Therapeutic Efficacy and Resistance Selection of a Lipopeptide Fusion Inhibitor in Simian Immunodeficiency Virus-Infected Rhesus Macaques

ABSTRACT We recently reported a group of lipopeptide-based membrane fusion inhibitors with potent antiviral activities against human immunodeficiency virus type 1 (HIV-1), HIV-2, and simian immunodeficiency virus (SIV). In this study, the in vivo therapeutic efficacy of such a lipopeptide, LP-52, was evaluated in rhesus macaques chronically infected with pathogenic SIVmac239. In a pilot study with one monkey, monotherapy with low-dose LP-52 rapidly reduced the plasma viral loads to below the limit of detection and maintained viral suppression during three rounds of structurally interrupted treatment. The therapeutic efficacy of LP-52 was further verified in four infected monkeys; however, three out of the monkeys had viral rebounds under the LP-52 therapy. We next focused on characterizing SIV mutants responsible for the in vivo resistance. Sequence analyses revealed that a V562A or V562M mutation in the N-terminal heptad repeat (NHR) and a E657G mutation in the C-terminal heptad repeat (CHR) of SIV gp41 conferred high resistance to LP-52 and cross-resistance to the peptide drug T20 and two newly designed lipopeptides (LP-80 and LP-83). Moreover, we showed that the resistance mutations greatly reduced the stability of diverse fusion inhibitors with the NHR site, and V562A or V562M in combination with E657G could significantly impair the functionality of viral envelopes (Envs) to mediate SIVmac239 infection and decrease the thermostability of viral six-helical bundle (6-HB) core structure. In conclusion, the present data have not only facilitated the development of novel anti-HIV drugs that target the membrane fusion step, but also help our understanding of the mechanism of viral evolution to develop drug resistance. IMPORTANCE The anti-HIV peptide drug T20 (enfuvirtide) is the only membrane fusion inhibitor available for treatment of viral infection; however, it exhibits relatively weak antiviral activity, short half-life, and a low genetic barrier to inducing drug resistance. Design of lipopeptide-based fusion inhibitors with extremely potent and broad antiviral activities against divergent HIV-1, HIV-2, and SIV isolates have provided drug candidates for clinical development. Here, we have verified a high therapeutic efficacy for the lipopeptide LP-52 in SIVmac239-infected rhesus monkeys. The resistance mutations selected in vivo have also been characterized, providing insights into the mechanism of action of newly designed fusion inhibitors with a membrane-anchoring property. For the first time, the data show that HIV-1 and SIV can share a similar genetic pathway to develop resistance, and that a lipopeptide fusion inhibitor could have a same resistance profile as its template peptide.

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Clinical Resistance to Enfuvirtide Does Not Affect Susceptibility ofHuman Immunodeficiency Virus Type 1 to Other Classes of Entry Inhibitors

Journal of Virology ◽

10.1128/jvi.02413-06 ◽

2007 ◽

Vol 81 (7) ◽

pp. 3240-3250 ◽

Cited By ~ 54

Author(s):

Neelanjana Ray ◽

Jessamina E. Harrison ◽

Leslie A. Blackburn ◽

Jeffrey N. Martin ◽

Steven G. Deeks ◽

...

Keyword(s):

