scholarly journals Rapid Dissociation of HIV-1 from Cultured Cells Severely Limits Infectivity Assays, Causes the Inactivation Ascribed to Entry Inhibitors, and Masks the Inherently High Level of Infectivity of Virions

2009 ◽  
Vol 84 (6) ◽  
pp. 3106-3110 ◽  
Author(s):  
Emily J. Platt ◽  
Susan L. Kozak ◽  
James P. Durnin ◽  
Thomas J. Hope ◽  
David Kabat
Keyword(s):  
Immunofluorescence Microscopy ◽  
Cultured Cells ◽  
Cell Entry ◽  
Inhibitory Effects ◽  
Entry Inhibitors ◽  
Ccr5 Antagonists ◽  
High Level ◽  
Hiv 1

ABSTRACT By using immunofluorescence microscopy to observe and analyze freshly made HIV-1 virions adsorbed onto cells, we found that they are inherently highly infectious, rather than predominantly defective as previously suggested. Surprisingly, polycations enhance titers 20- to 30-fold by stabilizing adsorption and preventing a previously undescribed process of rapid dissociation, strongly implying that infectivity assays for many viruses are limited not only by inefficient virus diffusion onto cells but also by a postattachment race between entry and dissociation. This kinetic competition underlies inhibitory effects of CCR5 antagonists and explains why adaptive HIV-1 mutations overcome many cell entry limitations by accelerating entry.

scholarly journals Pharmacotherapy of HIV-1 Infection: Focus on CCR5 Antagonist Maraviroc

2009 ◽  
Vol 1 ◽  
pp. CMT.S2365 ◽  
Author(s):  
Olga Latinovic ◽  
Janaki Kuruppu ◽  
Charles Davis ◽  
Nhut Le ◽  
Alonso Heredia
Keyword(s):  
Drug Resistance ◽  
Phase Iii ◽  
Ccr5 Antagonist ◽  
Drug Resistant ◽  
Drug Induced ◽  
Entry Inhibitors ◽  
Phase Iii Clinical Trials ◽  
Infection Focus ◽  
Ccr5 Antagonists ◽  
Hiv 1

Sustained inhibition of HIV-1, the goal of antiretroviral therapy, is often impeded by the emergence of viral drug resistance. For patients infected with HIV-1 resistant to conventional drugs from the viral reverse transcriptase and protease inhibitor classes, the recently approved entry and integration inhibitors effectively suppress HIV-1 and offer additional therapeutic options. Entry inhibitors are particularly attractive because, unlike conventional antiretrovirals, they target HIV-1 extracellularly, thereby sparing cells from both viral- and drug-induced toxicities. The fusion inhibitor enfuvirtide and the CCR5 antagonist maraviroc are the first entry inhibitors licensed for patients with drug-resistant HIV-1, with maraviroc restricted to those infected with CCR5-tropic HIV-1 (R5 HIV-1) only. Vicriviroc (another CCR5 antagonist) is in Phase III clinical trials, whereas the CCR5 antibodies PRO 140 and HGS 004 are in early stages of clinical development. Potent antiviral synergy between maraviroc and CCR5 antibodies, coupled with distinct patterns of resistance, suggest their combinations might be particularly effective in patients. In addition, given that oral administration of maraviroc achieves high drug levels in cervicovaginal fluid, combinations of maraviroc and other CCR5 inhibitors could be effective in preventing HIV-1 transmission. Moreover, since CCR5 antagonists prevent rejection of transplanted organs, maraviroc could both suppress HIV-1 and prolong organ survival for the growing number of HIV-1 patients with kidney or liver failure necessitating organ transplantation. Thus, maraviroc offers an important treatment option for patients with drug-resistant R5 HIV-1, who presently account for >50% of drug-resistance cases.

scholarly journals Naturally Occurring Variability in the Envelope Glycoprotein of HIV-1 and Development of Cell Entry Inhibitors

Biochemistry ◽  
2010 ◽  
Vol 49 (11) ◽  
pp. 2359-2367 ◽  
Author(s):  
Evan T. Brower ◽  
Arne Schön ◽  
Ernesto Freire
Keyword(s):  
Envelope Glycoprotein ◽  
Cell Entry ◽  
Entry Inhibitors ◽  
Naturally Occurring ◽  
Hiv 1

scholarly journals Altered Env conformational dynamics as a mechanism of resistance to peptide-triazole HIV-1 inactivators

Retrovirology ◽  
2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Shiyu Zhang ◽  
Andrew P. Holmes ◽  
Alexej Dick ◽  
Adel A. Rashad ◽  
Lucía Enríquez Rodríguez ◽  
...  
Keyword(s):  
Viral Entry ◽  
Conformational Dynamics ◽  
Viral Escape ◽  
Minor Effect ◽  
Entry Inhibitors ◽  
Monomeric Gp120 ◽  
Escape Mutants ◽  
High Level ◽  
Peptide Triazoles ◽  
Hiv 1

Abstract Background We previously developed drug-like peptide triazoles (PTs) that target HIV-1 Envelope (Env) gp120, potently inhibit viral entry, and irreversibly inactivate virions. Here, we investigated potential mechanisms of viral escape from this promising class of HIV-1 entry inhibitors. Results HIV-1 resistance to cyclic (AAR029b) and linear (KR13) PTs was obtained by dose escalation in viral passaging experiments. High-level resistance for both inhibitors developed slowly (relative to escape from gp41-targeted C-peptide inhibitor C37) by acquiring mutations in gp120 both within (Val255) and distant to (Ser143) the putative PT binding site. The similarity in the resistance profiles for AAR029b and KR13 suggests that the shared IXW pharmacophore provided the primary pressure for HIV-1 escape. In single-round infectivity studies employing recombinant virus, V255I/S143N double escape mutants reduced PT antiviral potency by 150- to 3900-fold. Curiously, the combined mutations had a much smaller impact on PT binding affinity for monomeric gp120 (four to ninefold). This binding disruption was entirely due to the V255I mutation, which generated few steric clashes with PT in molecular docking. However, this minor effect on PT affinity belied large, offsetting changes to association enthalpy and entropy. The escape mutations had negligible effect on CD4 binding and utilization during entry, but significantly altered both binding thermodynamics and inhibitory potency of the conformationally-specific, anti-CD4i antibody 17b. Moreover, the escape mutations substantially decreased gp120 shedding induced by either soluble CD4 or AAR029b. Conclusions Together, the data suggest that the escape mutations significantly modified the energetic landscape of Env’s prefusogenic state, altering conformational dynamics to hinder PT-induced irreversible inactivation of Env. This work therein reveals a unique mode of virus escape for HIV-1, namely, resistance by altering the intrinsic conformational dynamics of the Env trimer.

Recent Progress in Small Molecule CCR5 Antagonists as Potential HIV-1 Entry Inhibitors

2012 ◽  
Vol 18 (1) ◽  
pp. 100-112 ◽  
Author(s):  
Wenwen Chen ◽  
Peng Zhan ◽  
Erik De Clercq ◽  
Xinyong Liu
Keyword(s):  
Small Molecule ◽  
Recent Progress ◽  
Entry Inhibitors ◽  
Ccr5 Antagonists ◽  
Hiv 1
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