Retroviridae
The retroviruses are enveloped viruses that have two complete copies of (+) sense RNA. They also contain the enzyme reverse transcriptase which uses the viral RNA to form a complementary strand of DNA, which is then replicated to form a dsDNA. For the genetic information to be transcribed and translated, this DNA migrates to the host cell nucleus and become incorporated into chromosomes of host cells. Such integrated viral DNA is known as a provirus.
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Retroviruses cause tumours and leukemia in humans. The human retroviruses invade immune defense cells called T lymphocytes and are referred to as Human T cell Leukemia Viruses (HTLV). Both HTLV-1 and HTLV-2 are associated with malignancies (leukemia and other tumours), whereas the human immunodeficiency virus (HIV) causes acquired immune deficiency syndrome (AIDS).
Important Properties
· Spherical enveloped virion, 80-100nm
· Ribonucleoprotein in central nucleoid (concentric or truncated cone in lentivurses) within icosahedral capsid.
· Envelope with glycoprotein peplomers
· 2 copies of linear plus sense ssRNA each 7-10kb
· 3’ polyadenylated tail and 5’ cap
· Reverse transcriptase
· Formation of long terminal repeats before prpovirus DNA inserted into host genome
· Genome consists of gag, pol, env genes some regulatory genes, some oncogenes.
Human Immunodeficiency Virus
HIV is one of the human T-cell lymphotropic retroviruses. HIV preferentially infects and kills helper (CD4) T lymphocytes, resulting in a loss of cell mediated immunity and a high probability that the host will develop opportunistic infections. Other cells (e.g. macrophages and monocytes) that have CD4 proteins on their surfaces can be infected also.
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Genes and Proteins of the Human Immunodeficiency Virus
| Gene | Proteins Encoded by Gene | Function of Proteins |
| I. Structural Genes Found in All Retroviruses | ||
| gag | p24, p7 p17 | Nucleocapsid Matrix |
| pol | Reverse Transciptase Protease Integrase | Transcribes RNA genome into DNA Cleaves precursor polypeptide Integrates viral DNA into host cell DNA |
| env | gp120 gp41 | Attachment to CD4 protein Fusion with host cell |
| II. Regulatory Genes Found in Human Immunodeficiency Virus that are Required for Replication | ||
| tat | Tat | Activation of transcription of viral genes |
| rev | Rev | Transport of late mRNAs from nucleus to cytoplasm |
| III. Regulatory Genes Found in Human Immunodeficiency Virus that are NOT Required for Replication (accessory genes) | ||
| nef | Nef | Decreases CD4 proteins and class I MHC proteins on surface of infected cells; induces death of uninfected cytotoxic T cells; important for pathogenesis by SIV |
| vif | Vif | Stabilizes newly synthesized viral DNA and transports core through cytoplasm |
| vpr | Vpr | Transports viral core from cytoplasm into nucleus in non-dividng cells |
| vpu | Vpu | Enhances virion release from cell |
Replicative Cycle of HIV
The replication of HIV follows the typical retroviral cycle.
1. Inital step in the entry of HIV into the cell is the binding of the virion gp120 envelope protein to the CD4 protein on the cell surface.
2. The virion gp120 protein then interacts with a second protein on the cell surface, one of the chemokine receptors (CXCR4 and CCR5). Individuals with mutations in the gene encoding CCR5 have protection from infection with HIV.
3. The virion gp42 protein mediates fusion of the viral envelope with the cell membrane, and the virion enters the cell.
4. After uncoating, the virion RNA-dependent DNA polymerase transcribes the genome RNA into double-stranded DNA, which integrates into the host cell DNA, mediated by integrase.
5. The viral DNA can integrate at different sites in the host cell DNA, and multiple copies of viral DNA can integrate.
6. Viral mRNA is transcribed from the proviral DNA by host cell ENA polymerase and translated into several large polyproteins.
7. Precursor polyproteins can be assembled into nucleocapsid.
8. As immature virions buds from the cell membrane, the polyproteins are cleaved by the viral protease. This results in the formation of mature, infectious virions.
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Transmission
· Transfer of infected blood.
· Sexual contact (horizontal transfer)
· Perinatal transmission from infected mother to neonate: Either across the placenta, at birth, or via breast milk. (vertical transfer)
Pathogenesis
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· Primary Infection
o Acute stage
o Flu-like symptoms
o Fever
o Skin rash
o Swollen skin nodes
o Due to virulence factors such as rate of replication, propensity to mutate and cytopathogenicity.
o Also due to host resistance mechanisms such as the suppression by CD8 T suppressor cells and the presence of cytotoxic T-lymphocytes.
· Asymptomatic Stage
o No apparent disease
o Fall in CD4 T lymphocytes
o Possible signs:
§ Fatigue
§ Depression
§ Weight loss
§ Memory disorders
· Symptomatic Stage
o AIDS-related complex
§ Diseases not considered definitive of AIDS
§ May be attributed to HIV infection
§ Indicative of defect in cell-mediate immunity
o AIDS
§ Opportunistic infections as a result of fall in CD4 T lymphocytes. (e.g. Kaposi’s Sarcoma)
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Treatment
· Highly active antiretroviral therapy (HAART)
o Consists of two nucleoside inhibitors (zidovudine and lamivudine) and a protease inhibitor (indinavir)
o Effective in prolonging life, improving the quality of life, and reducing viral load but does not cure the chronic HIV infection i.e. a latent infection of CD4+ cells continues indefinitely.
o Such combination therapy able to combat resistance—which arise due to rapid mutations due to inefficiency of reverse transcriptase.
· Non-specific therapeutic management
· Immunomodulation
o Enhancement of immune system through treatment with interleukin-2 (still under study)
· No vaccine for human use is available.
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Prevention
Taking measures to avoid exposure to the virus:
· Using condoms
· Not sharing needles
· Discarding donated blood that is contaminated with HIV
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