Development of Neutralization Breadth against Diverse HIV‐1 by Increasing Ab–Ag Interface on V2

Gao, Nan; Gai, Yanxin; Meng, Linli; Wang, Chu; Wang, Wei; Li, Xiaojun; Gu, Tiejun; Louder, Mark K.; Doria‐Rose, Nicole A.; Wiehe, Kevin; Nazzari, Alexandra; Olia, Adam S.; Gorman, Jason; Rawi, Reda; Wu, Wenmin; Smith, Catherine Arnott; Khant, Htet; Val, Natalia de; Yu, Bin; Luo, Oscar Junhong; Niu, Haitao; Tsybovsky, Yaroslav; Liao, Hua‐Xin; Kepler, Thomas B.; Kwong, Peter D.; Mascola, John R.; Qin, Chuan; Zhou, Tongqing; Yu, Xianghui; Gao, Feng

doi:10.1002/advs.202200063

Cited by 3 publications

(4 citation statements)

References 64 publications

(81 reference statements)

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“…Studies on antibody–virus co-evolution in HIV-1-infected individuals who developed broad neutralization activities have demonstrated that bnAbs matured only after extensive diversification of the env gene [ 24 , 25 , 26 ]. Similar results were also observed in long-term-SHIV-infected rhesus macaques [ 27 , 28 ]. This indicates that the continuous diversification of the env genes plays an important role in the generation of bnAbs in the infected individuals [ 24 , 25 ].…”

Section: Introductionsupporting

confidence: 85%

“…This new approach demonstrates a great potential to improve nAb responses induced by HIV-1 vaccines. Continued optimization the Env trimer design such as by developing more stable UFO-BG trimers, Env trimers with a better exposed “up” position V2-apex [ 28 ] or nanoparticle vaccine approaches [ 56 ] may further improve the immunogenicity of the current approach.…”

Section: Discussionmentioning

confidence: 99%

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Enhancement of Neutralization Responses through Sequential Immunization of Stable Env Trimers Based on Consensus Sequences from Select Time Points by Mimicking Natural Infection

Wan

Xiao

Sun

et al. 2023

IJMS

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HIV-1 vaccines have been challenging to develop, partly due to the high level of genetic variation in its genome. Thus, a vaccine that can induce cross-reactive neutralization activities will be needed. Studies on the co-evolution of antibodies and viruses indicate that mimicking the natural infection is likely to induce broadly neutralizing antibodies (bnAbs). We generated the consensus Env sequence for each time point in subject CH505, who developed broad neutralization activities, and selected five critical time points before broad neutralization was detected. These consensus sequences were designed to express stable Env trimers. Priming with the transmitted/founder Env timer and sequential boosting with these consensus Env trimers from different time points induced broader and more potent neutralizing activities than the BG505 Env trimer in guinea pigs. Analysis of the neutralization profiles showed that sequential immunization of Env trimers favored nAbs with gp120/gp41 interface specificity while the BG505 Env trimer favored nAbs with V2 specificity. The unique features such as consensus sequences, stable Env trimers and the sequential immunization to mimic natural infection likely has allowed the induction of improved neutralization responses.

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Section: Introductionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Enhancement of Neutralization Responses through Sequential Immunization of Stable Env Trimers Based on Consensus Sequences from Select Time Points by Mimicking Natural Infection

Wan

Xiao

Sun

et al. 2023

IJMS

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“…Additionally, although not the subject of this study, our understanding of how gp120 interacts with ⍺ 4 β 7 is also incomplete, but relevant to the findings presented here. In contrast to the 1° ⍺ 4 β 7 binding site in CD4 D2, which is well exposed [ 10 ], the analogous ⍺ 4 β 7 binding site in gp120 V2 is partially hidden in the predominant ground state represented in prefusion trimers [ 13 , 74 – 78 ]. We do not know at which step in the transition of gp120 from the closed trimer to the open coreceptor bound state that V2 interacts with ⍺ 4 β 7 , nor whether this interaction precedes or follows CD4 interactions with gp120.…”

