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Viruses
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Structural Biology of HIV-1 Entry
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Structural Biology of HIV-1 Entry

A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "General Virology".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 31220

Special Issue Editor

Dr. Priyamvada Acharya

E-Mail Website
Guest Editor
Duke University School of Medicine, Durham, USA
Interests: structural biology and mechanism of HIV-1 entry; HIV-1 vaccine design; HIV-1 entry inhibitors; SARS-CoV-2 spike structural biology and vaccine design

Special Issue Information

HIV-1 entry is mediated by its trimeric Envelope (Env) surface glycoprotein.  Binding of the gp120 subunit to host cell surface CD4 receptor triggers Env conformational changes that expose the binding site for a co-receptor, typically CCR5 or CXCR4. Additional conformational changes that follow co-receptor binding lead to membrane fusion. Env conformational changes on the HIV-1 entry pathway are mediated by an allosteric network of protein contacts that facilitate receptor-mediated structural changes at sites distal from the receptor binding site. Env is the sole target for neutralizing antibodies on the HIV-1 surface. Regions that are critical for entry, such as receptor binding sites and the fusion peptide, are vulnerable and are thus protected by multiple immune evasion mechanisms. The HIV-1 entry pathway can also be effectively targeted by entry inhibitors, exemplified by enfuvirtide and maraviroc, both licensed antiretroviral drugs that target different steps on the entry pathway.  Structural biology of HIV-1 entry has been a subject of intense investigations for many years, and is closely tied to efforts to develop an effective HIV-1 vaccine. In this Special Issue, we will gather and connect existing knowledge in the field on the structural biology of HIV-1 entry and reflect on how this informs HIV-1 vaccine and therapeutics development.

Dr. Priyamvada Acharya
Guest Editor

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Keywords

  • HIV-1 entry
  • HIV-1 envelope
  • gp120
  • gp41
  • CD4
  • CCR5
  • CXCR5
  • Conformational change
  • Allostery
  • HIV-1 vaccine
  • Entry inhibitors

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Published Papers (7 papers)

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Research

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24 pages, 5132 KiB  
Article
Modeling of CCR5 Recognition by HIV-1 gp120: How the Viral Protein Exploits the Conformational Plasticity of the Coreceptor
by Célien Jacquemard, Florian Koensgen, Philippe Colin, Bernard Lagane and Esther Kellenberger
Viruses 2021, 13(7), 1395; https://doi.org/10.3390/v13071395 - 18 Jul 2021
Cited by 9 | Viewed by 4459
Abstract
The chemokine receptor CCR5 is a key player in HIV-1 infection. The cryo-EM 3D structure of HIV-1 envelope glycoprotein (Env) subunit gp120 in complex with CD4 and CCR5 has provided important structural insights into HIV-1/host cell interaction, yet it has not explained the [...] Read more.
The chemokine receptor CCR5 is a key player in HIV-1 infection. The cryo-EM 3D structure of HIV-1 envelope glycoprotein (Env) subunit gp120 in complex with CD4 and CCR5 has provided important structural insights into HIV-1/host cell interaction, yet it has not explained the signaling properties of Env nor the fact that CCR5 exists in distinct forms that show distinct Env binding properties. We used classical molecular dynamics and site-directed mutagenesis to characterize the CCR5 conformations stabilized by four gp120s, from laboratory-adapted and primary HIV-1 strains, and which were previously shown to bind differentially to distinct CCR5 forms and to exhibit distinct cellular tropisms. The comparative analysis of the simulated structures reveals that the different gp120s do indeed stabilize CCR5 in different conformational ensembles. They differentially reorient extracellular loops 2 and 3 of CCR5 and thus accessibility to the transmembrane binding cavity. They also reshape this cavity differently and give rise to different positions of intracellular ends of transmembrane helices 5, 6 and 7 of the receptor and of its third intracellular loop, which may in turn influence the G protein binding region differently. These results suggest that the binding of gp120s to CCR5 may have different functional outcomes, which could result in different properties for viruses. Full article
(This article belongs to the Special Issue Structural Biology of HIV-1 Entry)
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12 pages, 3863 KiB  
Article
Elicitation of Neutralizing Antibody Responses to HIV-1 Immunization with Nanoparticle Vaccine Platforms
by Amyn A. Murji, Juliana S. Qin, Tandile Hermanus, Lynn Morris and Ivelin S. Georgiev
Viruses 2021, 13(7), 1296; https://doi.org/10.3390/v13071296 - 2 Jul 2021
Cited by 6 | Viewed by 2631
Abstract
A leading strategy for developing a prophylactic HIV-1 vaccine is the elicitation of antibodies that can neutralize a large fraction of circulating HIV-1 variants. However, a major challenge that has limited the effectiveness of current vaccine candidates is the extensive global diversity of [...] Read more.
A leading strategy for developing a prophylactic HIV-1 vaccine is the elicitation of antibodies that can neutralize a large fraction of circulating HIV-1 variants. However, a major challenge that has limited the effectiveness of current vaccine candidates is the extensive global diversity of the HIV-1 envelope protein (Env), the sole target for HIV-neutralizing antibodies. To address this challenge, various strategies incorporating Env diversity into the vaccine formulation have been proposed. Here, we assessed the potential of two such strategies that utilize a nanoparticle-based vaccine platform to elicit broadly neutralizing antibody responses. The nanoparticle immunogens developed here consisted of different formulations of Envs from strains BG505 (clade A) and CZA97 (clade C), attached to the N-termini of bacterial ferritin. Single—antigen nanoparticle cocktails, as well as mosaic nanoparticles bearing both Env trimers, elicited high antibody titers in mice and guinea pigs. Furthermore, serum from guinea pigs immunized with nanoparticle immunogens achieved autologous, and in some cases heterologous, tier 2 neutralization, although significant differences between mosaic and single—antigen nanoparticles were not observed. These results provide insights into the ability of different vaccine strategies for incorporating Env sequence diversity to elicit neutralizing antibodies, with implications for the development of broadly protective HIV-1 vaccines. Full article
(This article belongs to the Special Issue Structural Biology of HIV-1 Entry)
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Review