Virologic Failure ◽

Viral Envelope ◽

Fusion Inhibitor ◽

Drug Resistant ◽

Resistance Mutations ◽

Entry Inhibitors ◽

Clinical Resistance ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT The clinical use of the human immunodeficiency virus (HIV) fusion inhibitor enfuvirtide (ENF) can select for drug-resistant HIV-1 strains bearing mutations in the HR1 region of the viral envelope (Env) protein. We analyzed the properties of multiple Env proteins isolated from five patients who experienced an initial decline in viral load after ENF therapy followed by subsequent rebound due to emergence of ENF-resistant HIV-1. Prior to ENF therapy, each patient harbored genetically and phenotypically diverse Env proteins that used CCR5 and/or CXCR4 to elicit membrane fusion. Coreceptor usage patterns of the Envs isolated from two patients underwent homogenization following ENF therapy, whereas in the other three patients, recombination appeared to allow the introduction of a single HR1 sequence with ENF resistance mutations into phenotypically distinct Env proteins. Analysis of individual Env clones also revealed that prior to ENF therapy, there was sometimes marked heterogeneity in the susceptibility of individual Env proteins to coreceptor inhibitors. After virologic failure, all Envs acquired resistance to ENF but exhibited no consistent change in their sensitivity to the fusion inhibitor T-1249 or to coreceptor inhibitors. In summary, using patient-derived Env proteins, we found that ENF failure was associated with emergence of high-level resistance to ENF due largely to mutations in HR1 but that susceptibility to other entry inhibitors was unaffected, that in these late-stage patients there was greater clonal variability to coreceptor than to fusion inhibitors, and that recombination events in vivo could sometimes restore Env genotypic and phenotypic heterogeneity by introducing drug-resistant gp41 sequences into heterologous gp120 backgrounds.

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Selective Excision of AZTMP by Drug-Resistant Human Immunodeficiency Virus Reverse Transcriptase

Journal of Virology ◽

10.1128/jvi.75.10.4832-4842.2001 ◽

2001 ◽

Vol 75 (10) ◽

pp. 4832-4842 ◽

Cited By ~ 185

Author(s):

Paul L. Boyer ◽

Stefan G. Sarafianos ◽

Edward Arnold ◽

Stephen H. Hughes

Keyword(s):

Human Immunodeficiency Virus ◽

Reverse Transcriptase ◽

Nucleoside Analogs ◽

Azido Group ◽

Resistance Mutations ◽

Immunodeficiency Virus ◽

Azt Resistance ◽

Hiv 1

ABSTRACT Two distinct mechanisms can be envisioned for resistance of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) to nucleoside analogs: one in which the mutations interfere with the ability of HIV-1 RT to incorporate the analog, and the other in which the mutations enhance the excision of the analog after it has been incorporated. It has been clear for some time that there are mutations that selectively interfere with the incorporation of nucleoside analogs; however, it has only recently been proposed that zidovudine (AZT) resistance can involve the excision of the nucleoside analog after it has been incorporated into viral DNA. Although this proposal resolves some important issues, it leaves some questions unanswered. In particular, how do the AZT resistance mutations enhance excision, and what mechanism(s) causes the excision reaction to be relatively specific for AZT? We have used both structural and biochemical data to develop a model. In this model, several of the mutations associated with AZT resistance act primarily to enhance the binding of ATP, which is the most likely pyrophosphate donor in the in vivo excision reaction. The AZT resistance mutations serve to increase the affinity of RT for ATP so that, at physiological ATP concentrations, excision is reasonably efficient. So far as we can determine, the specificity of the excision reaction for an AZT-terminated primer is not due to the mutations that confer resistance, but depends instead on the structure of the region around the HIV-1 RT polymerase active site and on its interactions with the azido group of AZT. Steric constraints involving the azido group cause the end of an AZT 5′-monophosphate-terminated primer to preferentially reside at the nucleotide binding site, which favors excision.

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Trimeric heptad repeat synthetic peptides HR1 and HR2 efficiently inhibit HIV-1 entry

Bioscience Reports ◽

10.1042/bsr20192196 ◽

2019 ◽

Vol 39 (9) ◽

Author(s):

Olfa Mzoughi ◽

Meritxell Teixido ◽

Rémi Planès ◽

Manutea Serrero ◽

Ibtissem Hamimed ◽

...

Keyword(s):

