Molecular Mechanism of HIV-1 Entry.
Ontology highlight
ABSTRACT:
SUBMITTER: Chen B
PROVIDER: S-EPMC6744290 | biostudies-literature | 2019 Oct
REPOSITORIES: biostudies-literature
Publications
HIV-1 envelope glycoprotein [Env; trimeric (gp160)<sub>3</sub> cleaved to (gp120/gp41)<sub>3</sub>] attaches the virion to a susceptible cell and induces fusion of viral and cell membranes to initiate infection. It interacts with the primary receptor CD4 and coreceptor (e.g., chemokine receptor CCR5 or CXCR4) to allow viral entry by triggering large structural rearrangements and unleashing the fusogenic potential of gp41 to induce membrane fusion. Recent advances in structural biology of HIV-1 E ...[more]
Similar Datasets
Project description:Infection by HIV starts when the virus attaches to a susceptible cell. For viral replication to continue, the viral envelope must fuse with a cellular membrane, thereby delivering the viral core to the cytoplasm, where the RNA genome is reverse-transcribed. The key players in this entry by fusion are the envelope glycoprotein, on the viral side, and CD4 and a co-receptor, CCR5 or CXCR4, on the cellular side. Here, the interplay of these molecules is reviewed from cell-biological, structural, mechanistic, and modelling-based perspectives. Hypotheses are evaluated regarding the cellular compartment for entry, the transfer of virus through direct cell-to-cell contact, the sequence of molecular events, and the number of molecules involved on each side of the virus-cell divide. An emerging theme is the heterogeneity among the entry mediators on both sides, a diversity that affects the efficacy of entry inhibitors, be they small-molecule ligands, peptides or neutralizing antibodies. These insights inform rational strategies for therapy as well as vaccination.
| S-EPMC3417324 | biostudies-literature
Project description:Antibody-dependent enhancement (ADE) of viral entry has been a major concern for epidemiology, vaccine development, and antibody-based drug therapy. However, the molecular mechanism behind ADE is still elusive. Coronavirus spike protein mediates viral entry into cells by first binding to a receptor on the host cell surface and then fusing viral and host membranes. In this study, we investigated how a neutralizing monoclonal antibody (MAb), which targets the receptor-binding domain (RBD) of Middle East respiratory syndrome (MERS) coronavirus spike, mediates viral entry using pseudovirus entry and biochemical assays. Our results showed that MAb binds to the virus surface spike, allowing it to undergo conformational changes and become prone to proteolytic activation. Meanwhile, MAb binds to cell surface IgG Fc receptor, guiding viral entry through canonical viral-receptor-dependent pathways. Our data suggest that the antibody/Fc-receptor complex functionally mimics viral receptor in mediating viral entry. Moreover, we characterized MAb dosages in viral-receptor-dependent, Fc-receptor-dependent, and both-receptors-dependent viral entry pathways, delineating guidelines on MAb usages in treating viral infections. Our study reveals a novel molecular mechanism for antibody-enhanced viral entry and can guide future vaccination and antiviral strategies.IMPORTANCE Antibody-dependent enhancement (ADE) of viral entry has been observed for many viruses. It was shown that antibodies target one serotype of viruses but only subneutralize another, leading to ADE of the latter viruses. Here we identify a novel mechanism for ADE: a neutralizing antibody binds to the surface spike protein of coronaviruses like a viral receptor, triggers a conformational change of the spike, and mediates viral entry into IgG Fc receptor-expressing cells through canonical viral-receptor-dependent pathways. We further evaluated how antibody dosages impacted viral entry into cells expressing viral receptor, Fc receptor, or both receptors. This study reveals complex roles of antibodies in viral entry and can guide future vaccine design and antibody-based drug therapy.
| S-EPMC7022351 | biostudies-literature
Project description:PURPOSE OF REVIEW:An HIV-1 vaccine that elicits broadly neutralizing antibodies (bNAbs) remains to be developed. Here, we review how knowledge of bNAbs and HIV-1 entry mechanism is guiding the structure-based design of vaccine immunogens and immunization regimens. RECENT FINDINGS:Isolation of bNAbs from HIV-1-infected donors has led to an unprecedented understanding of the sites of vulnerability that these antibodies target on the HIV-1 envelope (Env) as well as of the immunological pathways that these antibody lineages follow to develop broad and potent neutralization. Sites of vulnerability, however, reside in the context of diverse Env conformations required for HIV-1 entry, including a prefusion-closed state, a single-CD4-bound intermediate, a three-CD4-bound intermediate, a prehairpin intermediate and postfusion states, and it is not always clear which structural state optimally presents a particular site of vulnerability in the vaccine context. Furthermore, detailed knowledge of immunological pathways has led to debate among vaccine developers as to how much of the natural antibody-developmental pathway immunogens should mimic, ranging from only the recognized epitope to multiple antigens from the antibody-virus coevolution process. SUMMARY:A plethora of information on bNAbs is guiding HIV-1-vaccine development. We highlight consideration of the appropriate structural context from the HIV-1-entry mechanism and extraordinary progress with replicating template B-cell ontogenies.
