HIV-1 Adapts to a Retrocyclin with Cationic Amino Acid Substitutions That Reduce Fusion Efficiency of gp41

Cole, Amy L.; Yang, Otto O.; Warren, Andrew; Waring, Alan J.; Lehrer, Robert I.; Cole, Alexander M.

doi:10.4049/jimmunol.176.11.6900

Cited by 44 publications

(81 citation statements)

References 30 publications

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“…The mechanism of inhibition of HIV-1 entry by retrocyclin-1 revealed in this study is very similar to that exhibited by N-and C-peptides derived from the HIV-1 gp41 N-HR and C-HR, including the only fusion inhibitor approved by the FDA for antiretroviral treatment (T-20 or enfuvirtide). Further confirmation of this mechanism has been provided by recent studies of in vitro selection of HIV-1 resistance to retrocyclin-1 (46). This study reports that passaging HIV-1 under selective pressure by RC-101, a retrocyclin analog, results in a 5-10-fold decrease in viral susceptibility to RC-101.…”

Section: Discussionsupporting

confidence: 59%

θ-Defensins Prevent HIV-1 Env-mediated Fusion by Binding gp41 and Blocking 6-Helix Bundle Formation

Gallo

Wang

Rawat

et al. 2006

Journal of Biological Chemistry

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128

107

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Retrocyclin-1, a -defensin, protects target cells from human immunodeficiency virus, type 1 (HIV-1) by preventing viral entry. To delineate its mechanism, we conducted fusion assays between susceptible target cells and effector cells that expressed HIV-1 Env. Retrocyclin-1 (4 M) completely blocked fusion mediated by HIV-1 Envs that used CXCR4 or CCR5 but had little effect on cell fusion mediated by HIV-2 and simian immunodeficiency virus Envs. Retrocyclin-1 inhibited HIV-1 Env-mediated fusion without impairing the lateral mobility of CD4, and it inhibited the fusion of CD4-deficient cells with cells bearing CD4-independent HIV-1 Env. Thus, it could act without crosslinking membrane proteins or inhibiting gp120-CD4 interactions. Retrocyclin-1 acted late in the HIV-1 Env fusion cascade but prior to 6-helix bundle formation. Surface plasmon resonance experiments revealed that retrocyclin bound the ectodomain of gp41 with high affinity in a glycan-independent manner and that it bound selectively to the gp41 C-terminal heptad repeat. Native-PAGE, enzyme-linked immunosorbent assay, and CD spectroscopic analyses all revealed that retrocyclin-1 prevented 6-helix bundle formation. This mode of action, although novel for an innate effector molecule, resembles the mechanism of peptidic entry inhibitors based on portions of the gp41 sequence.

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Section: Discussionsupporting

confidence: 59%

θ-Defensins Prevent HIV-1 Env-mediated Fusion by Binding gp41 and Blocking 6-Helix Bundle Formation

Gallo

Wang

Rawat

et al. 2006

Journal of Biological Chemistry

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128

107

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“…Drug dependence is a relatively rare phenomenon in HIV-1 drug resistance. T20-or retrocyclin (RC101)-dependent viruses that involve a combination of substitutions in the HR1 binding site of the inhibitors and in HR2 have been described (44,45). The T20-dependent V549A/N637K virus did not show cross-resistance to or dependence on VIR165 ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Drug dependence can be classified as a special form of resistance, since the virus is able to replicate in the presence of the drug but the resistance mutations cause a severe replication defect in the absence of drug, which can only be overcome by addition of the drug. This phenomenon has been described for only a limited number of cases, although drug stimulatory effects and drug dependence were reported for several HIV-1 inhibitors targeting the Gag, protease, and Env proteins (44,45,(61)(62)(63). For Env, enhanced fusion kinetics can render HIV-1 resistant to fusion inhibitors (decreased opportunity), but "hyperfusogenic" Env variants can become dependent on the drug to avoid a premature HR1-HR2 collapse in the absence of a target membrane (44,45,59).…”

Section: Discussionmentioning

confidence: 99%

HIV-1 Escape from a Peptidic Anchor Inhibitor through Stabilization of the Envelope Glycoprotein Spike