Antiviral Activity ◽

Heptad Repeat ◽

Fusion Activity ◽

Helical Structures ◽

Fusion Inhibitors ◽

Immunodeficiency Virus ◽

Antiviral Activities ◽

Physical Interactions ◽

Kinetics Of ◽

Hiv 1

Abstract The trimeric heptad repeat domains HR1 and HR2 of the human immunodeficiency virus 1 (HIV-1) gp41 play a key role in HIV-1-entry by membrane fusion. To develop efficient inhibitors against this step, the corresponding trimeric-N36 and C34 peptides were designed and synthesized. Analysis by circular dichroism of monomeric and trimeric N36 and C34 peptides showed their capacities to adopt α-helical structures and to establish physical interactions. At the virological level, while trimeric-C34 conserves the same high anti-fusion activity as monomeric-C34, trimerization of N36-peptide induced a significant increase, reaching 500-times higher in anti-fusion activity, against R5-tropic virus-mediated fusion. This result was associated with increased stability of the N36 trimer peptide with respect to the monomeric form, as demonstrated by the comparative kinetics of their antiviral activities during 6-day incubation in a physiological medium. Collectively, our findings demonstrate that while the trimerization of C34 peptide had no beneficial effect on its stability and antiviral activity, the trimerization of N36 peptide strengthened both stability and antiviral activity. This approach, promotes trimers as new promising HIV-1 inhibitors and point to future development aimed toward innovative peptide fusion inhibitors, microbicides or as immunogens.

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Structural and Functional Characterization of the Secondary Mutation N126K Selected by Various HIV-1 Fusion Inhibitors

Viruses ◽

10.3390/v12030326 ◽

2020 ◽

Vol 12 (3) ◽

pp. 326

Author(s):

Danwei Yu ◽

Yang Su ◽

Xiaohui Ding ◽

Yuanmei Zhu ◽

Bo Qin ◽

...

Keyword(s):

Cell Fusion ◽

Functional Characterization ◽

Glycosylation Site ◽

Heptad Repeat ◽

Viral Fusion ◽

Secondary Mutation ◽

Fusion Inhibitors ◽

Hiv 1

Peptides derived from the C-terminal heptad repeat (CHR) region of HIV-1 gp41 is potent viral membrane fusion inhibitors, such as the first clinically approved peptide drug T20 and a group of newly-designed peptides. The resistance profiles of various HIV-1 fusion inhibitors were previously characterized, and the secondary mutation N126K in the gp41 CHR was routinely identified during the in vitro and in vivo selections. In this study, the functional and structural relevance of the N126K mutation has been characterized from multiple angles. First, we show that a single N126K mutation across several HIV-1 isolates conferred mild to moderate cross-resistances. Second, the N126K mutation exerted different effects on Env-mediated HIV-1 entry and cell-cell fusion. Third, the N126K mutation did not interfere with the expression and processing of viral Env glycoproteins, but it disrupted the Asn126-based glycosylation site in gp41. Fourth, the N126K mutation was verified to enhance the thermal stability of 6-HB conformation. Fifth, we determined the crystal structure of a 6-HB bearing the N126K mutation, which revealed the interhelical and intrahelical interactions underlying the increased thermostability. Therefore, our data provide new information to understand the mechanism of HIV-1 gp41-mediated cell fusion and its resistance mode to viral fusion inhibitors.

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Identification of a Critical Motif for the Human Immunodeficiency Virus Type 1 (HIV-1) gp41 Core Structure: Implications for Designing Novel Anti-HIV Fusion Inhibitors

Journal of Virology ◽

10.1128/jvi.00319-08 ◽

2008 ◽

Vol 82 (13) ◽

pp. 6349-6358 ◽

Cited By ~ 63

Author(s):

Yuxian He ◽

Jianwei Cheng ◽

Jingjing Li ◽

Zhi Qi ◽

Hong Lu ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Core Structure ◽

Heptad Repeat ◽

Fusion Inhibitors ◽

Immunodeficiency Virus ◽

Anti Hiv ◽

Hiv 1

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) entry into the host cell involves a cascade of events and currently represents one of most attractive targets in the search for new antiviral drugs. The fusion-active gp41 core structure is a stable six-helix bundle (6-HB) folded by its trimeric N-terminal heptad repeat (NHR) and C-terminal heptad repeat (CHR). Peptides derived from the CHR region of HIV-1 gp41 are potent fusion inhibitors that target the NHR to block viral and cellular membrane fusion in a dominant negative fashion. However, all CHR peptides reported to date are derived primarily from residues 628 to 673 of gp41; little attention has been paid to the upstream sequence of the pocket binding domain (PBD) in the CHR. Here, we have identified a motif (621QIWNNMT627) located at the upstream region of the gp41 CHR, immediately adjacent to the PBD (628WMEWEREI635). Biophysical characterization demonstrated that this motif is critical for the stabilization of the gp41 6-HB core. The peptide CP621-652, containing the 621QIWNNMT627 motif, was able to interact with T21, a counterpart peptide derived from the NHR, to form a typical 6-HB structure with a high thermostability (thermal unfolding transition [T m ] value of 82°C). In contrast, the 6-HB formed by the peptides N36 and C34, which has been considered to be a core structure of the fusion-active gp41, had a T m of 64°C. Different from T-20 (brand name Fuseon), which is the first and only HIV-1 fusion inhibitor approved for clinical use, CP621-652 could efficiently block 6-HB formation in a dose-dependent manner. Significantly, CP621-652 had potent inhibitory activity against HIV-1-mediated cell-cell fusion and infection, especially against T-20- and C34-resistant virus. Therefore, our works provide important information for understanding the core structure of the fusion-active gp41 and for designing novel anti-HIV peptides.

