Zika Virus News
: While we are awaiting confirmation from the Thai authorities if there is indeed a Zika virus crisis slowly unfolding in the country after Hungarian heath officials reported that two of its citizens contracted the Zika virus after visiting Thailand, new studies are emerging that the Zika virus is indeed mutating as a rapid rate!
An international team of researchers spanning from China, Pakistan and the United Kingdom has found in a new study that the zika virus is mutating at alarmingly rate and sadly most high-risk countries are not conducting any genomic surveillance! Considering the rate of mutations and substitutions found in the genomes, we are literally dealing with an almost new pathogenic virus that we know little about!
Furthermore, all experimental vaccines that were developed for Zika virus and some that are under clinical trials might no longer be effective against the new strains of Zika virus!
According to the study team, the Zika virus (ZIKV), which originated in Africa, has become a significant global health threat. It is an RNA virus that continues to mutate and accumulate multiple mutations in its genome.
Alarmingly, these genetic changes can impact the virus’s ability to infect, cause disease, spread, evade the immune system, and drug resistance.
In this new research, detailed genome-wide analysis of 175 ZIKV isolates deposited at the National Center for Biotechnology Information (NCBI), was carried out. The comprehensive mutational analysis of these isolates was carried out by DNASTAR and Clustal W software.
Shockingly, the study findings revealed 257 different substitutions at the proteome level in different proteins when compared to the reference sequence (KX369547.1).
The substitutions were capsid (17/257), preM (17/257), envelope (44/257), NS1 (34/257), NS2A (30/257), NS2B (11/257), NS3 (37/257), NS4A (6/257), 2K (1/257), NS4B (15/257), and NS5 (56/257).
Based on the coexisting mutational analysis, the MN025403.1 isolate from Guinea alone was identified as having 111 substitutions in proteins and 6 deletions!
The effect of coexisting/reoccurring mutations on the structural stability of each protein was also determined by I-mutant and MUpro online servers. Furthermore, molecular docking and simulation results showed that the coexisting mutations (I317V and E393D) in Domain III (DIII) of the envelope protein enhanced the bonding network with ZIKV-specific neutralizing antibodies.
The study findings highlighted the rapid accumulation of different substitutions in various ZIKV proteins circulating in different geographical regions of the world. Surveillance of such mutations in the respective proteins will be helpful in the development of effective ZIKV vaccines, neutralizing antibody engineering and antivirals.
The study findings were published week ago in the peer reviewed journal: Frontiers
To date, no Zika Virus News
coverages have touched on this alarming evolution seen in the Zika virus.
The virus has eventually spread to several countries and territories of the world. Similar to other RNA viruses, ZIKV has undergone several mutations and accumulated various mutations in structural and non-structural proteins. These mutations have enabled it to adapt to various epidemiological settings.
The study findings report all the reoccurring and coexisting mutations in both structural and non-structural proteins of ZIKV isolates. In addition, the effect of mutations (specifically mutations in domain III of the E protein) on the efficacy of already reported neutralizing antibodies was also evaluated.
It was noted that among the structural proteins of ZIKV, the preM and envelope (E) proteins have been used for the development of vaccines in which the E protein is the main target of ZIKV neutralizing antibodies.
Worryingly, this study highlighted that among the structural proteins, E protein is the most mutated, harboring 44 different mutations, followed by preM and capsid protein carrying 17 substitutions at different positions.
To date, the DIII of the E protein has been reported to be the main target of neutralizing antibodies against ZIKV. Hence, mutations in the E protein are of great importance regarding their involvement in the host immune system and their neutralization. Not all mutations are in the favor of the viruses; hence, mutations sometimes harness the viruses to the antibodies and become easy targets for neutralizing antibodies.
It was found that the coexisting mutations (I317 V and E393D) in the DIII domain of ZIKV E protein enhanced binding with the previously reported antibodies ZV64 and ZV67.
In the same light, the mutations N139S/S139N play a vital role in the incidence of microcephaly.
The 139N residue in the preM protein enhances the tropism of ZIKV for human progenitor cells and increases fetal microcephaly in mice.
The ZIKV strains circulating in Asian countries carry the 139S residue in the preM protein, which is occasionally reported to be involved in ZIKV-related microcephaly.
Interestingly, it was observed that the majority of the isolates of American origin carry the 139N residue in their preM protein; hence, the ratio of ZIKV-related microcephaly is higher (2-12 per 10,000 live births).
However, in contrast, all the isolates of European/Asian origin carry the 139S residue instead of the 139N residue in their preM protein; therefore, the incidence of ZIKV-related microcephaly in these regions is relatively lower (1 in 10,000 live births).
It was found that among the non-structural proteins, one of the biologically important mutations, 892 V/A, in NS1 has been reported to be involved in the secretions of ZIKV to the circulatory system, enhancing uptake of ZIKV by mosquitoes and participating in the phosphorylation of TBK1 and the transmission of the virus, thereby facilitating viral replication in humans.
Also, it was found that 892V/A is one of the re-occurring mutations in this current research findings.
Another important mutation was T233A (polyprotein T1026A) in the NS1, which has already been reported to destabilize the NS1 dimer and affect viral replication and pathogenesis.
Again, one of the re-occurring mutations in this study was M2634V, which was previously identified as neutral having no effect on the function of NS5 mutation.
Also, mutations such as I3046A/T, K3107G/R, and N3167R/S in NS5 have been reported to inhibit intracellular interferon pathways and increase viral replication.
The study team concluded, “Being an RNA virus, the ZIKV continues to mutate rapidly and accumulate multiple mutations within its genome. In the current study, we reported rapid accumulations of various substitutions of amino acids in both structural and non-structural proteins of ZIKV circulating in different geographical regions of the world. Among the isolates of the ZIKV that were studied, one particular isolate (MN025403.1) from Guinea had the most mutations. This isolate had 111 substitutions and 6 deletions. The molecular docking and simulation approaches in this study verified that the mutated E protein enhanced the binding affinity of the ZIKV to the human-neutralizing antibodies. The study also highlighted the importance of monitoring mutations in the targeted genes of the ZIKV in order to improve the efficacy of vaccines and therapeutic applications. By understanding the impact of mutations on the structure and function of the virus, scientists can develop more effective antiviral drugs and vaccines.”
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