A Twin-Cysteine Motif in the V2 Region of gp120 Is Associated with SIV Envelope Trimer Stabilization

Bohl, Christopher R.; Bowder, Dane; Thompson, Jay; Abrahamyan, Levon; González-Ramírez, Sandra; Mao, Youdong; Sodroski, Joseph; Wood, Charles; Xiang, Shi-Hua

doi:10.1371/journal.pone.0069406

Cited by 19 publications

(25 citation statements)

References 42 publications

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“…One challenge of targeting this epitope region is the flexibility of strand C=, which may render this region less immunogenic than the strand C region. However, strand C= can be stabilized by an additional disulfide bond as in the case of HIV-2 and some simian immunodeficiency virus (SIV) envelopes (45). In fact, mutations to introduce such a disulfide bond into certain virus strains improved the neutralization potency of 830A (C. Hioe, personal communications).…”

Section: Discussionmentioning

confidence: 99%

The V1V2 Region of HIV-1 gp120 Forms a Five-Stranded Beta Barrel

Pan

Gorny

Zolla‐Pazner

et al. 2015

J Virol

114

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The region consisting of the first and second variable regions (V1V2) of gp120 plays vital roles in the functioning of the HIV-1 envelope (Env). V1V2, which harbors multiple glycans and is highly sequence diverse, is located at the Env apex and stabilizes the trimeric gp120 spike on the virion surface. It shields V3 and the coreceptor binding sites in the prefusion state and exposes them upon CD4 binding. Data from the RV144 human HIV-1 vaccine trial suggested that antibody responses targeting the V1V2 region inversely correlated with the risk of infection; thus, understanding the antigenic structure of V1V2 can contribute to vaccine design. We have determined a crystal structure of a V1V2 scaffold molecule (V1V2 ZM109 -1FD6) in complex with 830A, a human monoclonal antibody that recognizes a V1V2 epitope overlapping the integrin-binding motif in V2. The structure revealed that V1V2 assumes a five-stranded beta barrel structure with the region of the integrin-binding site (amino acids [aa] 179 to 181) included in a "kink" followed by an extra beta strand. The complete barrel structure naturally presents the glycans on its outer surface and packs into its core conserved hydrophobic residues, including the Ile at position 181 which was highly correlated with vaccine efficacy in RV144. IMPORTANCEData from the RV144 phase III clinical trial suggested that the presence of antibodies to the first and second variable regions (V1V2) of gp120 was associated with the modest protection afforded by the vaccine. V1V2 is a highly variable and immunogenic region of HIV-1 surface glycoprotein gp120, and structural information about this region and its antigenic landscape will be crucial in the design of an effective HIV-1 vaccine. We have determined a crystal structure of V1V2 in complex with human MAb 830A and have shown that MAb 830A recognizes a region overlapping the ␣4␤7 integrin-binding site. We also showed that V1V2 forms a 5-stranded beta barrel, an elegant structure allowing sequence variations in the strand-connecting loops while preserving a conserved core. The HIV-1 envelope (Env) glycoprotein complex, consisting of glycoproteins gp120 and gp41, mediates the virus entry into the host cell. This heterotrimer is the major target for neutralizing antibodies (Abs) induced in HIV-1-infected patients and for HIV/ AIDS vaccine development (1). Glycoprotein gp120 has five variable and five conserved regions (2); the region consisting of the first and second variable regions (V1V2) is the most diverse in both sequence and length. V1V2, including residues 126 to 196 in the HXB2 numbering scheme (3), usually has two nested disulfide bonds; the V1 disulfide bond (between cysteine residues 131 and 157) is located within the V2 disulfide bond (between residues 126 and 196) (4). The average length of V1V2 is about 80 amino acids (aa), with a possibility of large length variations mostly derived from two regions, one in the middle of V1 and the other near the C-terminal end of V2. Recent data have shown that V1V2 is locate...

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Section: Discussionmentioning

confidence: 99%

The V1V2 Region of HIV-1 gp120 Forms a Five-Stranded Beta Barrel

Pan

Gorny

Zolla‐Pazner

et al. 2015

J Virol

114

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“…The envelope glycoproteins of lentiviruses form a trimeric complex with extensive N-linked glycosylation to shield key epitopes from antibody recognition [43]. This trimeric complex is involved in mediating the virus entry into the target cells [43,44].…”

Section: Hiv-1 and Hiv-2 Envelope Structuresmentioning

confidence: 99%

“…This trimeric complex is involved in mediating the virus entry into the target cells [43,44]. The surface (SU) glycoprotein (i.e., gp120-125; MW 120-125 kDa) is bound to a transmembrane glycoprotein (i.e., gp36-41; MW 36-41 kDa).…”

