What is a Retroviral Infection?
Retroviral infection – a group of infectious diseases caused by retroviruses.
Causes of Retroviral Infection
Retroviruses (Latin Retroviridae) – a family of RNA-containing viruses that infect mainly vertebrates. The most well-known and actively studied representative is the human immunodeficiency virus. After the cell is infected with a retrovirus, the synthesis of the viral DNA genome begins in the cytoplasm using virion RNA as a template. All retroviruses use the reverse transcription mechanism to replicate their genome: the viral enzyme reverse transcriptase (or revertase) synthesizes one DNA strand on the viral RNA template, and then completes the second, complementary strand to it on the template of the synthesized DNA strand. A double-stranded DNA molecule is formed, which, after penetrating the nuclear envelope, integrates into the chromosomal DNA of the cell and then serves as a template for the synthesis of viral RNA molecules. These RNAs leave the cell nucleus and in the cytoplasm the cells are packaged into viral particles that can infect new cells. According to one of the hypotheses, retroviruses could occur from retrotransposons – mobile regions of the eukaryotic genome. Retrovirus virions are composed of particles surrounded by a shell, approximately 100 nm in diameter. Virions also contain two identical single-stranded RNA molecules with a length of 7-10 kilobases. Although virions of different retroviruses do not have the same morphology or biology, all components of the virion are very similar to other members of the genus.
Composed of a lipid bilayer, which is obtained from the host plasma membrane during the budding process.
Consists of two-dimensional RNA. It has a cap at the 5′-end and polyadenylate at the 3′-end. The ribonucleic acid genome also has end non-coding regions that are important in replication, and internal regions that encode virion proteins for gene expression. The 5′-end of the RNA molecule includes four regions, such as R, U5, PB and L. The R-region is a short, repeatable sequence at each end of the genome during reverse transcription in order to ensure the correct end-to-end transfer to the growing chain. The U5 region, on the other hand, is a short sequence between the R and PB regions. The PB region consists of 18 bases complementary to the 3′-end of the tRNA sample. The L-region is a non-translated leading region, which gives the signal for packaging genomic RNA. The 3′-end includes three regions, among which PP (polyuric), U3 and R. The region of PP is a sample for the plus-strand of DNA synthesis during reverse transcription. The U3 region is a sequence between the PP and R regions, which possesses a signal that the provirus can use for transcription. Finally, the R region is the final repeating sequence at the 3′-end.
Consisting of gag, protease (PR), pol proteins and env proteins. The gag proteins are the main components of the viral capsid, in the amount of 2000-4000 copies per virion. Protease, on the other hand, is expressed differently in different viruses. It functions in proteolytic cleavage during maturation of the virions in order to obtain mature gag and pol proteins. The pol proteins are responsible for viral DNA synthesis and integration into the host DNA after infection. Finally, env proteins play a role in the combination and entry of the virion into the host cell.
Once the delta retroviruses have inserted their own genomes into the reproduction line, their genomes are passed on to the next generations. These endogenous retroviruses (ERV), distinguished from exogenous, now make up 5-8% of the human genome. Most inclusions have an unknown function and are often referred to as ‘useless DNA’.
Role in host biology
However, many endogenous delta-retroviruses play important roles in host biology, such as management of gene transcription, cell division during placental development during the reproduction of the embryo, and resistance of exogenous retroviral infection. Endogenous delta-retroviruses have also received special attention in the study of pathological conditions associated with immunology, in autoimmune diseases such as multiple sclerosis, although it has not yet been proved that endogenous delta-retroviruses play a causal role in this disease.
The role of endogenous delta-retroviruses in human gene evolution
This role was investigated in a 2005 article. While it was believed that classically transcription occurs from DNA to RNA, reverse transcriptase transcribes RNA into DNA. The term “retro” in retroviruses refers to this reverse process (production of DNA from RNA) of the central dogma of molecular biology. Reverse transcriptase activity outside of retroviruses was found in almost all eukaryotes, creating the possibility of producing and incorporating new copies of retrotransposons into the host genome. These inserts are transcribed using host enzymes into new RNA molecules that enter the cytosol. Following this, some of these RNA molecules are translated into viral proteins. For example, the gag gene is translated into a capsid protein molecule, the pol gene is transcribed into reverse transcriptase molecules, and the env gene is translated into envelope protein molecules. It is important to note that any retrovirus must “insert” its own reverse transcriptase into its capsid; otherwise, it is unable to use the enzymes of the infected cell to perform the task as a result of the unusual nature of the formed DNA from RNA.
The nature of drug resistance
Industrially produced drugs that are designed as protease and reverse transcriptase inhibitors may quickly be ineffective, because the gene sequences that encode this protease and reverse transcriptase can undergo many substitutions. Such substitutions of the nitrogenous bases that form the DNA strand can make proteases or reverse transcriptase difficult to attack. Amino acid substitution makes enzymes able to shy away from drug treatment regimens, because mutations in a sequence of genes can cause a physical or chemical change that makes it difficult to detect them with medication. Due to the fact that reverse transcriptase does not check the correctness of DNA replication, the retrovirus mutates very often. This allows the virus to become resistant to antiviral pharmaceuticals and inhibits the development of effective vaccines and inhibitors for retroviruses.
Perspectives to overcome resistance
When drugs are developed that are designed to attack enzymes such as protease, manufacturers target specific sites on this enzyme. One way to attack these targets may be through the hydrolysis of molecular bonds, which means that this drug will add H₂O (water) molecules to certain bonds. By adding water molecules to a virus site, this drug will break the previous connections that existed with each other. If several of these bonds are broken, this result can lead to lysis, death of the virus.
Pathogenesis during Retroviral Infection
Retroviral infection can be benign (for example, the genomes of many animal species contain the nucleotide sequences of retroviruses in an inactive state) or in the form of a rapidly developing severe disease with a fatal outcome (for example, Rous sarcoma in chickens caused by an exogenous virus). The discovery of the ability of retroviruses to disrupt the structure and function of a host cell’s DNA has become a new step towards understanding the molecular mechanisms of carcinogenesis. Embedded in the cellular genome, retroviruses acquire the properties of transposons (mobile genetic elements). They can activate or inhibit the activity of nearby genes. Retroviruses are characterized by a high level of genetic variability due to recombinations, as well as mutations arising under the influence of environmental factors. The pathogenesis of most viral infections in humans consists of the damaging effects of the virus on tissue and the response of the body. In addition, retroviruses cause transformation of infected cells and impaired immunity, leading to malignant neoplasms and opportunistic infections.