Functional and immunochemical cross-reactivity of V2-specific monoclonal antibodies from HIV-1-infected individuals

Gorny, Miroslaw K.; Pan, Ruimin; Williams, Constance; Wang, Xiaohong; Volsky, Barbara; O'Neal, Timothy; Spurrier, Brett; Sampson, Jared M.; Li, Liuzhe; Seaman, Michael S.; Kong, Xiang‐Peng; Zolla‐Pazner, Susan

doi:10.1016/j.virol.2012.02.003

Cited by 85 publications

(154 citation statements)

References 62 publications

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“…These Abs do not exhibit unusual structural or genetic characteristics, and their immunoglobulin genes undergo relatively little somatic hypermutation from germline (17,18). Conventional Abs have long been known to protect against infection in animal systems.…”

Section: Types Of Antibodies Conventional Absmentioning

confidence: 99%

“…The structure of this region has so far not been solved, suggesting that it is highly flexible and dynamic. Abs targeting V2i are highly cross-reactive in binding to monomeric gp120 but do not neutralize HIV well (18), suggesting that the epitope is mostly occluded from Ab recognition in the trimeric envelope. V2p epitope.…”

Section: Abs Targeting Variable Loops 1 and 2 (V1v2)mentioning

confidence: 99%

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Antibodies Targeting the Envelope of HIV-1

Mayr

Zolla‐Pazner²

2015

Microbiol Spectr

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Antibodies (Abs) are a critical component of the human immune response against viral infections. In HIV-infected patients, a robust Ab response against the virus develops within months of infection; however, due to numerous strategies, the virus usually escapes the biological effects of the various Abs. Here we provide an overview of the different viral evasion mechanisms, including glycosylation, high mutation rate, and conformational masking by the envelope glycoproteins of the virus. In response to virus infection and to its evolution within a host, "conventional Abs" are generated, and these can also be induced by immunization; generally, these Abs are limited in their neutralization breadth and potency. In contrast, "exceptional Abs" require extended exposure to virus to generate the required hypermutation in the immunoglobulin variable regions, and they occur only in rare HIV-infected individuals, but they display impressive breadth and potency. In this review, we describe the major regions of the HIV envelope spike that are targeted by conventional and exceptional Abs. These include the first, second, and third variable loops (V1, V2, and V3) located at the apex of the envelope trimer, the CD4 binding site, and the membrane-proximal external region of the gp41 ectodomain. Lastly, we discuss the challenging task of HIV immunogen design and approaches for choosing which immunogens might be used to elicit protective Abs.

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Section: Types Of Antibodies Conventional Absmentioning

confidence: 99%

Section: Abs Targeting Variable Loops 1 and 2 (V1v2)mentioning

confidence: 99%

Antibodies Targeting the Envelope of HIV-1

Mayr

Zolla‐Pazner²

2015

Microbiol Spectr

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“…Their epitopes are also located in strand B, overlapping the V2q epitope region, but have a helical or helical-coil structure, different from the beta strand structure of the V2q type (22). The V2i type is defined by a panel of seven human MAbs, including 830A, 697-30D, and 2158 (17,23). Extensive immunological, mutagenesis, and computational modeling data have shown that the V2i epitopes overlap the integrin-binding site and likely recognize discontinuous regions in V1V2 (17,18,23).…”

mentioning

confidence: 99%

“…The V2i type is defined by a panel of seven human MAbs, including 830A, 697-30D, and 2158 (17,23). Extensive immunological, mutagenesis, and computational modeling data have shown that the V2i epitopes overlap the integrin-binding site and likely recognize discontinuous regions in V1V2 (17,18,23). However, the precise nature of the V2i epitopes is still unknown.…”

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confidence: 99%

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

Pan

Gorny

Zolla‐Pazner

et al. 2015

J Virol

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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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“…15 We tested the possibility that the rescued IgG1s recognize the heterodimer in its native membrane-bound form by using 293T cells transfected with constructs encoding full E1E2 polypeptides. 12 We specifically selected E1E2 of the HCV genotypes 1b and 2a matching the infected patients genotypes, as well as E1E2 derived from the HCV isolate H77 of genotype 1a.…”

Section: Resultsmentioning

confidence: 99%

B-cell receptors expressed by lymphomas of hepatitis C virus (HCV)–infected patients rarely react with the viral proteins

Kuo

Wang

et al. 2014

Blood

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Key Points• We tested the hypothesis that B-cell lymphomas arising in HCV-infected patients express B-cell receptors specific to the virus.• We analyzed the reactivity of these B-cell receptors with HCV proteins using several experimental approaches, none of which supported the hypothesis.Chronic hepatitis C virus (HCV) infection has been implicated in the induction and maintenance of B-cell lymphomas. The strongest evidence for this derives from clinical observations of tumor regressions upon antiviral treatments. Here we used multiple methods to test the hypothesis that the expansion of HCV-specific B cells gives rise to lymphomas. We obtained lymphoma tissues from HCV-infected lymphoma patients, including some that later regressed upon antiviral treatments. suggesting immunoglobulin G (IgG)'s importance for lymphoma cell survival. Yet lymphomas' cognate antigens are not known. B-cell proliferative diseases such as mixed cryoglobulinemia (MC) and B-cell non-Hodgkin lymphoma (B-NHL) that arise in hepatitis C virus (HCV)-infected patients represent a special opportunity to study antigenic drive in lymphomagenesis. First, both MC and B-NHL use a restricted V-gene repertoire shared by anti-HCV envelope antibodies.4,5 Second, elimination of HCV by antiviral therapies in patients with these B-cell diseases has been associated with their regression.6 Moreover, we previously identified an HCV-associated lymphoma whose BCR bound the HCV envelope protein E2.7 Normal B cells aimed at eliminating HCV would be expected to bind the virus via 2 receptors: the cognate BCR and the viral entry receptor CD81, which is a member of a costimulatory complex with CD19/CD21. Such B cells would receive dual stimulatory signals and might undergo unchecked proliferation during chronic HCV infection.Here we tested this hypothesis by expressing BCRs from lymphomas of HCV-infected patients as soluble IgGs, suggesting their importance, and as membrane IgMs. We included patients who had tumor regressions after antiviral therapies, 8 expecting that they would be more likely to express anti-HCV BCRs. We used several methods to test the reactivity of the rescued lymphoma BCRs with viral proteins and particles. However, we found no reactivity and therefore no evidence to support the hypothesis that viral antigens drive B-cell lymphomas. Methods PatientsBiopsy specimens of patients with B-NHL and chronic HCV infection were collected at Stanford University Medical Center, Sloan Kettering Memorial Cancer Center, and the University of Pavia Medical School. Patients' medical record numbers were de-identified and reassigned numbers. The institutional review boards at each center approved this study, and written informed consent was obtained from all patients in accordance with the Declaration of Helsinki.V-gene rescue mRNA was isolated using RNeasy (Qiagen, Valencia, CA), cDNA was amplified using SMARTer RACE (Clontech, Mountain View, CA), and The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to i...

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Functional and immunochemical cross-reactivity of V2-specific monoclonal antibodies from HIV-1-infected individuals

Cited by 85 publications

References 62 publications

Antibodies Targeting the Envelope of HIV-1

Antibodies Targeting the Envelope of HIV-1

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

B-cell receptors expressed by lymphomas of hepatitis C virus (HCV)–infected patients rarely react with the viral proteins

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