Diss. (sammanfattning) Umeå : Umeå universitet, 2008. / Härtill 5 uppsatser.

Viruses cause human diseases by entering in to human cells. Many drugs have been developed that act at various stages of viral infection, but they fail due to their toxic side effects and high mutation rates of viruses. Recently, a new class of drugs called entry inhibitors has been developed which acts on the early stages of viral infection. These drugs have been developed by studying the entry process of viruses in to host cells. The success of these drugs, however, is still limited and research is being done to quantify the optimum dosage of these drugs and find new drugs targets. We developed a mathematical model based on chemical reaction kinetics to estimate the threshold number of complexes between viral and target cell surface proteins necessary for HIV-1 entry into target cells. Our model quantitatively describes data of HIV entry in the presence of several entry inhibitors and presents an avenue for identifying optimal drug levels for restricting HIV entry. Majority of viruses enter into host cells by either endocytosis of fusion. But when virus enters through endocytosis and when through fusion is still not clear. We developed a theory that predicts the virus entry pathway based on the underlying biophysical properties like membrane bending modulus, viral and cellular receptor concentration and the energy released by the formation of protein complexes. Through this theory of viruses we presented the entry of viruses through fusion or endocytosis on a phase diagram. We validated the phase diagram by comparing it with known pathways of existing viruses. This study may aid in unraveling the entry pathways of new viruses and may also help in identifying new drug targets.

Most viruses can infect only a reduced range of organisms and an effective replication is possible only in selected hosts. These hosts are called permissive for the virus. Molecular principles of a nonpermissiveness and viral mechanisms of overcoming replication obstacles are still not clearly elucidated. This thesis discusses the molecular causes of the cellular nonpermissiveness against a model retrovirus - Rous sarcoma virus. The research is conducted on duck cells which are semipermis- sive to the subgroup C of Rous sarcoma virus. The virus can enter those cells, but it is not able to produce enough infectious viral progeny. Two blocks of the viral replication cycle in the duck cells are described in the thesis. The first one is the probably not optimal cellular receptor recognition. The second one is in the late phase of the replication cycle when the viral proteins are synthesized. The amount of the envelope glyco- protein coding mRNA is reduced due to the altered splicing ratios, and the virions produced from the duck cells are less infectious. This block is recessive and can be partially omitted by cell fusions with permissive chicken cells; therefore, the block is not caused by specific restriction fac- tors in sensu stricto. Additionally, the influence of mutations in duck adapted Rous...

One of the important tasks of virology and immunology is to explore the species- and cell-barriers preventing virus horizontal transmission and reveal the ways how viruses overcome these barriers and "adapt" to different species. This work is based on a well- established retroviral model - avian Rous sarcoma virus (RSV) and studies virus replication blocks in mammalian cells at both pre- and post-integration level. Interaction of the viral envelope glycoprotein (Env) with a specific cellular receptor mediates virus entry into cells. Although mammalian orthologues of specific chicken receptors do not support RSV entry, it was observed that some RSV strains are able to enter mammalian cells. Several RSV-transformed rodent cells lines were described and analysis of provirus H20- RSV in one these cells lines (hamster H-20 tumor cell line) showed multiple mutations including two crucial amino acid substitutions in different regions of Env. Substitutions D32G and L378S confer virus transmission to hamster, human and also chicken cells lacking the appropriate receptor. Altered conformation of H20-RSV Env is similar to a receptor-primed (activated) state of Env. This observation indicates that virus can circumvent the need of original cell receptor because of spontaneous Env activation caused by single...