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Design of potent membrane fusion inhibitors against SARS-CoV-2, an emerging coronavirus with high fusogenic activity

10.1101/2020.03.26.009233 ◽

2020 ◽

Cited By ~ 4

Author(s):

Yuanmei Zhu ◽

Danwei Yu ◽

Hongxia Yan ◽

Huihui Chong ◽

Yuxian He

Keyword(s):

Membrane Fusion ◽

Cell Receptor ◽

Heptad Repeat ◽

Fusion Inhibitor ◽

Fusion Activity ◽

Global Public Health ◽

S Protein ◽

Entry Pathway ◽

Fusion Inhibitors ◽

A Cell

AbstractThe coronavirus disease COVID-19, caused by emerging SARS-CoV-2, has posed serious threats to global public health, economic and social stabilities, calling for the prompt development of therapeutics and prophylactics. In this study, we firstly verified that SARS-CoV-2 uses human ACE2 as a cell receptor and its spike (S) protein mediates high membrane fusion activity. Comparing to that of SARS-CoV, the heptad repeat 1 (HR1) sequence in the S2 fusion protein of SARS-CoV-2 possesses markedly increased α-helicity and thermostability, as well as a higher binding affinity with its corresponding heptad repeat 2 (HR1) site. Then, we designed a HR2 sequence-based lipopeptide fusion inhibitor, termed IPB02, which showed highly poent activities in inibibiting the SARS-CoV-2 S protein-mediated cell-cell fusion and pseudovirus infection. IPB02 also inhibited the SARS-CoV pseudovirus efficiently. Moreover, the strcuture and activity relationship (SAR) of IPB02 were characterzized with a panel of truncated lipopeptides, revealing the amino acid motifs critical for its binding and antiviral capacities. Therefore, the presented results have provided important information for understanding the entry pathway of SARS-CoV-2 and the design of antivirals that target the membrane fusion step.

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Relative Replicative Fitness of Human Immunodeficiency Virus Type 1 Mutants Resistant to Enfuvirtide (T-20)

Journal of Virology ◽

10.1128/jvi.78.9.4628-4637.2004 ◽

2004 ◽

Vol 78 (9) ◽

pp. 4628-4637 ◽

Cited By ~ 101

Author(s):

Jing Lu ◽

Prakash Sista ◽

Françoise Giguel ◽

Michael Greenberg ◽

Daniel R. Kuritzkes

Keyword(s):

Human Immunodeficiency Virus ◽

Relative Order ◽

Wild Type ◽

Resistance Mutations ◽

Recombinant Viruses ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT Resistance to enfuvirtide (ENF; T-20), a fusion inhibitor of human immunodeficiency virus type 1 (HIV-1), is conferred by mutations in the first heptad repeat of the gp41 ectodomain. The replicative fitness of recombinant viruses carrying ENF resistance mutations was studied in growth competition assays. ENF resistance mutations, selected in vitro or in vivo, were introduced into the env gene of HIV-1NL4-3 by site-directed mutagenesis and expressed in HIV-1 recombinants carrying sequence tags in nef. The doubling time of ENF-resistant viruses was highly correlated with decreasing ENF susceptibility (R 2 = 0.859; P < 0.001). Initial fitness experiments focused on mutants identified by in vitro selection in the presence of ENF (L. T. Rimsky, D. C. Shugars, and T. J. Matthews, J. Virol. 72:986-993, 1998). In the absence of drug, these mutants displayed reduced fitness compared to wild-type virus with a relative order of fitness of wild type > I37T > V38 M > D36S/V38 M; this order was reversed in the presence of ENF. Likewise, recombinant viruses carrying ENF resistance mutations selected in vivo displayed reduced fitness in the absence of ENF with a relative order of wild type > N42T > V38A > N42T/N43K ≈ N42T/N43S > V38A/N42D ≈ V38A/N42T. Fitness and ENF susceptibility were inversely correlated (r = −0.988; P < 0.001). Similar results were obtained with recombinants expressing molecularly cloned full-length env genes obtained from patient-derived HIV-1 isolates before and after ENF treatment. Further studies are needed to determine whether the reduced fitness of ENF-resistant viruses alters their pathogenicity in vivo.