Eggink

Taeye

Bontjer

et al. 2016

J Virol

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The trimeric HIV-1 envelope glycoprotein spike (Env) mediates viral entry into cells by using a spring-loaded mechanism that allows for the controlled insertion of the Env fusion peptide into the target membrane, followed by membrane fusion. Env is the focus of vaccine research aimed at inducing protective immunity by antibodies as well as efforts to develop drugs that inhibit the viral entry process. The molecular factors contributing to Env stability and decay need to be understood better in order to optimally design vaccines and therapeutics. We generated viruses with resistance to VIR165, a peptidic inhibitor that binds the fusion peptide of the gp41 subunit and prevents its insertion into the target membrane. Interestingly, a number of escape viruses acquired substitutions in the C1 domain of the gp120 subunit (A60E, E64K, and H66R) that rendered these viruses dependent on the inhibitor. These viruses could infect target cells only when VIR165 was present after CD4 binding. Furthermore, the VIR165-dependent viruses were resistant to soluble CD4-induced Env destabilization and decay. These data suggest that VIR165-dependent Env proteins are kinetically trapped in the unliganded state and require the drug to negotiate CD4-induced conformational changes. These studies provide mechanistic insight into the action of the gp41 fusion peptide and its inhibitors and provide new ways to stabilize Env trimer vaccines. IMPORTANCEBecause of the rapid development of HIV-1 drug resistance, new drug targets need to be explored continuously. The fusion peptide of the envelope glycoprotein can be targeted by anchor inhibitors. Here we describe virus escape from the anchor inhibitor VIR165. Interestingly, some escape viruses became dependent on the inhibitor for cell entry. We show that the identified escape mutations stabilize the ground state of the envelope glycoprotein and should thus be useful in the design of stabilized envelopebased HIV vaccines. With over 35 million people currently infected, HIV-1 remains a major health problem. Although progress has been made in the development of antiviral drugs, the potential of the virus to acquire resistance remains an issue. Neither a cure nor an effective vaccine is available. HIV-1 enters target cells by using its envelope glycoprotein (Env) spikes on the virus surface. Env is the target for drugs that inhibit the viral entry process and for broadly neutralizing antibodies (bNAbs) that researchers aim to induce with Env-based vaccines.Env is a trimeric complex consisting of three gp41 transmembrane subunits and three noncovalently attached gp120 subunits. The entry process is initiated by binding of gp120 to the CD4 receptor. This interaction induces conformational changes in Env, revealing the binding site for a chemokine coreceptor, generally CXCR4 or CCR5. Additional conformational changes in gp41 involve two heptad repeat regions (HR1 and HR2) in gp41 and the fusion peptide (FP) (1). The FP might be partially exposed in the prefusion, native state of Env. In a com...

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“…We and others have also revealed that retrocyclin analogs can remarkably protect CD4 + T cells against infection by clinical isolates of HIV-1 from a number of different clades 80 and induce very little resistance in HIV-1. 81 Retrocyclins are highly effective in the presence of human vaginal fluid, 82 are not proinflammatory, 38,82 and can prevent organotypic cervicovaginal tissues from HIV-1 BaL infection. Moreover, retrocyclins exhibited little to no hemolytic activity nor cytotoxicity against H9 cells and ME-180 cervical carcinoma cells at up to 500 lg ⁄ mL, a concentration that far exceeds the amount required for complete protection against most strains of HIV-1 (2-10 lg ⁄ mL).…”

Section: Bacterial Vaginosis Causes Dysfunction In Innate Immunity Ofmentioning

confidence: 99%

REVIEW ARTICLE: Antimicrobial Polypeptides are Key Anti‐HIV‐1 Effector Molecules of Cervicovaginal Host Defense

Cole

2007

American J Rep Immunol

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Mucosal surfaces of the cervix and vagina are portals for heterosexual transmission of human immunodeficiency virus type 1 (HIV‐1) and, therefore, play a fundamental role in the pathogenesis of primary infection. Cationic antimicrobial polypeptides including defensins are the principal effector molecules of mucosal innate immunity against microbes and viruses such as HIV. In cervicovaginal secretions, antimicrobial polypeptides constitute the majority of the intrinsic anti‐HIV‐1 activity, synergism between cationic polypeptides is complex, and full anti‐HIV‐1 activity involves the complete complement of cationic polypeptides. Periods in which cationic antimicrobial polypeptide expression is reduced are likely associated with increased susceptibility to HIV‐1 infection. This review provides an overview of the role of cationic antimicrobial polypeptides in innate cervicovaginal anti‐HIV‐1 host defense, and discusses how hormones and bacterial infections can regulate their expression. Emphasis is placed on the θ‐defensin (retrocyclin) class of anti‐HIV‐1 peptides and their potential for development as topical microbicides to prevent HIV‐1 transmission.

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HIV-1 Adapts to a Retrocyclin with Cationic Amino Acid Substitutions That Reduce Fusion Efficiency of gp41

Cited by 44 publications

References 30 publications

θ-Defensins Prevent HIV-1 Env-mediated Fusion by Binding gp41 and Blocking 6-Helix Bundle Formation

θ-Defensins Prevent HIV-1 Env-mediated Fusion by Binding gp41 and Blocking 6-Helix Bundle Formation

HIV-1 Escape from a Peptidic Anchor Inhibitor through Stabilization of the Envelope Glycoprotein Spike

REVIEW ARTICLE: Antimicrobial Polypeptides are Key Anti‐HIV‐1 Effector Molecules of Cervicovaginal Host Defense

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