Introduction to Immunodeficiency:
- Defects in the development and functions of the immune system cause a host to be more prone to newly acquired infections and can even cause reactivation of latent infections. This defective immunity leads to disorders known as immunodeficiency diseases.
- Immunodeficiency can be attributed to genetic malformations in a single or more than one components of the immune system, and such immunodeficiency is termed as Primary or Congenital immunodeficiencies. A primary immunodeficiency may affect either the innate (eg, phagocytes and complement proteins) or adaptive arm (B and T lymphocytes) of the immune system.
- Immunodeficiency may also arise from nutritional deficiencies (eg, protein-calorie deficiency), medical treatments (eg, use of immunosuppressive drugs), disease (eg, infarction in sickle cell anemia), and nutritional abnormalities. This can also undermine the functions of key players of both the innate and adaptive immune system. Such immunodeficiency is known as secondary or acquired immunodeficiency.
- Acquired immunodeficiency syndrome (AIDS) is one of the most common secondary immunodeficiencies. It is caused by the Human immunodeficiency virus (HIV). HIV is a retrovirus, containing two copies of negative-stranded single-stranded RNA as a genetic material.
Life Cycle of HIV:
HIV infection is usually transmitted vertically from an infected mother to the baby via the placenta or by breastfeeding. Horizontally, HIV can be transmitted through activities like non-screened blood transplantation, use of infected needle sticks, needle stick injury, and unsafe sexual contact. So, the virus can be transmitted through semen, blood, and other body fluids. HIV attaches to the host cell using its envelope glycoprotein (Env) on both Helper T cell (CD4) and a coreceptor, which are the receptors of HIV. The two subunits that make up Env are gp41 and gp120. To improve gp41’s binding to the coreceptor, gp120 first attaches itself to CD4 molecules. As a result, the viral and target cell membranes fuse together. Lytic cycle manifests, causing the release of free viral particles from one infected cell to an uninfected cell, thus spreading the infection.
In the host cell, the nucleoprotein core of the virus becomes disrupted. Double-stranded DNA is synthesized by the virus using RNA as a template by using the viral reverse transcriptase enzyme, and the viral DNA enters the nucleus. The viral integrase catalyzes the integration of viral DNA into the host cell genome. The integrated HIV DNA is called the provirus. The provirus can remain in a latent stage, producing little or no viral particles. When T cells are activated by viral antigen or cytokines, HIV gene transcription in CD4 cells begins. This phenomenon is significant to the pathogenesis of AIDS because the normal response of a latently infected T cell to a microbe may be how latency is ended and virus production begins.
The Tat enhances the production of complete viral mRNA transcripts. The Tat protein binds to the nascent mRNA, allowing transcription to be completed to produce a functional viral mRNA. Synthesis of mature, infectious viral particles begins after full-length viral RNA transcripts are produced and the viral genes are expressed as proteins.
The Rev, Tat, and Nef proteins are early gene products that are exported from the nucleus and translated into proteins in the cytoplasm soon after infection of a cell. Late gene products include env, gag, and pol, which encode the structural components of the virus. The Rev protein initiates the switch from early to late gene expression. The pol gene product is cleaved to form reverse transcriptase, protease, ribonuclease, and integrase enzymes. The gag gene encodes a protein that is proteolytically cleaved into p24, p17, and p15 polypeptides by the viral protease encoded by the pol gene. The primary product of the env gene is gp160, which is cleaved by cellular proteases within the endoplasmic reticulum into the gp120 and gp41 proteins.
Assembly of infectious viral particles begins by packaging RNA transcripts of the proviral genome within a nucleoprotein complex. Viral exit occurs by budding of this nucleoprotein complex from the host cell membrane, capturing Env and host glycoproteins as part of its envelope.
Fig: Replication of HIV in human host
Mechanism of immunodeficiency caused by HIV:
Cell-mediated immunity plays an active role in fighting HIV infection as the virus stays intracellularly in helper T cells. HIV causes cytopathic effects on the T cells that lead to the loss of CD4 cells in the infected patients and thus compromises cell-mediated immunity. Also, it is suggested that chronic activation of uninfected cells by the infections that are common in patients infected with HIV, and also by cytokines produced in response to these infections. Apoptotic death of activated lymphocytes may account for the observation that the loss of T cells greatly exceeds the number of HIV-infected cells. HIV-specific Cytotoxic T lymphocytes (CD8 cells) are present in many patients with AIDS, and these cells can kill infected CD4 T cells. Also, antibodies produced against HIV envelope proteins may bind to HIV-infected CD4 T cells and target the cells for antibody-dependent cell-mediated cytotoxicity (ADCC). Binding of gp120 to newly synthesized intracellular CD4 may interfere with normal protein processing and stop the cell surface expression of CD4, making the cells incapable of responding to antigenic stimulation. It is also suggested that the maturation of CD4 T cells in the thymus will be defective. Functional defects in the immune system of HIV infected individuals worsen the immune deficiency caused by depletion of CD4 T cells. Innate immunity (Macrophages, dendritic cells, and follicular dendritic cells) also has roles in HIV infection and the progression of immunodeficiency.
References:
- Abbas, A. K., Lichtman, A. H., & Pillai, S. (2012). Cellular and molecular immunology. 7th ed. Elsevier/Saunders.
- Renzi, G., Carta, F., & Supuran, C. T. (2023). The Integrase: An Overview of a Key Player Enzyme in the Antiviral Scenario. International journal of molecular sciences, 24(15), 12187. https://doi.org/10.3390/ijms241512187
- Owen, J. A., Jones, P. P., Kuby, J., Punt, J., & Stranford, S. A. (2013). Kuby immunology (7th ed.). New York: W.H. Freeman