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

Mzoughi, Olfa; Teixidó, Meritxell; Planès, Rémi; Serrero, Manutea; Hamimed, Ibtissem; Zurita, Esther; Moreno, Miguel; Granados, G.; Lakhdar-Ghazal, Faouzi; BenMohamed, Lbachir; Giralt, Ernest; Bahraoui, Elmostafa

doi:10.1042/bsr20192196

Cited by 8 publications

(6 citation statements)

References 65 publications

(74 reference statements)

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“…However, these domains play crucial roles during the process of fusion [28][29][30][31][32]. Overall, these findings indicate that GTEs may have their own complex evolutionary history, which involves multiple internal recombination events of different regions and results in the observed diversity.…”

Section: Discussionmentioning

confidence: 81%

Evolution and Genetic Diversity of the Retroviral Envelope in Anamniotes

Chen

Wang

Liao

et al. 2021

Preprint

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Retroviruses are widely distributed in all vertebrates, as are their endogenous form, endogenous retrovirus (ERV), which serves as “fossil” evidence to trace the ancient origins and history of virus-host interactions over millions of years. The retroviral envelope (Env) plays a significant role in host range determination, but major information on genetic diversification in anamniotes is lacking. Here, by incorporating multiple-round in silico similarity search and phylogenomic analysis, 25498 ERVs with gamma-type Env (GTE), covalently associated Env, were discovered by searching against all 974 available fish and 19 amphibian genomes, but no beta-type Env (BTE), noncovalently associated Env, were found. Furthermore, a nine-type classification system of anamniote GTE was proposed by combining phylogenetic and domain/motif analyses. The elastic genomic organization and overall phylogenetic incongruence between anamniotic Env and its neighboring polymerase (Pol) implied that early retroviral diversification in anamniotic vertebrates was facilitated by frequent recombination. At last, host opioid growth factor receptor (OGFr) gene capturing by anamniotic ERVs with GTE was reported for the first time. Overall, our findings overturn traditional Pol genotyping and reveal a complex evolutionary history of anamniotic retroviruses inferred by Env evolution.Author summaryAlthough the retroviral envelope (Env) protein in amniotes has been well studied, its evolutionary history in anamniotic vertebrates is ambiguous. By analyzing more than 25000 ERVs with gamma-type Env (GTE) in anamniotes, several important evolutionary features were identified. First, GTE were found to be widely distributed among different amphibians and fish. Second, nine types of GTE were discovered, revealing the great genetic diversity. Third, GTE-containing ERVs have rampantly proliferated in certain amphibians such as Ambystoma mexicanum, and the copy number was found to be markedly higher than 10000. Fourth, the incongruence between the Env and Pol phylogenies suggested that frequent recombination shaped the early evolution of anamniote retroviruses. Fifth, an ancient horizontal gene transfer event was discovered from anamniotes to ERVs with GTE. These findings reveal a complex evolution pattern for retroviral Env in anamniotes.

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Section: Discussionmentioning

confidence: 81%

Evolution and Genetic Diversity of the Retroviral Envelope in Anamniotes

Chen

Wang

Liao

et al. 2021

Preprint

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“…Interaction between three HR1 and HR2 domains of the trimeric fusion protein, leads to the formation of the 6-HB, which is critical for bringing the viral and host membranes in close proximity, hence driving their fusion ( 6 , 8 , 30–32 ). This makes the 6-HB structure an attractive drug target for blocking membrane fusion and viral entry ( 11–15 , 33–38 ). However, till date, the 6-HB structure has been mostly targeted using long peptides (35 to 50 amino acids) mimicking either HR1 or HR2 helices ( 11 , 13 , 39–41 ).…”

Section: Discussionmentioning

confidence: 99%

Targeting an evolutionarily conserved “E-L-L” motif in spike protein to identify a small molecule fusion inhibitor against SARS-CoV-2

