Tag Archives: antiviral drugs

New Treatment Found for Chronic Hepatitis B Virus

Contributed by Guest Blogger: S. Bhutani ’14

Chronic Hepatitis B virus (HBV) is a common infectious disease. HBV infects hepatocytes, which are liver cells, thereby impairing liver function and leading to disease such as liver cancer. In chronic HBV the responses from the CD8 cytotoxic T-cell and CD4 helper T-cell are not substantial enough because high amounts of HBV impair T-cell immunity. Thus, ideal anti-viral treatments would need to reduce the amount of virus. In the past decade, the introduction of nucleoside and nucleotide analogs, compounds that look similar to nucleotides and deceive the virus into thinking it is being replicated, has improved treatment for HBV. However, the prominent nucleoside analog, lamivudine, that inhibits HBV replication, is no longer as effective because the virus has developed mutations that resist the drug. One new nucleotide analog, called adefovir dipivoxil, has been tested on chronic HBV patients in China.
In China 22 patients were tested along with 20 healthy controls. The patients were treated with adefovir dipivoxil once daily for 10 weeks. The presence of cytokines producing certain T-helper cells was measured, as was the amount of HBV DNA using biochemical markers. Before adefovir dipivoxil, the cytokines producing helper and killer T-cells were lower in the patients than the healthy individuals. There were two patients with HBV mutations, one which was lamivudine resistant and one which was adefovir dipivoxil resistant. Adefovir dipivoxil treatment resulted in an increase of Th1 and Th2 cytokines that produce CD4 T-cells in all patients except for the one with the adefovir dipivoxil resistant mutation, proving that this new drug can combat lamivudine resistant HBV mutations. The treated patients’ levels of cytokines peaked and then dropped and stayed at the cytokine levels of the healthy individuals. There was an inverse correlation between the amount of HBV DNA and cytokine levels; after treatment as cytokine levels increased, HBV DNA decreased.
Thus, this study suggests that adefovir dipivoxil inhibits HBV DNA polymerase thereby reducing the amount HBV and restoring T-cell immunity. However, it should be noted that even after the recent development of the drug, HBV mutations were still found. Thus will there ever be development of a treatment for which there no resistant mutations have already evolved?


Shotgun Approach to Keeping Viruses Off

Contributed by Guest Blogger: J. Moon ’14

The amount of human resources to develop therapeutics on a single-pathogen basis is limited. A single-pathogen approach is made more impractical with the ever increasing number of viral pathogens. But there are alternatives to this approach: broad-spectrum antivirals that target various groups of viral pathogens. Recent studies have found that LJ001, a broad-spectrum small molecule antiviral , is effective against numerous lipid enveloped viruses including Influnza A, filoviruses, poxviruses, areanviruses, bunyaviruses, paramyxoviruses,flaviviruses, and HIV-1. Against nonenveloped viruses, however, LJ001 has no effect.
The LJ001 antiviral acts by attaching to the membranes of both the cell and virus and inhibits virus-cell fusion. The antiviral begins by injecting itself into the lipid bilayer of the cell. But it is only activated upon contact with the other antiviral on the virus. Once activated, the molecule damages the lipid membrane of the virus. This damage to the lipid membrane results in loss of fluidity/rigidity that is necessary to undergo fusion into the cell. Since viral membranes do not have the ability to repair themselves, the viral membrane is deactivated by the LJ001 antiviral. Therefore, LJ001 is effective against various enveloped virus groups including the previously mentioned.
One of the first experiments was to see the comparative effects of the antiviral on viruses. The experiment consisted of testing enveloped and nonenveloped cells. The conclusion reached after data collection was that the LJ001 antiviral has no effect on nonenveloped viruses. Experiments were also conducted to determine whether or not the LJ001 antiviral was acting on the virus or on the cell. This included the introduction of the antiviral to the cell culture before and after attachment of the virions to cells. Results showed high infection rates near 100% for the cell cultures introduced to the antiviral after the virus attachment whereas infection rates for the cell cultures pre-treated with the antiviral were near zero. Experiments were also conducted with the antiviral being applied to a wide variety of large-scale lipid enveloped viruses. These results showed that there are varying degrees of effectiveness across different viruses. The conclusions reached on these observations are that LJ001 affects only non-enveloped viruses on varying degrees of effectiveness and that the LJ001 deactivates virions and prohibits virus-cell fusion.
What impact does this have on these enveloped virus groups? Although the lipid membrane of a virus remains fairly static from generation to generation, is it likely or possible that these viruses will somehow develop mechanisms to counter the effect of the antiviral? What are some possibilities?


Millions of Viruses and Only One Drug

Contributed by Guest Blogger: M. Carraher ’14

A former leader of the Pentagon considers, “Mother Nature among the worst terrorists.” Throughout modern time, the threat of a virus pandemic has seemed more likely, and more deadly than a nuclear war. Swine flu, HIV, and SARS have all frightened average citizens and leading microbiologists into a frenzy. The biggest threats have been the viruses that were least expected. If you don’t see them coming, how can you protect against a deadly outbreak? The general strategy for antivirals is “one bug, one drug”. However, any small mutation of the virus might render the drug useless. Research is currently being poured into developments of a broader range of antivirals. The current hypothesis is that certain proteins inside cells are vital for virus replication. But what if those cellular proteins aren’t necessarily vital for host life? A promising target is the TSG101 protein, which is involved in the transport of viruses out of a cell. A small-molecule drug has been developed to inhibit that interaction between the protein and virus. Researchers have identified more than 30 viruses that rely on this protein, so the drug does protect over a broader range infections. One hundred percent of Ebola-infected mice survive if exposed to the drug, a day after infection. Eighty percent survive if treated two days post infection, and 40% live four days after infection. The early test results seem promising for a strong, broad ranged antiviral drug, that does not hurt the host.
The most promising broad spectrum antiviral targets the host instead of the virus. Healthy cell membranes express a substance called phosphatidylserine on their inner surfaces. When under stress from a viral infection, this substance ends up on the outer surface. All viral infections seem to exhibit this behavior, making it a key target for drugs. An antibody called bavituximab has been developed, which binds to the phosphatidylserine. Once bound, the immune system should clearly recognize the infected cell and destroy, thus limiting viral replication. This method was tested on guinea pigs exposed to a Pichinde virus. Half the animals treated with bavituximab survived, compared 100% death for the control group, not injected with the antibody.
The antibody is currently being tested for a broader range of viruses, such as HIV, hepatitis, and influenza. So far, all infected cells express this molecule on the outside of their membranes, as compared to healthy cells, which maintain the molecule within the cell. This antibody could potentially protect against all known viruses, and some unknown as well, considering all viruses are believed to exhibit this behavior. However, viruses do evolve. Could they evolve to become immune to the antibody at some point? Further testing with humans is also needed to determine any potential side-effects. But, this is one step closer to a universal antiviral.