Cross-Clade HIV-1 Neutralizing Antibodies Induced with V3-Scaffold Protein Immunogens following Priming with gp120 DNA

Zolla‐Pazner, Susan; Kong, Xiang‐Peng; Jiang, Xunqing; Cardozo, Timothy; Nádas, Arthur; Cohen, Sandra; Totrov, Maxim; Seaman, Michael S.; Wang, Shixia; Lu, Shan

doi:10.1128/jvi.05086-11

Cited by 56 publications

(53 citation statements)

References 77 publications

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“…We had previously tested cholera toxin B subunit (CTB)-based immunogens carrying HIV-1 V3 epitopes and showed that they were highly immunogenic and elicited cross-clade neutralizing Ab responses in rabbits (48)(49)(50). To test CTB's effects on V1V2 immunogens, we chemically conjugated the structurally constrained V1V2(ZM109)-1FD6 with the CTB and showed that it preserved the V2q and V2i epitopes in the V1V2 scaffold (Fig.…”

Section: Resultsmentioning

confidence: 99%

Rationally Designed Immunogens Targeting HIV-1 gp120 V1V2 Induce Distinct Conformation-Specific Antibody Responses in Rabbits

Jiang

Totrov

et al. 2016

J Virol

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The V1V2 region of HIV-1 gp120 harbors a major vulnerable site targeted by a group of broadly neutralizing monoclonal antibodies (MAbs) such as PG9 through strand-strand recognition. However, this epitope region is structurally polymorphic as it can also form a helical conformation recognized by RV144 vaccine-induced MAb CH58. This structural polymorphism is a potential mechanism for masking the V1V2 vulnerable site. Designing immunogens that can induce conformation-specific antibody (Ab) responses may lead to vaccines targeting this vulnerable site. We designed a panel of immunogens engrafting the V1V2 domain into trimeric and pentameric scaffolds in structurally constrained conformations. We also fused V1V2 to an Fc fragment to mimic the unconstrained V1V2 conformation. We tested these V1V2-scaffold proteins for immunogenicity in rabbits and assessed the responses by enzyme-linked immunosorbent assay (ELISA) and competition assays. Our V1V2 immunogens induced distinct conformation-specific Ab responses. Abs induced by structurally unconstrained immunogens reacted preferentially with unconstrained V1V2 antigens, suggesting recognition of the helical configuration, while Abs induced by the structurally constrained immunogens reacted preferentially with constrained V1V2 antigens, suggesting recognition of the ␤-strand conformation. The Ab responses induced by the structurally constrained immunogens were more broadly reactive and had higher titers than those induced by the structurally unconstrained immunogens. Our results demonstrate that immunogens presenting the different structural conformations of the gp120 V1V2 vulnerable site can be designed and that these immunogens induce distinct Ab responses with epitope conformation specificity. Therefore, these structurally constrained V1V2 immunogens are vaccine prototypes targeting the V1V2 domain of the HIV-1 envelope. IMPORTANCEThe correlates analysis of the RV144 HIV-1 vaccine trial suggested that the presence of antibodies to the V1V2 region of HIV-1 gp120 was responsible for the modest protection observed in the trial. In addition, V1V2 harbors one of the key vulnerable sites of HIV-1 Env recognized by a family of broadly neutralizing MAbs such as PG9. Thus, V1V2 is a key target for vaccine development. However, this vulnerable site is structurally polymorphic, and designing immunogens that present different conformations is crucial for targeting this site. We show here that such immunogens can be designed and that they induced conformation-specific antibody responses in rabbits. Our immunogens are therefore prototypes of vaccine candidates targeting the V1V2 region of HIV-1 Env.

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Section: Resultsmentioning

confidence: 99%

Rationally Designed Immunogens Targeting HIV-1 gp120 V1V2 Induce Distinct Conformation-Specific Antibody Responses in Rabbits

Jiang

Totrov

et al. 2016

J Virol

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“…This immunogenic region is likely another vulnerable site in V1V2, in addition to the strand C targeted by PG9 and other QNE MAbs. Precise structural mapping of this epitope region provides an opportunity to rationally design scaffold immunogens to focus antibody responses on this region (43,44). 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.…”

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

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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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“…For this, the V3 loop was spliced into a conformationally correct site on the highly immunogenic protein, cholera toxin subunit B, a protein which forms a pentameric structure and therefore presents five copies of V3 (94), serving as a particularly strong antigen for induction of Abs (95). High anti-V3 Ab titers were elicited in rabbits with one or a combination of V3-cholera toxin subunit B immunogens, and these immune sera were able to neutralize numerous diverse HIV strains (33,94).…”

Section: Abs Targeting Variable Loop 3 (V3)mentioning

confidence: 99%

“…Thus, even though conventional nAbs are limited in their breadth and potency, they are commonly made by HIV-positive individuals (32), by immunized humans (24), and by immunized animals (33,34), and the previously mentioned studies suggest that they can reduce infection rates. Therefore, such Abs, induced by vaccines, have substantial potential for influencing the course of the HIV epidemic.…”

Section: Types Of Antibodies Conventional Absmentioning

confidence: 99%

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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Cross-Clade HIV-1 Neutralizing Antibodies Induced with V3-Scaffold Protein Immunogens following Priming with gp120 DNA

Cited by 56 publications

References 77 publications

Rationally Designed Immunogens Targeting HIV-1 gp120 V1V2 Induce Distinct Conformation-Specific Antibody Responses in Rabbits

Rationally Designed Immunogens Targeting HIV-1 gp120 V1V2 Induce Distinct Conformation-Specific Antibody Responses in Rabbits

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

Antibodies Targeting the Envelope of HIV-1

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