Section: Hiv-1 and Hiv-2 Envelope Structuresmentioning

confidence: 99%

“…The V2 region, which together with V1 and V3 regulates the stability of the trimer complex, has been shown to be immunogenic and in some cases is a target for broadly cross-reactive neutralizing antibodies [43,[53][54][55]. Alignment of the primate lentivirus V2 sequences revealed the presence of two conserved cysteine residues in HIV-2 and SIV strains, which are absent in all HIV-1 strains [43].…”

Section: Hiv-1 and Hiv-2 Envelope Structuresmentioning

confidence: 99%

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How does the humoral response to HIV-2 infection differ from HIV-1 and can this explain the distinct natural history of infection with these two human retroviruses?

Makvandi‐Nejad

Rowland‐Jones²

2015

Immunology Letters

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“…The V1/V2 region is implicated in exposure of the variable region 3 (V3) to HIV host cell receptors (36). Conversely, the lack of a pair of cysteines present in the V2 region of HIV-2 and SIV strains but not in the HIV-1 Env glycoprotein has been suggested as a factor contributing to the high virulence of HIV-1 (37).…”

mentioning

confidence: 99%

Role of Cysteines in Stabilizing the Randomized Receptor Binding Domains within Feline Leukemia Virus Envelope Proteins

Valdivieso-Torres

Sarangi

Whidby

et al. 2016

J Virol

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Retargeting of gammaretroviral envelope proteins has shown promising results in the isolation of novel isolates with therapeutic potential. However, the optimal conditions required to obtain high-affinity retargeted envelope proteins with narrow tropism are not understood. This study highlights the advantage of constrained peptides within receptor binding domains and validates the random library screening technique of obtaining novel retargeted Env proteins. Using a modified vector backbone to screen the envelope libraries on 143B osteosarcoma cells, three novel and unique retargeted envelopes were isolated. The use of complex disulfide bonds within variable regions required for receptor binding is found within natural gammaretroviral envelope isolates. Interestingly, two of the isolates, named AII and BV2, have a pair of cysteines located within the randomized region of 11 amino acids similar to that identified within the CP Env, an isolate identified in a previous Env library screen on the human renal carcinoma Caki-1 cell line. The amino acids within the randomized region of AII and BV2 envelopes that are essential for viral infection have been identified in this study and include these cysteine residues. Through mutagenesis studies, the putative disulfide bond pairs including and beyond the randomized region were examined. In parallel, the disulfide bonds of CP Env were identified using mass spectrometry. The results indicate that this pair of cysteines creates the structural context to position key hydrophobic (F and W) and basic (K and H) residues critical for viral titer and suggest that AII, BV2, and CP internal cysteines bond together in distinct ways. T he specificity of retroviral vectors is initially conferred by the envelope (Env) protein present on the surface of virus particles. This Env protein is responsible for binding to a host cell receptor, thereby initiating virus entry. In gammaretroviruses, the Env protein is composed of a transmembrane protein (TM) and a surface protein (SU). For murine leukemia virus (MLV) and feline leukemia virus (FeLV) SUs, primary receptor binding is localized to the N-terminal half of SU (1, 2, 12). Critical residues for specificity are encoded within the N-terminal variable regions, VRA and VRB. Secondary receptor binding sites that promote viral infection have also been identified within the SU C terminus (3-5).FeLV Envs are classified as A, B, and C, originally based on interference assays (6, 7). The receptors for these three major subgroups have been identified as THTR1 (8), PiT1 (9), and FLVCR1 (10, 11), respectively, molecularly confirming the distinct receptor usage for each subgroup. For FeLV-A, 19 residues in the VRA can be replaced with 16 residues of FeLV-C VRA to sufficiently alter the binding specificity, thus switching receptor usage (12). In FeLV-A, the VRA and VRB each include a pair of cysteines, which have the potential to form intramolecular disulfide bonds (5). The cysteine contents of MLV and FeLV-B SUs are more complex; ecotropic MLV ...

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A Twin-Cysteine Motif in the V2 Region of gp120 Is Associated with SIV Envelope Trimer Stabilization

Cited by 19 publications

References 42 publications

The V1V2 Region of HIV-1 gp120 Forms a Five-Stranded Beta Barrel

The V1V2 Region of HIV-1 gp120 Forms a Five-Stranded Beta Barrel

How does the humoral response to HIV-2 infection differ from HIV-1 and can this explain the distinct natural history of infection with these two human retroviruses?

Role of Cysteines in Stabilizing the Randomized Receptor Binding Domains within Feline Leukemia Virus Envelope Proteins

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