The Regulatory Network of Cyclic GMP-AMP Synthase-Stimulator of Interferon Genes Pathway in Viral Evasion

Virus infection has been consistently threatening public health. The cyclic GMP-AMP synthase (cGAS)-Stimulator of Interferon Genes (STING) pathway is a critical defender to sense various pathogens and trigger innate immunity of mammalian cells. cGAS recognizes the pathogenic DNA in the cytosol and then synthesizes 2′3′-cyclic GMP-AMP (2′3′cGAMP). As the second messenger, cGAMP activates STING and induces the following cascade to produce type I interferon (IFN-I) to protect against infections. However, viruses have evolved numerous strategies to hinder the cGAS-STING signal transduction, promoting their immune evasion. Here we outline the current status of the viral evasion mechanism underlying the regulation of the cGAS-STING pathway, focusing on how post-transcriptional modifications, viral proteins, and non-coding RNAs involve innate immunity during viral infection, attempting to inspire new targets discovery and uncover potential clinical antiviral treatments.

Grass Carp Reovirus VP56 Allies VP4, Recruits, Blocks, and Degrades RIG-I to More Effectively Attenuate IFN Responses and Facilitate Viral Evasion

Grass carp reovirus (GCRV) fibrin VP56 and major outer capsid protein VP4 inlay and locate on the outer surface of GCRV-II and GCRV-III, which causes tremendous loss in grass carp and black carp industries. Fibrin is involved in cell attachment and plays an important role in reovirus infection.

Special Issue: “Innate Immune Sensing of Viruses and Viral Evasion”

In this Special Issue, a wide variety of original and review articles provide a timely overview of how viruses are recognized by and evade from cellular innate immunity, which represents the first line of defense against viruses [...]

A Rare Mutation in an Infant-Derived HIV-1 Envelope Glycoprotein Alters Interprotomer Stability and Susceptibility to Broadly Neutralizing Antibodies Targeting the Trimer Apex

ABSTRACT The envelope glycoprotein (Env) of human immunodeficiency virus type 1 (HIV-1) is the sole target of broadly neutralizing antibodies (bnAbs). Several mechanisms, such as the acquisition of mutations, variability of the loop length, and alterations in the glycan pattern, are employed by the virus to shield neutralizing epitopes on Env to sustain survival and infectivity within the host. The identification of mutations that lead to viral evasion of the host immune response is essential for the optimization and engineering of Env-based trimeric immunogens. Here, we report a rare leucine-to-phenylalanine escape mutation (L184F) at the base of hypervariable loop 2 (population frequency of 0.0045%) in a 9-month-old perinatally HIV-1-infected infant broad neutralizer. The L184F mutation altered the trimer conformation by modulating intramolecular interactions stabilizing the trimer apex and led to viral escape from autologous plasma bnAbs and known N160 glycan-targeted bnAbs. The L184F amino acid change led to the acquisition of a relatively open trimeric conformation, often associated with tier 1 HIV-1 isolates and increased susceptibility to neutralization by polyclonal plasma antibodies of weak neutralizers. While there was no impact of the L184F mutation on free virus transmission, a reduction in cell-to-cell transmission was observed. In conclusion, we report a naturally selected viral mutation, L184F, that influenced a change in the conformation of the Env trimer apex as a mechanism of escape from contemporaneous plasma V2 apex-targeted nAbs. Further studies should be undertaken to define viral mutations acquired during natural infection, to escape selection pressure exerted by bnAbs, to inform vaccine design and bnAb-based therapeutic strategies. IMPORTANCE The design of HIV-1 envelope-based immunogens capable of eliciting broadly neutralizing antibodies (bnAbs) is currently under active research. Some of the most potent bnAbs target the quaternary epitope at the V2 apex of the HIV-1 Env trimer. By studying naturally circulating viruses from a perinatally HIV-1-infected infant with plasma neutralizing antibodies targeted to the V2 apex, we identified a rare leucine-to-phenylalanine substitution, in two out of six functional viral clones, that destabilized the trimer apex. This single-amino-acid alteration impaired the interprotomeric interactions that stabilize the trimer apex, resulting in an open trimer conformation and escape from broadly neutralizing autologous plasma antibodies and known V2 apex-directed bnAbs, thereby favoring viral evasion of the early bnAb response of the infected host. Defining the mechanisms by which naturally occurring viral mutations influence the sensitivity of HIV-1 to bnAbs will provide information for the development of vaccines and bnAbs as anti-HIV-1 reagents.

Special Issue “Viral Evasion or Suppression of Host Immunity”

Viruses have evolved to survive in hosts, presumably by devising meticulous strategies to elude or suppress host immunity [...]

A rare mutation in an infant derived HIV-1 envelope glycoprotein alters interprotomer stability and susceptibility to broadly neutralizing antibodies targeting the trimer apex

The envelope glycoprotein (Env) of human immunodeficiency virus-1 (HIV-1) is the sole target of broadly neutralizing antibodies (bnAbs). Several mechanisms, such as acquisition of mutations due to the error prone reverse transcriptase, variability of loop length and alterations in glycan pattern are employed by the virus to shield neutralizing epitopes on the env, to sustain survival and infectivity within the host. Identification of mutations that can lead to viral evasion from host immune response is essential for optimization and engineering of Env based trimeric immunogens. Herein, we report a rare leucine to phenylalanine escape mutation (L184F) at the base of hypervariable loop 2 (population frequency of 0.0045%) in a nine-month-old perinatally HIV-1 infected infant broad neutralizer. The L184F mutation disrupted the intramolecular interaction, stabilizing the trimer apex thereby leading to viral escape from autologous plasma bnAbs and known bnAbs, targeting exclusively the N160 glycan at trimer apex and not any other known epitope. The L184F amino acid change led to acquisition of a relatively open trimeric configuration, often associated with tier 1 HIV-1 isolates and an increased susceptibility to neutralization by polyclonal plasma antibodies of weak neutralizers. While there was no impact of the L184F mutation on free virus transmission, a reduction in cell-to-cell transmission was observed. In conclusion, we report a viral escape mutation that plausibly destabilized the trimer apex and favoured evasion from broadly neutralizing antibodies. Such mutations, though rare, should be taken into consideration while designing an immunogen, based on a stable correctly-folded HIV-1 Env trimer.ImportanceDesign of HIV-1 envelope-based immunogens, capable of eliciting broadly neutralizing antibodies (bnAbs), are currently under active research. Some of the most potent bnAbs target the quaternary epitope at the V2 apex of HIV-1 Env trimer. By studying naturally circulating viruses from an HIV-1 perinatally infected infant, with plasma neutralizing antibodies targeted to the V2-apex, we identified a rare leucine to phenylalanine substitution in two out of six functional viral clones, that destabilized the trimer apex. This single amino acid alteration impaired the interprotomeric interactions that stabilize the trimer apex, resulting in an open trimer conformation, and escape from broadly neutralizing autologous plasma antibodies and known V2-apex directed bnAbs, thereby favouring viral evasion of the early bnAb response of the infected host. Defining the mechanisms by which viral mutations influence the sensitivity of HIV-1 to bnAbs is crucial for the development of effective vaccines against HIV-1 infection.