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A Lipopeptide HIV-1/2 Fusion Inhibitor with Highly Potent In Vitro, Ex Vivo, and In Vivo Antiviral Activity

Journal of Virology ◽

10.1128/jvi.00288-17 ◽

2017 ◽

Vol 91 (11) ◽

Cited By ~ 28

Author(s):

Huihui Chong ◽

Jing Xue ◽

Shengwen Xiong ◽

Zhe Cong ◽

Xiaohui Ding ◽

...

Keyword(s):

Antiviral Activity ◽

Viral Entry ◽

Ex Vivo ◽

Rhesus Macaques ◽

Fusion Inhibitor ◽

Clinical Use ◽

Viral Fusion ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT Peptides derived from the C-terminal heptad repeat (CHR) region of the human immunodeficiency virus type 1 (HIV-1) fusogenic protein gp41 are potent viral entry inhibitors, and currently, enfuvirtide (T-20) is the only one approved for clinical use; however, emerging drug resistance largely limits its efficacy. In this study, we generated a novel lipopeptide inhibitor, named LP-19, by integrating multiple design strategies, including an N-terminal M-T hook structure, an HIV-2 sequence, intrahelical salt bridges, and a membrane-anchoring lipid tail. LP-19 showed stable binding affinity and highly potent, broad, and long-lasting antiviral activity. In in vitro studies, LP-19 efficiently inhibited HIV-1-, HIV-2-, and simian immunodeficiency virus (SIV)-mediated cell fusion, viral entry, and infection, and it was highly active against diverse subtypes of primary HIV-1 isolates and inhibitor-resistant mutants. Ex vivo studies demonstrated that LP-19 exhibited dramatically increased anti-HIV activity and an extended half-life in rhesus macaques. In short-term monotherapy, LP-19 reduced viral loads to undetectable levels in acutely and chronically simian-human immunodeficiency virus (SHIV)-infected monkeys. Therefore, this study offers an ideal HIV-1/2 fusion inhibitor for clinical development and emphasizes the importance of the viral fusion step as a drug target. IMPORTANCE The peptide drug T-20 is the only viral fusion inhibitor in the clinic, which is used for combination therapy of HIV-1 infection; however, it requires a high dosage and easily induces drug resistance, calling for a new drug with significantly improved pharmaceutical profiles. Here, we have developed a short-lipopeptide-based fusion inhibitor, termed LP-19, which mainly targets the conserved gp41 pocket site and shows highly potent inhibitory activity against HIV-1, HIV-2, and even SIV isolates. LP-19 exhibits dramatically increased antiviral activity and an extended half-life in rhesus macaques, and it has potent therapeutic efficacy in SHIV-infected monkeys, highlighting its high potential as a new viral fusion inhibitor for clinical use.

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Rapid Clearance of Simian Immunodeficiency Virus Particles from Plasma of Rhesus Macaques

Journal of Virology ◽

10.1128/jvi.73.1.855-860.1999 ◽

1999 ◽

Vol 73 (1) ◽

pp. 855-860 ◽

Cited By ~ 69

Author(s):

Linqi Zhang ◽

Peter J. Dailey ◽

Tian He ◽

Agegnehu Gettie ◽

Sebastian Bonhoeffer ◽

...