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15 pages, 2141 KiB  
Review
A Structural Update of Neutralizing Epitopes on the HIV Envelope, a Moving Target
by Emma Parker Miller, Maxwell T. Finkelstein, Molly C. Erdman, Paul C. Seth and Daniela Fera
Viruses 2021, 13(9), 1774; https://doi.org/10.3390/v13091774 - 5 Sep 2021
Cited by 10 | Viewed by 3916
Abstract
Antibodies that can neutralize diverse HIV-1 strains develop in ~10–20% of HIV-1 infected individuals, and their elicitation is a goal of vaccine design. Such antibodies can also serve as therapeutics for those who have already been infected with the virus. Structural characterizations of [...] Read more.
Antibodies that can neutralize diverse HIV-1 strains develop in ~10–20% of HIV-1 infected individuals, and their elicitation is a goal of vaccine design. Such antibodies can also serve as therapeutics for those who have already been infected with the virus. Structural characterizations of broadly reactive antibodies in complex with the HIV-1 spike indicate that there are a limited number of sites of vulnerability on the spike. Analysis of their structures can help reveal commonalities that would be useful in vaccine design and provide insights on combinations of antibodies that can be used to minimize the incidence of viral resistance mutations. In this review, we give an update on recent structures determined of the spike in complex with broadly neutralizing antibodies in the context of all epitopes on the HIV-1 spike identified to date. Full article
(This article belongs to the Special Issue Structural Biology of HIV-1 Entry)
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13 pages, 4497 KiB  
Review
Quaternary Interaction of the HIV-1 Envelope Trimer with CD4 and Neutralizing Antibodies
by Qingbo Liu, Peng Zhang and Paolo Lusso
Viruses 2021, 13(7), 1405; https://doi.org/10.3390/v13071405 - 20 Jul 2021
Cited by 5 | Viewed by 2504
Abstract
The entry of HIV-1 into host cells is initiated by the interaction of the viral envelope (Env) spike with the CD4 receptor. During this process, the spike undergoes a series of conformational changes that eventually lead to the exposure of the fusion peptide [...] Read more.
The entry of HIV-1 into host cells is initiated by the interaction of the viral envelope (Env) spike with the CD4 receptor. During this process, the spike undergoes a series of conformational changes that eventually lead to the exposure of the fusion peptide located at the N-terminus of the transmembrane glycoprotein, gp41. Recent structural and functional studies have provided important insights into the interaction of Env with CD4 at various stages. However, a fine elucidation of the earliest events of CD4 contact and its immediate effect on the Env conformation remains a challenge for investigation. Here, we summarize the discovery of the quaternary nature of the CD4-binding site in the HIV-1 Env and the role of quaternary contact in the functional interaction with the CD4 receptor. We propose two models for this initial contact based on the current knowledge and discuss how a better understanding of the quaternary interaction may lead to improved immunogens and antibodies targeting the CD4-binding site. Full article
(This article belongs to the Special Issue Structural Biology of HIV-1 Entry)
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12 pages, 1997 KiB  
Review
HIV-1 Envelope Conformation, Allostery, and Dynamics
by Ashley Lauren Bennett and Rory Henderson
Viruses 2021, 13(5), 852; https://doi.org/10.3390/v13050852 - 7 May 2021
Cited by 6 | Viewed by 3585
Abstract
The HIV-1 envelope glycoprotein (Env) mediates host cell fusion and is the primary target for HIV-1 vaccine design. The Env undergoes a series of functionally important conformational rearrangements upon engagement of its host cell receptor, CD4. As the sole target for broadly neutralizing [...] Read more.
