What is a retrovirus?

Retrovirus is a type of virus that employs RNA as its genetic material. Thus, retroviruses comprise the most diverse family of enveloped RNA and can be defined by common taxonomical features including composition, replicative properties and structure. The virions possess an envelope made up of lipid and also comprise of viral glycoproteins. When a cell gets infected by a retrovirus, it transforms the viral RNA into DNA, and this newly formed DNA integrates into the host cell's genetic material. Subsequently, the infected cell generates additional retroviruses, spreading the infection to other cells. Numerous retroviruses are linked to various diseases, such as AIDS and certain types of cancer.

In the 1970s, retroviruses were recognized as causing cancers in animals, but their role in human diseases was unclear. The discovery of T-cell growth factor, later known as interleukin-2, enabled researchers, led by Robert Gallo at the IRP, to culture human T cells in vitro, where they observed the first instance of retroviruses in human cells, marking a significant advancement in understanding the connection between retroviruses and human diseases.

Structure of Retroviruses

Retroviruses constitute a sizable category of enveloped viruses with a single-stranded RNA genome. The examination of retrovirus proteins and particles has been thoroughly conducted through methodologies like nuclear magnetic resonance (NMR), X-ray crystallography, cryo-electron microscopy (cryo-EM), and cryo-electron tomography (cryo-ET).

Retroviruses encompass key components such as envelope, capsid, and a single-stranded RNA genome. These viruses infect host cells by fusion with the cellular membranes, mediated by the envelope glycoprotein (Env), leading to the delivery of the viral core into the cytoplasm. These viruses infect host cells by fusion with the cellular membranes, mediated by the envelope glycoprotein (Env), leading to the delivery of the viral core into the cytoplasm.

Replication of Retrovirus Life Cycle

Retrovirus replication involves entry into host cells, reverse transcription of viral RNA into DNA, integration of the provirus into the host genome, transcription and translation of viral genes, and the final release of new virions through budding.

• Entry: Retroviruses enter host cells by binding to specific cell surface receptors, facilitating fusion of the viral and cellular membranes, and releasing viral RNA into the host cell cytoplasm.
• Reverse Transcription: Upon entry, the viral enzyme reverse transcriptase converts the single-stranded viral RNA genome into double-stranded DNA, creating a provirus that can integrate into the host cell genome.
• Integration: The newly synthesized viral DNA integrates into the host cell's genomic DNA with the help of the integrase enzyme, becoming a provirus and ensuring the viral genetic material is passed on to daughter cells during cell division.
• Transcription and translation: The host cell machinery transcribes and translates the integrated proviral DNA, producing viral RNA and proteins necessary for the assembly of new viral particles.
• Budding: Viral components reach the cell membrane, where they assemble into new virions and bud off from the host cell. They acquire a covering which comes from the cell membrane of the host, ready to infect new target cells.

Common Retroviral Infections in Humans

Human T-cell lymphotropic viruses (HTLV) are horizontally transmitted retroviruses associated with rare retroviral diseases, originating from simian viruses.

Human Immunodeficiency Virus (HIV), another exogenous retrovirus, causes asymptomatic infection, acute symptoms, and acquired immune deficiency syndrome (AIDS), affecting CD4-bearing cells.

HTLVs manifest as asymptomatic infection, adult T-cell leukemia (ATL), and tropical spastic paraparesis, affecting T cells and having an incubation period of 30 to 40 years. Pathogenesis involves the transactivator protein (tax) inducing uncontrolled proliferation of target cells, with an unclear mechanism for tropical spastic paraparesis; host defenses include antibodies and T cells, while infection is prevalent in regions like southwestern Japan, the Caribbean, and sub-Saharan Africa.

HIV shares structural similarities with HTLV, but with a larger genome; CD4 cell receptor binding initiates multiplication, and pathogenesis involves immune dysfunction due to T4 cell killing, impacting the brain in AIDS, although neurologic disease mechanisms are unclear. Host defenses include immune responses and interferon production, with HIV infection diagnosed through specific antibodies, polymerase chain reaction, and p24 antigen detection.