Section: Discussionmentioning

confidence: 99%

“…We do not know at which step in the transition of gp120 from the closed trimer to the open coreceptor bound state that V2 interacts with ⍺ 4 β 7 , nor whether this interaction precedes or follows CD4 interactions with gp120. Perhaps a more detailed understanding of V2 conformation as the trimer moves away from its ground state will resolve the context in which gp120 engages ⍺ 4 β 7 [ 14 , 78 ].…”

Section: Discussionmentioning

confidence: 99%

The V2 domain of HIV gp120 mimics an interaction between CD4 and integrin ⍺4β7

Van Ryk,

Vimonpatranon,

Hiatt

et al. 2023

PLoS Pathog

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The CD4 receptor, by stabilizing TCR-MHC II interactions, plays a central role in adaptive immunity. It also serves as the HIV docking receptor. The HIV gp120 envelope protein binds directly to CD4. This interaction is a prerequisite for viral entry. gp120 also binds to ⍺4β7, an integrin that is expressed on a subset of memory CD4+ T cells. HIV tropisms for CD4+ T cells and gut tissues are central features of HIV pathogenesis. We report that CD4 binds directly to ⍺4β7 in a dynamic way, consistent with a cis regulatory interaction. The molecular details of this interaction are related to the way in which gp120 interacts with both receptors. Like MAdCAM-1 and VCAM-1, two recognized ligands of ⍺4β7, the binding interface on CD4 includes 2 sites (1° and accessory), distributed across its two N-terminal IgSF domains (D1 and D2). The 1° site includes a sequence in the G β-strand of CD4 D2, KIDIV, that binds directly to ⍺4β7. This pentapeptide sequence occurs infrequently in eukaryotic proteins. However, a closely related and conserved sequence, KLDIV, appears in the V2 domain of gp120. KLDIV mediates gp120-⍺4β7 binding. The accessory ⍺4β7 binding site on CD4 includes Phe43. The Phe43 aromatic ring protrudes outward from one edge of a loop connecting the C’C” strands of CD4 D1. Phe43 is a principal contact for HIV gp120. It interacts with conserved residues in the recessed CD4 binding pocket. Substitution of Phe43 abrogates CD4 binding to both gp120 and ⍺4β7. As such, the interactions of gp120 with both CD4 and ⍺4β7 reflect elements of their interactions with each other. These findings indicate that gp120 specificities for CD4 and ⍺4β7 are interrelated and suggest that selective pressures which produced a CD4 tropic virus that replicates in gut tissues are linked to a dynamic interaction between these two receptors.

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Development of Neutralization Breadth against Diverse HIV‐1 by Increasing Ab–Ag Interface on V2

et al. 2022

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Understanding maturation pathways of broadly neutralizing antibodies (bnAbs) against HIV-1 can be highly informative for HIV-1 vaccine development. A lineage of J038 bnAbs is now obtained from a long-term SHIV-infected macaque. J038 neutralizes 54% of global circulating HIV-1 strains. Its binding induces a unique "up" conformation for one of the V2 loops in the trimeric envelope glycoprotein and is heavily dependent on glycan, which provides nearly half of the binding surface. Their unmutated common ancestor neutralizes the autologous virus. Continuous maturation enhances neutralization potency and breadth of J038 lineage antibodies via expanding antibody-Env contact areas surrounding the core region contacted by germline-encoded residues. Developmental details and recognition features of J038 lineage antibodies revealed here provide a new pathway for elicitation and maturation of V2-targeting bnAbs.

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Development of Neutralization Breadth against Diverse HIV‐1 by Increasing Ab–Ag Interface on V2

Cited by 3 publications

References 64 publications

Enhancement of Neutralization Responses through Sequential Immunization of Stable Env Trimers Based on Consensus Sequences from Select Time Points by Mimicking Natural Infection

Enhancement of Neutralization Responses through Sequential Immunization of Stable Env Trimers Based on Consensus Sequences from Select Time Points by Mimicking Natural Infection

The V2 domain of HIV gp120 mimics an interaction between CD4 and integrin ⍺4β7

Development of Neutralization Breadth against Diverse HIV‐1 by Increasing Ab–Ag Interface on V2

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