The HIV-1 envelope glycoprotein (Env) mediates host cell fusion and is the primary target for HIV-1 vaccine design. The Env undergoes a series of functionally important conformational rearrangements upon engagement of its host cell receptor, CD4. As the sole target for broadly neutralizing antibodies, our understanding of these transitions plays a critical role in vaccine immunogen design. Here, we review available experimental data interrogating the HIV-1 Env conformation and detail computational efforts aimed at delineating the series of conformational changes connecting these rearrangements. These studies have provided a structural mapping of prefusion closed, open, and transition intermediate structures, the allosteric elements controlling rearrangements, and state-to-state transition dynamics. The combination of these investigations and innovations in molecular modeling set the stage for advanced studies examining rearrangements at greater spatial and temporal resolution. Full article
(This article belongs to the Special Issue Structural Biology of HIV-1 Entry)
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12 pages, 12289 KiB  
Review
Small Molecule HIV-1 Attachment Inhibitors: Discovery, Mode of Action and Structural Basis of Inhibition
by Yen-Ting Lai
Viruses 2021, 13(5), 843; https://doi.org/10.3390/v13050843 - 6 May 2021
Cited by 23 | Viewed by 4550
Abstract
Viral entry into host cells is a critical step in the viral life cycle. HIV-1 entry is mediated by the sole surface envelope glycoprotein Env and is initiated by the interaction between Env and the host receptor CD4. This interaction, referred to as [...] Read more.
Viral entry into host cells is a critical step in the viral life cycle. HIV-1 entry is mediated by the sole surface envelope glycoprotein Env and is initiated by the interaction between Env and the host receptor CD4. This interaction, referred to as the attachment step, has long been considered an attractive target for inhibitor discovery and development. Fostemsavir, recently approved by the FDA, represents the first-in-class drug in the attachment inhibitor class. This review focuses on the discovery of temsavir (the active compound of fostemsavir) and analogs, mechanistic studies that elucidated the mode of action, and structural studies that revealed atomic details of the interaction between HIV-1 Env and attachment inhibitors. Challenges associated with emerging resistance mutations to the attachment inhibitors and the development of next-generation attachment inhibitors are also highlighted. Full article
(This article belongs to the Special Issue Structural Biology of HIV-1 Entry)
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19 pages, 2411 KiB  
Review
HIV-1 Entry and Membrane Fusion Inhibitors
by Tianshu Xiao, Yongfei Cai and Bing Chen
Viruses 2021, 13(5), 735; https://doi.org/10.3390/v13050735 - 23 Apr 2021
Cited by 50 | Viewed by 8193
Abstract
HIV-1 (human immunodeficiency virus type 1) infection begins with the attachment of the virion to a host cell by its envelope glycoprotein (Env), which subsequently induces fusion of viral and cell membranes to allow viral entry. Upon binding to primary receptor CD4 and [...] Read more.
HIV-1 (human immunodeficiency virus type 1) infection begins with the attachment of the virion to a host cell by its envelope glycoprotein (Env), which subsequently induces fusion of viral and cell membranes to allow viral entry. Upon binding to primary receptor CD4 and coreceptor (e.g., chemokine receptor CCR5 or CXCR4), Env undergoes large conformational changes and unleashes its fusogenic potential to drive the membrane fusion. The structural biology of HIV-1 Env and its complexes with the cellular receptors not only has advanced our knowledge of the molecular mechanism of how HIV-1 enters the host cells but also provided a structural basis for the rational design of fusion inhibitors as potential antiviral therapeutics. In this review, we summarize our latest understanding of the HIV-1 membrane fusion process and discuss related therapeutic strategies to block viral entry. Full article
(This article belongs to the Special Issue Structural Biology of HIV-1 Entry)
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