Small CD4 Mimetics Prevent HIV-1 Uninfected Bystander CD4 + T Cell Killing Mediated by Antibody-dependent Cell-mediated Cytotoxicity

Richard, Jonathan; Veillette, Maxime; Ding, Shilei; Zoubchenok, Daria; Alsahafi, Nirmin; Coutu, Mathieu; Brassard, Nathalie; Park, Jongwoo; Courter, Joel R.; Melillo, Bruno; Smith, Amos B.; Shaw, George M.; Hahn, Beatrice H.; Sodroski, Joseph; Kaufmann, Daniel E.; Finzi, Andrés

doi:10.1016/j.ebiom.2015.12.004

Cited by 69 publications

(117 citation statements)

References 88 publications

Supporting

Mentioning

107

Contrasting

Order By: Relevance

“…Measurement of the luciferase activity in the target cells 48 h later provided an indication of the level of infection. Under the conditions of the assay, virus activation by the CD4mc is minimal because of the short half-life of the activated state and the slow diffusion of the virus to the target cell (42,46,49). As previously observed (39), BNM-III-170, a recently developed analogue, exhibited dramatically greater antiviral activity against the three HIV-1 strains than the prototypic CD4mc, NBD-556 (Table 1).…”

Section: Resultssupporting

confidence: 54%

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

Madani

Princiotto

Zhao

et al. 2017

J Virol

Self Cite

View full text Add to dashboard Cite

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

show abstract

Section: Resultssupporting

confidence: 54%

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

Madani

Princiotto

Zhao

et al. 2017

J Virol

Self Cite

View full text Add to dashboard Cite

show abstract

“…In contrast to the limited recognition of clade B, C, and D HIV-1-infected cells by A32, 17b, and antibodies within HIV ϩ sera (Fig. 2) (13,18,20,22,37), cells infected with wild-type CRF01_AE Env (H375) were better recognized by both CD4i monoclonal antibodies (MAbs) as well as polyclonal sera (Fig. 4C to F).…”

Section: Resultsmentioning

confidence: 99%

“…Binding of HIV-1-infected cells by HIV ϩ sera (1:1,000 dilution) or anti-CD4 (OKT4) or anti-Env MAbs (5 g/ml) was performed 48 h after in vitro infection. Detection of green fluorescent protein-positive (GFP ϩ ), p24 ϩ , or p27 ϩ infected cells was performed as described previously (37). The percentage of infected cells (i.e., GFP ϩ , p24 ϩ , or p27 ϩ cells) was determined by gating the living cell population based on viability dye staining (Aqua Vivid, catalog number L43957; Thermo Fisher Scientific).…”

Section: Methodsmentioning

confidence: 99%

Influence of the Envelope gp120 Phe 43 Cavity on HIV-1 Sensitivity to Antibody-Dependent Cell-Mediated Cytotoxicity Responses

Prévost

Zoubchenok

Richard

et al. 2017

J Virol

Self Cite

View full text Add to dashboard Cite

HIV-1-infected cells presenting envelope glycoproteins (Env) in the CD4-bound conformation on their surface are preferentially targeted by antibodydependent cellular-mediated cytotoxicity (ADCC). HIV-1 has evolved sophisticated mechanisms to avoid the exposure of Env ADCC epitopes by downregulating CD4 and by limiting the overall amount of Env on the cell surface. In HIV-1, substitution of large residues such as histidine or tryptophan for serine 375 (S375H/W) in the gp120 Phe 43 cavity, where Phe 43 of CD4 contacts gp120, results in the spontaneous sampling of an Env conformation closer to the CD4-bound state. While residue S375 is well conserved in the majority of group M HIV-1 isolates, CRF01_ AE strains have a naturally occurring histidine at this position (H375). Interestingly, CRF01_AE is the predominant circulating strain in Thailand, where the RV144 trial took place. In this trial, which resulted in a modest degree of protection, ADCC responses were identified as being part of the correlate of protection. Here we investigate the influence of the Phe 43 cavity on ADCC responses. Filling this cavity with a histidine or tryptophan residue in Env with a natural serine residue at this position (S375H/W) increased the susceptibility of HIV-1-infected cells to ADCC. Conversely, the replacement of His 375 by a serine residue (H375S) within HIV-1 CRF01_AE decreased the efficiency of the ADCC response. Our results raise the intriguing possibility that the presence of His 375 in the circulating strain where the RV144 trial was held contributed to the observed vaccine efficacy.

show abstract

“…This occurs by shed gp120 binding to CD4 on uninfected CD4 T cells which then become opsonised by CD4i specific anti-gp120 Abs. As such uninfected cells express high CD4 levels, they are efficiently killed by ADCC [132]. Since almost half of anti-HIV antibody specificities may be directed against CD4i (e.g.…”

Section: Hiv Evasion and Subversion Of Fcγr-mediated Ab Functionsmentioning

confidence: 99%

“…First, these act with coreceptor binding site Abs to reveal CD4i epitopes on the unliganded Env to make infected cells ADCC targets [138]. Secondly, they have the benefit of inhibiting shed gp120 binding to uninfected CD4 T cells and so sparing them from possible bystander ADCC killing [132]. Third, they sensitise HIV for neutralisation such that otherwise ineffective Ab responses elicited by infection or various immunization regimens, if of sufficient anti-gp120 titre, can effectively neutralise CD4 mimetic treated virus [139].…”

Section: Hiv Evasion and Subversion Of Fcγr-mediated Ab Functionsmentioning

confidence: 99%

Antibody functional assays as measures of Fc receptor-mediated immunity to HIV - new technologies and their impact on the HIV vaccine field.

Wines¹,

Billings²,

Mcleand³

et al. 2017

CHR

View full text Add to dashboard Cite

Background:There is now intense interest in the role of HIV-specific antibodies and the engagement of FcγR functions in the control and prevention of HIV infection. The analyses of the RV144 vaccine trial, natural progression cohorts, and macaque models all point to a role for Fc-dependent effector functions, such as cytotoxicity (ADCC) or phagocytosis (ADCP), in the control of HIV. However, reliable assays that can be reproducibly used across different laboratories to measure Fcdependent functions, such as antibody dependent cellular cytotoxicity (ADCC) are limited. Method: This brief review highlights the importance of Fc properties for immunity to HIV, particularly via FcγR diversity and function. We discuss assays used to study FcR mediated functions of HIV-specific Ab, including our recently developed novel cell-free ELISA using homo-dimeric FcγR ectodomains to detect functionally relevant viral antigen-specific antibodies. Results: The binding of these dimeric FcγR ectodomains, to closely spaced pairs of IgG Fc, mimics the engagement and cross-linking of Fc receptors by IgG opsonized virions or infected cells as the essential prerequisite to the induction of Ab-dependent effector functions. The dimeric FcγR ELISA reliably correlates with ADCC in patient responses to influenza. The assay is amenable to high throughput and could be standardized across laboratories. Conclusion: We propose the assay has broader implications for the evaluation of the quality of antibody responses in viral infections and for the rapid evaluation of responses in vaccine development campaigns for HIV and other viral infections.

show abstract

Small CD4 Mimetics Prevent HIV-1 Uninfected Bystander CD4 + T Cell Killing Mediated by Antibody-dependent Cell-mediated Cytotoxicity

Cited by 69 publications

References 88 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

Influence of the Envelope gp120 Phe 43 Cavity on HIV-1 Sensitivity to Antibody-Dependent Cell-Mediated Cytotoxicity Responses

Antibody functional assays as measures of Fc receptor-mediated immunity to HIV - new technologies and their impact on the HIV vaccine field.

Contact Info

Product

Resources

About