Question 19: Discuss the molecular interactions between HIV and host cells, and how these interactions almost never lead to eradication of HIV

Question 19: Discuss the molecular interactions between HIV and host cells, and how these interactions almost never lead to eradication of HIV from a person

Sajnee Kotecha:

Structure

• Intro
• Body 1 (Molecular Interactions between HIV and Host Cells)
• Body 2 (Why Eradication is not possible)
• Conclusion
  

Introduction

• Eradication of HIV from a person has not been possible due to the molecular interactions between HIV and host cells
• HIV can have no independent existence without serial infection, and replication within, human cells.
• Two main reasons why eradication does not occur:
  A) Affects T-Lymphocytes, thus immune system is directly affected, leading to immunodeficiency.
  B) Escape from specific host immune responses through Mutation and Constitutive escape.

Body 1 Molecular Interactions between HIV and host cells

• HIV replication is a multistage process, infection of the host cell commences when HIV binds to specific receptors on the cell membrane.
• This interaction occurs by the recognition of two-cell surface-receptor proteins by the viral gp120 envelope protein and the transmembrane gp41.
• The first surface-receptor protein is CD4 which is present predominately on the cells of the T lymphocyte and macrophage lineages.
• Viral entry also requires a second co-receptor which may be performed by a range of proteins within the class of seven-transmembrane receptors, although the most important are CCR5 and CXCR4
• The presence or absence of these cognate cellular proteins restricts the range of host-cell types that are susceptible to infection by HIV
• Once HIV gp120 binds to CD4 and the co-receptor, a conformational change in gp41 causes insertion of the N-terminal hydrophobic fusion-peptide region into the target-cell membrane.
• Resulting in membrane fusion and the entry of the into viral particle contents into the cytoplasm.
• The genetic content of HIV is contained within an RNA genome.
• Upon infection of a new host-cell, viral reverse transcriptase which is co-packaged in the viral particle, first transcribes the HIV RNA genome into a single-stranded DNA and then further into a double stranded DNA for integration into the host-cell genome.
• The double stranded DNA genome forms a complex with host-cell and viral proteins and is actively transported to the nucleus.
• The double stranded HIV genome is either randomly integrated into the host-cell genome by means of DNA splicing performed by the viral integrase or forms stable DNA circles.
• The transcribed HIV RNA molecules may either be spliced in preparation for translation of viral proteins, or exported from the nucleus in an unspliced form for packaging into newly produced virons.
• Viral proteins perform a variety of roles to subvert normal cellular function and facilitate viral replication.
• The assembly of HIV RNA and proteins into virions requires an orchestration of the cellular machinery to produce, process and transport these components to their correct position beneath the cell membrane
• Viral proteins have pivotal functions in this process. Immature viral polypeptides are processed into their functional forms by the enzyme protease and assembled with full-length HIV RNA transcripts into nascent viral particles
• Virion release from the cell membrane, which occurs by a process of budding
• The released viral particles complete the cycle of replication by subsequent infection of a new host cell.

Body 2 – Why Eradication is not possible.

• Infection with HIV-1 is associated with a progressive decrease of the CD4+ T cell count and an increase in viral load. Multiple reasons why eradication is not possible
  
  A) HIV primarily infects vital cells in the human immune system such as helper T cells (specifically CD4+ T cells), macrophages, and dendritic cells. HIV infection leads to low levels of CD4+ T cells through three main mechanisms: firstly, direct viral killing of infected cells; secondly, increased rates of apoptosis in infected cells; and thirdly, killing of infected CD4+ T cells by CD8 cytotoxic lymphocytes that recognize infected cells. When CD4+ T cell numbers decline below a critical level, cell-mediated immunity is lost, and the body becomes progressively more susceptible to opportunistic infections.
  Affects the cells of the immune system directly: many of the CD4+ cells, macrophages and resting T cells are relatively long-lived, including some of those that might be HIV infected. --> Over time, so many CD4 -T cells are destroyed that the immune system is no longer able to protect the body from infection, disease and many cancers (thus, decline in number and function of CD4 cells) --> therefore the HIV virus can not be fought off resulting in it’s ongoing presence within the body.
  
  B) Multiple mechanisms exist by which HIV evades the immune response --> escape strategies are mutational or constitutive à resulting in evasion of cellular and humoral immune responses.
  
  * Mutational Escape --> Evidence suggests that mutational escape plays an important role in HIV disease pathogenesis --> the high error rate and lack of proofreading ability of reverse transcriptase, leading to accumulations of mutations in the viral particles expressing surface proteins and enzymes that are subtly diverse molecularly --> viral mutants which have escaped HIV specific CTL’s evolve lacking the targeted epitope and thus escape control of these CTLs à results in poorer clinical outcome..
  
  * Constitutive Escape --> Firstly, Post integration viral latency protects the infected cell from immune surveillance, as viral antigens are not expressed on the cell surface. These latently infected cells produce infection HIV following subsequent cellular activation. Secondarily, Number of HIV proteins interfere with critical cellular processes that facilitate the host immune response.

Conclusion

• There are many cellular barriers that stand in the way of eradication of HIV.
• Since HIV infects cells responsible for the immune response, a decline in the number and function of these cells leads to the potentiation of HIV pathogenesis and the long term presence of HIV infected cells within the body.
• Latently infected cells form a reservoir where HIV persists, despite immune host responses --> represents the major barrier to the eradication of HIV.
• Eradication of HIV infection has not been possible, even with potent combination antiretroviral therapy (ART), because the virus persists in resting CD4 cells and other viral reservoirs