Release of gp120 Restraints Leads to an Entry-Competent Intermediate State of the HIV-1 Envelope Glycoproteins

Herschhorn, Alon; Ma, Xiaochu; Gu, Chong; Ventura, John D.; Castillo-Menendez, Luis R.; Melillo, Bruno; Terry, Daniel S.; Smith, Amos B.; Blanchard, Scott C.; Munro, James B.; Mothes, Walther; Finzi, Andrés; Sodroski, Joseph

doi:10.1128/mbio.01598-16

Cited by 149 publications

(312 citation statements)

References 62 publications

(70 reference statements)

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“…We introduced additional changes in the HIV-1 JR-FL gp120 V2 region to identify Env mutants with increased reactivity. Such mutants typically exhibit increased sensitivity to soluble CD4, CD4mc, and antibodies against CD4-induced gp120 epitopes; many HIV-1 Env mutants with increased reactivity exhibit decreased sensitivity to blockers of conformational change, like BMS-806 (17,51,54,56). We identified HIV-1 JR-FL V2 mutants that exhibited phenotypes consistent with those associated with increased Env reactivity (Table 2) (56).…”

Section: Resultsmentioning

confidence: 99%

“…We hypothesized that differences in Env reactivities among HIV-1 strains might contribute to variation in sensitivity to CD4mc. Some changes in the HIV-1 gp120 V2 region have been shown to result in an increase in Env reactivity (53)(54)(55)(56). We introduced additional changes in the HIV-1 JR-FL gp120 V2 region to identify Env mutants with increased reactivity.…”

Section: Resultsmentioning

confidence: 99%

“…The HIV-1 Env trimer is maintained in its unliganded state (state 1) by multiple inter-and intrasubunit interactions, thus averting premature triggering and inactivation. Changes in particular gp120 and gp41 residues apparently release these restraints and lower the energy barriers that separate state 1 from downstream conformations (56). For example, alteration of several residues in the gp120 V2 region resulted in more reactive Envs that exhibited increased sensitivity to both activation and inhibition by CD4mc.…”

Section: Discussionmentioning

confidence: 99%

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Activation and Inactivation of Primary Human Immunodeficiency Virus Envelope Glycoprotein Trimers by CD4-Mimetic Compounds

Madani

Princiotto

Zhao

et al. 2017

J Virol

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Human immunodeficiency virus type 1 (HIV-1) entry into cells is mediated by the viral envelope glycoproteins (Env), a trimer of three gp120 exterior glycoproteins, and three gp41 transmembrane glycoproteins. The metastable Env is triggered to undergo entry-related conformational changes when gp120 binds sequentially to the receptors, CD4 and CCR5, on the target cell. Small-molecule CD4-mimetic compounds (CD4mc) bind gp120 and act as competitive inhibitors of gp120-CD4 engagement. Some CD4mc have been shown to trigger Env prematurely, initially activating Env function, followed by rapid and irreversible inactivation. Here, we study CD4mc with a wide range of anti-HIV-1 potencies and demonstrate that all tested CD4mc are capable of activating as well as inactivating Env function. Biphasic dose-response curves indicated that the occupancy of the protomers in the Env trimer governs viral activation versus inactivation. One CD4mc bound per Env trimer activated HIV-1 infection. Envs with two CD4mc bound were activated for infection of CD4-negative, CCR5-positive cells, but the infection of CD4-positive, CCR5-positive cells was inhibited. Virus was inactivated when all three Env protomers were occupied by the CD4mc, and gp120 shedding from the Env trimer was increased in the presence of some CD4mc. Env reactivity and the on rates of CD4mc binding to the Env trimer were found to be important determinants of the potency of activation and entry inhibition. Cross-sensitization of Env protomers that do not bind the CD4mc to neutralization by an anti-V3 antibody was not evident. These insights into the mechanism of antiviral activity of CD4mc should assist efforts to optimize their potency and utility.IMPORTANCE The trimeric envelope glycoproteins of human immunodeficiency virus type 1 (HIV-1) mediate virus entry into host cells. Binding to the host cell receptors, CD4 and CCR5, triggers changes in the conformation of the HIV-1 envelope glycoprotein trimer important for virus entry. Small-molecule CD4-mimetic compounds inhibit HIV-1 infection by multiple mechanisms: (i) direct blockade of the interaction between the gp120 exterior envelope glycoprotein and CD4; (ii) premature triggering of conformational changes in the envelope glycoproteins, leading to irreversible inactivation; and (iii) exposure of cryptic epitopes to antibodies, allowing virus neutralization. The consequences of the binding of the CD4-mimetic compound to the HIV-1 envelope glycoproteins depends upon how many of the three subunits of the trimer are bound and upon the propensity of the envelope glycoproteins to undergo conformational changes. Understanding the mechanistic factors that influence

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Activation and Inactivation of Primary Human Immunodeficiency Virus Envelope Glycoprotein Trimers by CD4-Mimetic Compounds

