virus resulted in a virus that was replication competent, the same modification introduced on the background of two other R5-tropic isolates, SF128A (clade B) or SF170 (clade A), abrogated the ability of these envelopes to mediate virus-cell entry.

Antigenic and Immunogenic Study of Membrane-Proximal External Region-Grafted gp120 Antigens by a DNA Prime-Protein Boost Immunization Strategy

“…For Graft2 antigen-immunized mice, some of the animals did not produce detectable anti-V3 antibodies (e.g., three of four mice in group G2C), and the specificities towards different V3 peptides varied between animals, with more frequent reactivity towards peptide 8839. This suggests that alterations in the V1/2 loops not only have local effects but also may affect the immunogenicity of V3 in monomeric gp120, supporting the notion that V1/2 interacts with V3 and affects its conformation and sensitivity to anti-V3 NAbs (55,58,63,76).…”

Replication-Competent Variants of Human Immunodeficiency Virus Type 2 Lacking the V3 Loop Exhibit Resistance to Chemokine Receptor Antagonists

“…Envs with partial or complete deletions of V1/V2 are more neutralization sensitive (25,50,56,70) and in the case of SIV are less dependent on CD4 (43). Not surprisingly, given the importance of V3 for interacting with CCR5 and CXCR4, Envs lacking V3 function poorly in fusion assays and infectious viruses without V3 have not been described (50).…”

“…The structure, function, and immunogenicity of the HIV (or simian immunodeficiency virus [SIV]) Env have been explored by deriving replication-competent viruses with functional Envs that lack variable loops (25,50,56,65,67,70). Envs with partial or complete deletions of V1/V2 are more neutralization sensitive (25,50,56,70) and in the case of SIV are less dependent on CD4 (43).…”

“…Envs with partial or complete deletions of V1/V2 are more neutralization sensitive (25,50,56,70) and in the case of SIV are less dependent on CD4 (43). Not surprisingly, given the importance of V3 for interacting with CCR5 and CXCR4, Envs lacking V3 function poorly in fusion assays and infectious viruses without V3 have not been described (50). Although V3 shows extensive amino acid diversity across HIV and SIV phylogeny, unlike V1/V2 and V4, which can tolerate insertions and deletions (4,10,22,46), the V3 length is highly conserved and is typically 34 or 35 amino acids (8,16,18,22).…”

“…The recently solved V3 structure on a CD4-bound gp120 core shows that its base is contiguous with the surface formed by the bridging sheet while its more distal region projects toward the cell membrane, where it has been proposed to contact the coreceptor's extracellular loops (ECLs) (22). However, despite extensive data from mutagenesis, the precise nature of these interactions is unknown, as are their contributions to Env function (18).The structure, function, and immunogenicity of the HIV (or simian immunodeficiency virus [SIV]) Env have been explored by deriving replication-competent viruses with functional Envs that lack variable loops (25,50,56,65,67,70). Envs with partial or complete deletions of V1/V2 are more neutralization sensitive (25,50,56,70) and in the case of SIV are less dependent on CD4 (43).…”