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Common helical V1V2 conformations of HIV-1 Envelope expose the α4β7 binding site on intact virions

Journal Article · · Nature Communications
 [1];  [2];  [3];  [3];  [3];  [4];  [4]
  1. The Scripps Research Inst., La Jolla, CA (United States); National Inst. for Communicable Diseases (NICD), of the National Health Lab. Service (NHLS), Johannesburg (South Africa); Univ. of Witwatersrand, Johannesburg (South Africa)
  2. National Inst. for Communicable Diseases (NICD), of the National Health Lab. Service (NHLS), Johannesburg (South Africa); Univ. of Witwatersrand, Johannesburg (South Africa)
  3. National Inst. of Health (NIH), Bethesda, MD (United States)
  4. National Inst. for Communicable Diseases (NICD), of the National Health Lab. Service (NHLS), Johannesburg (South Africa); Univ. of Witwatersrand, Johannesburg (South Africa); Univ. of KwaZulu-Natal, Durban (South Africa)
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The α4β7 integrin is a non-essential HIV-1 adhesion receptor, bound by the gp120 V1V2 domain, facilitating rapid viral dissemination into gut-associated lymphoid tissues. Antibodies blocking this interaction early in infection can improve disease outcome, and V1V2-targeted antibodies were correlated with moderate efficacy reported from the RV144 HIV-1 vaccine trial. Monoclonal α4β7-blocking antibodies recognise two slightly different helical V2 conformations, and current structural data suggests their binding sites are occluded in prefusion envelope trimers. Here, we report cocrystal structures of two α4β7-blocking antibodies from an infected donor complexed with scaffolded V1V2 or V2 peptides. Both antibodies recognised the same helix-coil V2 conformation as RV144 antibody CH58, identifying a frequently sampled alternative conformation of full-length V1V2. In the context of Envelope, this α-helical form of V1V2 displays highly exposed α4β7-binding sites, potentially providing a functional role for non-native Envelope on virion or infected cell surfaces in HIV-1 dissemination, pathogenesis, and vaccine design.
Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Organization:
NIH; South African Research Chairs Initiative of the Dept. of Science and Technology and National Research Foundation of South Africa; USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
Grant/Contract Number:
W-31109-ENG-38
OSTI ID:
1480349
Journal Information:
Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 9; ISSN 2041-1723
Publisher:
Nature Publishing GroupCopyright Statement
Country of Publication:
United States
Language:
ENGLISH

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Cited By (5)

AAV-Mediated Expression of Broadly Neutralizing and Vaccine-like Antibodies Targeting the HIV-1 Envelope V2 Region journal September 2019
Vaccine-induced V1V2-specific antibodies control and or protect against infection with HIV, SIV and SHIV journal January 2019
HIV-1 Vaccine Sequences Impact V1V2 Antibody Responses: A Comparison of Two Poxvirus Prime gp120 Boost Vaccine Regimens journal February 2020
How can monoclonal antibodies be harnessed against neglected tropical diseases and other infectious diseases? journal July 2019
HIV vaccine delayed boosting increases Env variable region 2–specific antibody effector functions journal January 2020

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
HIV infections
X-ray crystallography
antibodies
vaccines