| S-EPMC5557343 | biostudies-literature
Project description:Tyrosine sulfate-mediated interactions play an important role in HIV-1 entry. After engaging the CD4 receptor at the cell surface, the HIV-1 gp120 glycoprotein binds to the CCR5 co-receptor via an interaction that requires two tyrosine sulfates, at positions 10 and 14 in the CCR5-N terminus. Building on previous structure determinations of this interaction, here we report the targeting of these tyrosine sulfate binding sites for drug design through in silico screening of small molecule libraries, identification of lead compounds, and characterization of biological activity. A class of tyrosine sulfate-mimicking small molecules containing a "phenyl sulfonate-linker-aromatic" motif was identified that specifically inhibited binding of gp120 to the CCR5-N terminus as well as to sulfated antibodies that recognize the co-receptor binding region on gp120. The most potent of these compounds bound gp120 with low micromolar affinity and its CD4-induced conformation with K(D)'s as tight as ∼50 nM. Neutralization experiments suggested the targeted site to be conformationally inaccessible prior to CD4 engagement. Primary HIV-1 isolates were weakly neutralized, preincubation with soluble CD4 enhanced neutralization, and engineered isolates with increased dependence on the N terminus of CCR5 or with reduced conformational barriers were neutralized with IC(50) values as low as ∼1 μM. These results reveal the potential of targeting the tyrosine sulfate interactions of HIV-1 and provide insight into how mechanistic barriers, evolved by HIV-1 to evade antibody recognition, also restrict small-molecule-mediated neutralization.
| S-EPMC3205951 | biostudies-literature
Project description:Despite the unquestionable success of antiretroviral therapy (ART) in the treatment of HIV infection, the cost, need for daily adherence, and HIV-associated morbidities that persist despite ART all underscore the need to develop a cure for HIV. The cure achieved following an allogeneic hematopoietic stem cell transplant (HSCT) using HIV-resistant cells, and more recently, the report of short-term but sustained, ART-free control of HIV replication following allogeneic HSCT, using HIV susceptible cells, have served to both reignite interest in HIV cure research, and suggest potential mechanisms for a cure. In this review, we highlight some of the obstacles facing HIV cure research today, and explore the roles of gene therapy targeting HIV entry, and allogeneic stem cell transplantation in the development of strategies to cure HIV infection.
| S-EPMC3970157 | biostudies-other
Project description:AbstractBackgroundHIV-1 entry into cells is mediated by sequential binding of target cell CD4 and CCR5 or CXCR4 to the metastable envelope (Env) trimer of gp120-gp41 heterodimers (Figure 1). We determined that MF275, a single diastereomer of the small molecule entry inhibitor PF-68742, is necessary and sufficient to inhibit entry of a subset of HIV-1 strains. We investigated the mechanism of MF275.MethodsRecombinant luciferase-expressing HIV-1 pseudotyped by wild-type or mutant HIV-1 Envs was incubated with MF275, other entry inhibitors, and/or antibodies. The virus-inhibitor mixture was added to CD4+ CCR5+ or CD4? CCR5+ target cells and luciferase activity measured.ResultsUnlike other entry inhibitors, MF275 not only reversibly inhibited the infection of CD4+ CCR5+ cells by some HIV-1 strains, but also irreversibly enhanced the infection of CD4? CCR5+ cells by others. In both cases, the strain susceptibility profiles were unique from those of CD4-mimetics, BMS-378806, and maraviroc. Furthermore, MF275 activity was not affected by mutations conferring resistance to other entry inhibitors and vice versa. In line with its activating activity, MF275 sensitized susceptible Envs to neutralization by a variety of broadly neutralizing antibodies against different epitopes. Changes in the gp120 C5 and gp41 FP regions conferred resistance to MF275 inhibition but not activation. Furthermore, sensitivity to other entry inhibitors in the presence of MF275 indicated that inhibition and activation target different conformational intermediates along the entry pathway, with the former targeting the prehairpin intermediate.ConclusionMF275 is unique among HIV-1 entry inhibitors. Depending on the conformation of the target Env, which appears related to the gp120-gp41 interface, MF275 mediates inhibition or activation via distinct mechanisms (Figure 2). Further characterization of the MF275 mechanisms and binding site/s will advance understanding of the HIV-1 entry pathway as well as assist optimization of its clinical utility as an antiretroviral in multi-class drug resistance and potentially as an adjunct to vaccines. Disclosures All authors: No reported disclosures.