Madani

Princiotto

Zhao

et al. 2017

J Virol

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“…CD4 binding also induces the prehairpin intermediate, in which the heptad repeat 1 (HR1) coiled coil in the gp41 ectodomain is formed and exposed (18)(19)(20)(21). In the process of making the transition from its "ground" unliganded conformation (state 1) to the CD4-bound conformation (state 3), the HIV-1 Env trimer passes through a functional intermediate conformation (state 2) (22,23). Chemokine receptor binding results in the formation of a stable six-helix bundle composed of the HR1 and HR2 heptad repeat regions, promoting fusion of the viral and target cell membranes (3,5,24).…”

mentioning

confidence: 99%

“…The inhibition of HIV-1 by antibodies and small molecules is influenced by envelope reactivity and the perturbation factor of the Env ligand (43). Envelope reactivity describes the propensity of the HIV-1 Env to move from the unliganded state 1 conformation to downstream conformations, such as that of state 2 (35); Env reactivity is inversely related to the activation barriers that separate state 1 and state 2 (23,35). The perturbation factor describes the degree of Env conformational change required for the ligand to bind the Env trimer and influences the impact of Env reactivity on HIV-1 neutralization by the ligand (43).…”

mentioning

confidence: 99%

Residues in the gp41 Ectodomain Regulate HIV-1 Envelope Glycoprotein Conformational Transitions Induced by gp120-Directed Inhibitors

Pacheco

Alsahafi

Débbeche

et al. 2017

J Virol

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Interactions between the gp120 and gp41 subunits of the human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein (Env) trimer maintain the metastable unliganded form of the viral spike. Binding of gp120 to the receptor, CD4, changes the Env conformation to promote gp120 interaction with the second receptor, CCR5 or CXCR4. CD4 binding also induces the transformation of Env into the prehairpin intermediate, in which the gp41 heptad repeat 1 (HR1) coiled coil is assembled at the trimer axis. In nature, HIV-1 Envs must balance the requirements to maintain the noncovalent association of gp120 with gp41 and to evade the host antibody response with the need to respond to CD4 binding. Here we show that the gp41 HR1 region contributes to gp120 association with the unliganded Env trimer. Changes in particular amino acid residues in the gp41 HR1 region decreased the efficiency with which Env moved from the unliganded state. Thus, these gp41 changes decreased the sensitivity of HIV-1 to cold inactivation and ligands that require Env conformational changes to bind efficiently. Conversely, these gp41 changes increased HIV-1 sensitivity to small-molecule entry inhibitors that block Env conformational changes induced by CD4. Changes in particular gp41 HR1 amino acid residues can apparently affect the relative stability of the unliganded state and CD4-induced conformations. Thus, the gp41 HR1 region contributes to the association with gp120 and regulates Env transitions from the unliganded state to downstream conformations.IMPORTANCE The development of an efficient vaccine able to prevent HIV infection is a worldwide priority. Knowledge of the envelope glycoprotein structure and the conformational changes that occur after receptor engagement will help researchers to develop an immunogen able to elicit antibodies that block HIV-1 transmission. Here we identify residues in the HIV-1 transmembrane envelope glycoprotein that stabilize the unliganded state by modulating the transitions from the unliganded state to the CD4-bound state.

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Mechanisms of HIV-1 cell-to-cell transfer to myeloid cells

Han

Woottum

Mascarau

et al. 2022

Journal of Leukocyte Biology

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In addition to CD4+ T lymphocytes, cells of the myeloid lineage such as macrophages, dendritic cells (DCs), and osteoclasts (OCs) are emerging as important target cells for HIV‐1, as they likely participate in all steps of pathogenesis, including sexual transmission and early virus dissemination in both lymphoid and nonlymphoid tissues where they can constitute persistent virus reservoirs. At least in vitro, these myeloid cells are poorly infected by cell‐free viral particles. In contrast, intercellular virus transmission through direct cell‐to‐cell contacts may be a predominant mode of virus propagation in vivo leading to productive infection of these myeloid target cells. HIV‐1 cell‐to‐cell transfer between CD4+ T cells mainly through the formation of the virologic synapse, or from infected macrophages or dendritic cells to CD4+ T cell targets, have been extensively described in vitro. Recent reports demonstrate that myeloid cells can be also productively infected through virus homotypic or heterotypic cell‐to‐cell transfer between macrophages or from virus‐donor‐infected CD4+ T cells, respectively. These modes of infection of myeloid target cells lead to very efficient spreading in these poorly susceptible cell types. Thus, the goal of this review is to give an overview of the different mechanisms reported in the literature for cell‐to‐cell transfer and spreading of HIV‐1 in myeloid cells.

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Release of gp120 Restraints Leads to an Entry-Competent Intermediate State of the HIV-1 Envelope Glycoproteins

Cited by 149 publications

References 62 publications

Activation and Inactivation of Primary Human Immunodeficiency Virus Envelope Glycoprotein Trimers by CD4-Mimetic Compounds

Activation and Inactivation of Primary Human Immunodeficiency Virus Envelope Glycoprotein Trimers by CD4-Mimetic Compounds

Residues in the gp41 Ectodomain Regulate HIV-1 Envelope Glycoprotein Conformational Transitions Induced by gp120-Directed Inhibitors

Mechanisms of HIV-1 cell-to-cell transfer to myeloid cells

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