Endogenous retroviruses (ERVs) are residual elements of previously infectious external retroviruses that have become integrated into our DNA and are now inherited through Mendelian genetics. Although many ERVs are typically inactive, they can be triggered to become active by various stimuli, such as viral infections. HIVs have been demonstrated to stimulate the transcription and translation of endogenous retroviral elements.

Retrovirus and Cancer

Retroviruses play a significant role in cancer development through the integration of viral oncogenes into the host genome, disrupting normal cellular regulation.

Oncogenes are genes when mutated or activated, have the potential to cause normal cells to become cancerous. In the context of retroviruses, they carry specific oncogenes that can contribute to tumor formation. Retroviruses induce tumors through the integration and activation of viral oncogenes, disrupting normal cellular regulatory mechanisms and promoting uncontrolled cell growth, which can lead to the development of various cancers in infected individuals. Retroviruses, like HTLV-1 and HIV-1, contribute to cancer by integrating viral oncogenes into host DNA. These oncogenes, such as HTLV-1's "tax" and HIV-1's Tat, disrupt normal cell regulation, promoting uncontrolled growth. For example, HTLV-1's Tax enhances gene transcription and suppresses tumor suppressor genes, leading to adult T-cell leukemia. HIV-1, though lacking a classical oncogene, increases cancer risk by inducing immunological dysregulation. The interaction with co-factors like HHV-8 in HIV-1-infected individuals amplifies the risk, as seen in Kaposi's sarcoma.

Retroviral Vectors and Gene Therapy

Retroviral vectors are designed with proviral sequences to accommodate the gene of interest, incorporating it into target cells along with viral and cellular gene promoters like CMV to enhance gene expression. The use of packaging cells, containing DNA plasmids expressing viral gene products, facilitates the production of virions containing the vector genome, enabling integration with the genome of dividing target cells.

Applications of viral vectors in gene therapy include expressing genes in embryonic tissues for developmental studies, manipulating the germline in transgenic animals, and identifying integration sites to understand retroviral replicative strategies. In clinical settings, retroviral vectors are commonly employed for gene transfer in gene therapy, with applications in introducing drug susceptibility genes for targeted cell killing, correcting genetic defects like adenosine deaminase deficiency, and enhancing the immune response to tumors by various strategies, though success has been limited in some cases.

Prevention and Treatment of Retrovirus Infections

Preventive measures for retroviral infections, particularly HIV, include screening blood products to minimize the risk of transmission through transfusions, and education initiatives to promote safe sex practices and discourage the sharing of needles, reducing the risk of viral transmission.

In terms of antiretroviral therapies, drugs like azidothymidine (AZT) and other antiviral agents are utilized for both prophylaxis against the progression of retroviral infections to disease and for the treatment of established infections. These medications work by inhibiting the replication of the virus, helping to control viral load and delay disease progression. Additionally, in the context of retroviral infections like HIV, antiretroviral therapy is crucial for managing opportunistic infections and neoplasms that may arise due to the weakened immune system associated with the viral infection. Treatment is often tailored to address individual opportunistic infections and complications.

Current Research and Future Directions

Studies have concentrated on employing molecular methods to identify and characterize retroviral infections, enhancing diagnostic precision and deepening our comprehension of viral dynamics. Research is focused on cell line development for high-titer retrovirus production. These cells must have the ability to transfer genes to the hematopoietic stem cells of rhesus monkeys and achieve efficient and reproducible results in genetic experiments. Scientists are actively researching innovative methods to enhance retrovirus production for gene therapy applications, aiming to improve the efficiency and scalability of viral vector manufacturing.

The prevention of retroviral infections has been a significant area of emphasis, with research endeavors aimed at creating vaccines and preventive approaches. Investigations have delved into the possibility of formulating vaccines for retroviruses like the feline immunodeficiency virus (FIV) to eliminate or manage the spread of the virus in affected populations. Furthermore, research has explored the implementation of preventive measures and public health interventions to alleviate the impact of retroviral infections, particularly in the context of human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS).

recent-articles