| S-EPMC6255539 | biostudies-other
Project description:The first step of the human immunodeficiency virus (HIV) replication cycle-binding and entry into the host cell-plays a major role in determining viral tropism and the ability of HIV to degrade the human immune system. HIV uses a complex series of steps to deliver its genome into the host cell cytoplasm while simultaneously evading the host immune response. To infect cells, the HIV protein envelope (Env) binds to the primary cellular receptor CD4 and then to a cellular coreceptor. This sequential binding triggers fusion of the viral and host cell membranes, initiating infection. Revealing the mechanism of HIV entry has profound implications for viral tropism, transmission, pathogenesis, and therapeutic intervention. Here, we provide an overview into the mechanism of HIV entry, provide historical context to key discoveries, discuss recent advances, and speculate on future directions in the field.
| S-EPMC3405824 | biostudies-literature
Project description:Despite structural knowledge of broadly neutralizing monoclonal antibodies (NMAbs) complexed to HIV-1 gp120 and gp41 envelope glycoproteins, virus inactivation mechanisms have been difficult to prove, in part because neutralization assays are complex and were previously not understood. Concordant with recent evidence that HIV-1 titers are determined by a race between entry of cell-attached virions and competing inactivation processes, we show that NMAb 2G12, which binds to gp120 N-glycans with ? (1, 2)-linked mannose termini and inhibits replication after passive transfer into patients, neutralizes by slowing entry of adsorbed virions. Accordingly, apparent neutralization is attenuated when a kinetically competing virus inactivation pathway is blocked. Moreover, removing 2G12 from media causes its dissociation from virions coupled to accelerated entry and restored infectivity, demonstrating the reversibility of neutralization. A difference between 2G12 dissociation and infectivity recovery rates implies that the inhibited complexes at virus-cell junctions contain several 2G12's that must dissociate before entry commences. Quantitative microscopy of 2G12 binding and dissociation from single virions and studies using a split CCR5 coreceptor suggest that 2G12 competitively inhibits interactions between gp120's V3 loop and the tyrosine sulfate-containing CCR5 amino terminus, thereby reducing assembly of complexes that catalyze entry. These results reveal a unique reversible kinetic mechanism for neutralization by an antibody that binds near a critical V3 region in the glycan shield of gp120.
| S-EPMC3356642 | biostudies-literature
Project description:This review discusses recent progress in the development of anti-HIV agents targeting the viral entry process. The three main classes (attachment inhibitors, co-receptor binding inhibitors, and fusion inhibitors) are further broken down by specific mechanism of action and structure. Many of these inhibitors are in advanced clinical trials, including the HIV maturation inhibitor bevirimat, from the authors' laboratories. In addition, the CCR5 inhibitor maraviroc has recently been FDA-approved. Possible roles for these agents in anti-HIV therapy, including treatment of virus resistant to current drugs, are also discussed.
| S-EPMC3773846 | biostudies-literature
Project description:Nearly 70% of HIV-1-infected individuals suffer from HIV-associated neurocognitive disorders (HAND). HIV-1 transactivator of transcription (Tat) protein is known to synergize with abused drugs and exacerbate the progression of central nervous system (CNS) pathology. Cumulative evidence suggest that the HIV-1 Tat protein exerts the neurotoxicity through interaction with human dopamine transporter (hDAT) in the CNS. Through computational modeling and molecular dynamics (MD) simulations, we develop a three-dimensional (3D) structural model for HIV-1 Tat binding with hDAT. The model provides novel mechanistic insights concerning how HIV-1 Tat interacts with hDAT and inhibits dopamine uptake by hDAT. In particular, according to the computational modeling, Tat binds most favorably with the outward-open state of hDAT. Residues Y88, K92, and Y470 of hDAT are predicted to be key residues involved in the interaction between hDAT and Tat. The roles of these hDAT residues in the interaction with Tat are validated by experimental tests through site-directed mutagensis and dopamine uptake assays. The agreement between the computational and experimental data suggests that the computationally predicted hDAT-Tat binding mode and mechanistic insights are reasonable and provide a new starting point to design further pharmacological studies on the molecular mechanism of HIV-1-associated neurocognitive disorders.
| S-EPMC4400243 | biostudies-literature