Jana

Bhattacharya²,

Mayilsamy

et al. 2022

PNAS Nexus

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As newer variants of SARS-CoV-2 continue to pose major threats to global human health and economy, identifying novel druggable antiviral targets is the key towards sustenance. Here, we identify an evolutionary conserved “E-L-L” motif present within the HR2 domain of all human and non-human coronavirus spike (S) proteins that play a crucial role in stabilizing its post-fusion six-helix bundle (6-HB) structure and thus, fusion-mediated viral entry. Mutations within this motif reduces the fusogenicity of the S protein without affecting its stability or membrane localization. We found that posaconazole, an FDA-approved drug, binds to this “E-L-L” motif and impedes the formation of 6-HB, thus effectively inhibiting SARS-CoV-2 infection in cells. While posaconazole exhibits high efficacy in blocking S protein-mediated viral entry, mutations within the “E-L-L” motif rendered the protein completely resistant to the drug, establishing its specificity towards this motif. Our data demonstrate that posaconazole restricts early stages of infection through specific inhibition of membrane fusion and viral genome release into the host cell and is equally effective towards all major variants of concerns of SARS-CoV-2 including beta, kappa, delta, and omicron. Together, we show that this conserved essential “E-L-L” motif is an ideal target for the development of prophylactic and therapeutic interventions against SARS-CoV-2.

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“…The V3 region is integrally involved in both receptor binding and the determination of viral tropism 33,34 . The CH2 terminal region plays a key role in HIV-1 entry by membrane fusion 35 . When we compared the enrichment of these envelope peptides between NS and AS escape subjects, we found that AS escape subjects more highly enriched the CH2 terminal epitope relative to NS escape subjects.…”

Section: Discussionmentioning

confidence: 99%

Unbiased serology reveals autoimmunity and HIV antibody signatures in HIV CNS Escape

Hawes

Alvarenga

Browne

et al. 2022

Preprint

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Background: Antiretroviral therapy (ART) suppresses plasma and cerebrospinal fluid (CSF) HIV replication with occasional asymptomatic episodes of detectable HIV RNA known as asymptomatic (AS) escape. Neurosymptomatic (NS) CSF escape is a rare exception in which CNS HIV replication occurs in the setting of neurologic impairment. The origins of NS escape are not fully understood. Methods: Using a large cohort of PLWH (n=111), including elite controllers (n=4), viral controllers (n=4), ART untreated subjects (n=18), HIV-associated dementia (n=4), ART suppressed (n=16), AS escape (n=19), NS escape (n=35), secondary escape (n=5) subjects, and HIV-negative controls (n=6), we investigated immunoreactivity to self-antigens in the CSF of NS escape by employing neuroanatomic CSF immunostaining and massively multiplexed self-antigen serology (PhIP-Seq). Additionally, we utilized pan-viral serology (VirScan) to deeply profile the CSF anti-viral antibody response and metagenomic next-generation sequencing (mNGS) for pathogen detection. Results: We detected Epstein-Barr virus (EBV) DNA more frequently in the CSF of NS escape subjects than in AS escape controls. Based on immunostaining and PhIP-Seq, there was evidence for increased immunoreactivity against self-antigens in NS escape CSF. Finally, VirScan revealed several immunodominant epitopes that map to the HIV env and gag proteins in the CSF of PLWH. Discussion: We deployed agnostic tools to study whether there was evidence for a neuroinvasive co-infection and/or autoimmunity in HIV escape syndromes. We more frequently detected EBV DNA and immunoreactivity to self-antigens in NS escape. Whether these additional inflammatory markers are byproducts of an HIV-driven inflammatory process or whether they independently contribute to the neuropathogenesis of NS escape will require further study.

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

Cited by 8 publications

References 65 publications

Evolution and Genetic Diversity of the Retroviral Envelope in Anamniotes

Evolution and Genetic Diversity of the Retroviral Envelope in Anamniotes

Targeting an evolutionarily conserved “E-L-L” motif in spike protein to identify a small molecule fusion inhibitor against SARS-CoV-2

Unbiased serology reveals autoimmunity and HIV antibody signatures in HIV CNS Escape

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