Keyword(s):

Simian Immunodeficiency Virus ◽

Rhesus Macaques ◽

Burst Size ◽

Accurate Estimate ◽

Short Period ◽

Immunodeficiency Virus ◽

Infected Cells ◽

Rapid Clearance ◽

Hiv 1

ABSTRACT Perturbation of the equilibrium between human immunodeficiency virus type 1 (HIV-1) and the infected host by administering antiretroviral agents has revealed the rapid turnover of both viral particles and productively infected cells. In this study, we used the infusion of simian immunodeficiency virus (SIV) particles into rhesus macaques to obtain a more accurate estimate of viral clearance in vivo. Consistently, exogenously infused virions were cleared from plasma with an extremely short half-life, on the order of minutes (a mean of 3.3 min). This new estimate is ∼100-fold lower than the upper bound of 6 h previously reported for HIV-1 in infected humans. In select animals, multiple tissues were collected at the completion of each experiment to track the potential sites of virion clearance. Detectable levels of SIV RNA were found in lymph nodes, spleen, lungs, and liver, but not in other tissues examined. However, only ∼1 to 10% or less of the infused virions were accounted for by the thorough tissue sampling, indicating that the vast majority of the infused particles must have been degraded over a short period of time. Should the rapid clearance of virions described here be applicable to infected patients, then HIV-1 production and thus the number of productively infected CD4+ T lymphocytes or the viral burst size must be proportionally higher than previous minimal estimates.

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Design of Novel HIV-1/2 Fusion Inhibitors with High Therapeutic Efficacy in Rhesus Monkey Models

Journal of Virology ◽

10.1128/jvi.00775-18 ◽

2018 ◽

Vol 92 (16) ◽

Cited By ~ 15

Author(s):

Huihui Chong ◽

Jing Xue ◽

Yuanmei Zhu ◽

Zhe Cong ◽

Ting Chen ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Drug Resistance ◽

Ex Vivo ◽

Fusion Inhibitor ◽

Infected Monkey ◽

Viral Loads ◽

Fusion Inhibitors ◽

Immunodeficiency Virus ◽

Anti Hiv ◽

Hiv 1

ABSTRACTT-20 (enfuvirtide) is the only approved viral fusion inhibitor that is used for the treatment of human immunodeficiency virus type 1 (HIV-1) infection; however, it has relatively low antiviral activity and easily induces drug resistance. We recently reported a T-20-based lipopeptide fusion inhibitor (LP-40) showing improved anti-HIV activity (X. Ding et al., J Virol 91:e00831-17, 2017,https://doi.org/10.1128/JVI.00831-17). In this study, we designed LP-50 and LP-51 by refining the structure and function of LP-40. The two new lipopeptides showed dramatically enhanced secondary structure and binding stability and were exceptionally potent inhibitors of HIV-1, HIV-2, simian immunodeficiency virus (SIV), and chimeric simian-human immunodeficiency virus (SHIV), with mean 50% inhibitory concentrations (IC50s) in the very low picomolar range. They also exhibited dramatically increased potencies in inhibiting a panel of T-20- and LP-40-resistant mutant viruses. In line with theirin vitrodata, LP-50 and LP-51 exhibited extremely potent and long-lastingex vivoanti-HIV activities in rhesus monkeys: serum dilution peaks that inhibited 50% of virus infection were >15,200-fold higher than those for T-20 and LP-40. Low-dose, short-term monotherapy of LP-51 could sharply reduce viral loads to undetectable levels in acutely and chronically SHIV infected monkey models. To our knowledge, LP-50 and LP-51 are the most potent and broad HIV-1/2 and SIV fusion inhibitors, which can be developed for clinical use and can serve as tools for exploration of the mechanisms of viral entry and inhibition.IMPORTANCET-20 remains the only membrane fusion inhibitor available for the treatment of viral infection, but its relatively low anti-HIV activity and genetic barrier for drug resistance have significantly limited its clinical application. Here we report two new lipopeptide-based fusion inhibitors (LP-50 and LP-51) showing extremely potent inhibitory activities against diverse HIV-1, HIV-2, SIV, and T-20-resistant variants. Promisingly, both inhibitors exhibited potent and long-lastingex vivoanti-HIV activity and could efficiently suppress viral loads to undetectable levels in SHIV-infected monkey models. We believe that LP-50 and LP-51 are the most potent and broad-spectrum fusion inhibitors known to date and thus have high potential for clinical development.

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