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

Question 15. Discuss the following (fictional) press release... "The world is a safer place with the advent of a new vaccine against tuberculosis...

COMMENTARY+ADDITIONAL DISCUSSION

Full Question: Discuss the following (fictional) press release... "The world is a safer place with the advent of a new vaccine against tuberculosis announced the Health Minister during a visit to Gambia. The vaccine should be available to treat disease caused by the tubercle virus within two years, but travelers are warned to continue boiling water and avoiding contact with mosquito-infested water".

The announcement of the Health Minister heralds something that is very significant, a supposed vaccine (finally a new one to replace the 100 y.o. BCG vaccine) to fight the tubercle virus to be released within two years. You may be asking yourself, why has the question got stuff about boiling water and avoiding mosquito-infested waters?

Well, it’s probably got to do with the fact that TB and mosquito-borne diseases are largely prevalent in poor developing (third-world) countries (such as Gambia). You have to understand, that even if the TB vaccine is SO EFFECTIVE, and it rids the world of TB (which I’m highly skeptical, as they haven’t even released this vaccine in the real-world yet).. the third world will still face the public health problems like malaria, dengue, etc (mosquito-borne diseases). Fixing ONE problem is great, but in the overall scheme of things: socio-economic disparity will always be the main barrier to public health (along with political stability).

As touched on before, you can express your optimism/concern in regards to the vaccine announcement itself… Is it too good to be true? (my opinion: Yes). How do we know it’s going to work in two years time when it’s released? Even if it does, can poor countries afford to vaccinate everyone? The problems of vaccine availability become apparent. How about it’s efficacy in all populations? (BCG had crazy efficacy rates ranging from 0% to 80%) How about TB’s likelihood of vaccine resistance?

You boil water in third-world countries to minimize chance of drinking contaminated water with microbials (such as cryptosporidium or more closely related to the question: mosquito larvae). Avoiding the waters means less chance of getting bitten. People are being advised to take heed, to exemplify that even if TB is gone, many other diseases will remain.

In a way, this very strange question asks you to think about optimistic press releases and how true they can be? We should have doubts on the actual TB vaccine announcement, but also, we are shown that curing one disease, is still something small in the bigger picture. It should stir up opinions in regards to the differences between first-world and third-world. Why are diseases highly prevalent in poorer countries, and not in rich ones?

ALL PLEASE READ

Hi! Welcome to the Infectious Diseases -End of Semester Collaboration Site.
Here are some quick rules/suggestions to writing the answers.

1. Be considerate. If you have access to this website, and haven't contributed, then please do. It's only fair to everyone else. It is advisable to focus on questions that have not been attempted, but in all fairness, do what you please- any additional information is appreciated
2. Be wise. Only post information that is true (if it's a personal opinion, make that clear) and readers, be aware of personal bias or opinion. But only share information that you are willing to share. You are not obliged to give 'everything' you know, any pieces of information must be posted in good faith, but that does not mean that you write the absolute best on here, especially in regards to essay structure (Ian will not like reading generic structures, be original, be it hit-or-miss in some cases)
3. Be succinct. Write things that may give people general background to a topic (some people will have no clue/background to something), but more importantly, devote your posting to specifically answer the question. Repeating important themes, opinions is advisable, but don't go over the top.
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That's all for now, but thank you, and good luck to all!

Question 20. Design a program to eradicate rabies as a human disease, based on your understanding of the virus' life cycle.

This is one of the most specific questions in the exam. The question wants you to design a programme, a strategy (which allows much freedom), but the program you propose must be based on the virus’ life cycle (therefore you MUST learn the rabies cycle). One question arises (and therefore adds to variability in exam answers): Is it even possible to eradicate a disease like rabies with current methods?

BACKGROUND (Textbook Schaechter, 2007, pp. 357-362)
Zoonosis caused by lyssavirus (RNA virus) from infected domesticated (dogs, cats) and wild animals (bats, raccons, jackals). Prevalent in many countries (50,000-100,000 deaths/year), more deaths common in developing countries (90%) where there is less programmes to combat disease. Virtually all people exhibiting symptoms will die (as they weren’t vaccinated), only few notable exceptions in recent times overruled this (see Wikipedia article HERE).

THE RABIES VIRUS LIFE CYCLE
Virus enters from the site of the bite, travelling in the peripheral nervous system (PNS) via nerves to CNS. It travels from the brain to peripheral sites (other organs) eliciting symptoms (virus retroactively travels back and forth brain and organs). Notably, salivary glands in mouth and cheeks will store high concentrations of the virus allowing transmissibility (especially if bitten). Incubation period varies from about 1 month to 3 months, but can be a year or more! (Depends on virulence strain-different locales or even point of infection-worse if face or neck).

SYMPTOMS
Important: Causes acute, progressive, incurable encephalitis (inflamm of the brain caused by infection/allergic reaction)- causes brain damage.
Acute progressive fever, headache, difficulty swallowing + hydrophobia (cannot swallow water to quench thirst), paresthesia (abnormal tingling, nerve damage), muscle spasms, hypersalivation (like rabid dogs), paralysis, mania (confusion, anxiety, etc)

PROGRAMMES

This programme has to tie in to YOUR UNDERSTANDING of the virus’ life cycle.
Methods have to be utilising already present strategies (ie. Cannot say.. we have to design a better vaccine that’s 100% effective before + after infection, that's not a program, that's a wish)

Vaccination of humans, wild and domesticated animals is most effective.
You may decide how far to take this: surely you can’t vaccinate every single living thing in the world, but maybe highly populated areas: suburbs, places of high prevalence. Or maybe people with high risk in contracting disease: kids, vet workers, gardeners, rangers, etc.

Surveillance/Animal control is key in human-populated areas. Ensure wild populations of bats are controlled (various methods to do that… ethically), but use of animal shelters/animal control rangers to isolate rabid stray dogs (euthanasing them, etc). Local leash laws to prevent pets becoming strays.

Education of the community. Advertising, schools-education, brochures to tell people to look for the symptoms (urgent intervention important), stay away from touching wild animals or strays (to prevent getting bitten)

POINTS TO CONSIDER NOW:
1. EACH OF THESE COMPONENTS NEED TO BE TIED BACK TO LIFE CYCLE (how it affects it)…
2. Ian Peak has put forth a rather ideological question, in how do you eradicate rabies as a human disease. My basis, if this were to be on the exam is that it is not possible to eradicate Rabies as a human disease with current methods. The only way is prevention, via vaccination, animal control and education to prevent infection (as you cannot feasibly enact a strategy to destroy all rabid animals, wild or domestic). In relating to stopping disease manifestation with a programme based on the virus life cycle, this is a difficult question. You will always have the possibility of infection as long as there are infected animals present. We can only control it to prevent infection in the first place, or find methods to fix the problem once infected (eg. the induced coma method as shown in Wikipedia).
3. Eventually, it culminates to the thought: What is eradication of a human disease. Strictly speaking, eradication is 'complete destruction', as in no chance of returning. However, this is not possible realistically (unless someone can tell me how), are we content to suggest eradication is like prevalence of Rabies in USA (about 1-3 cases a year, while 50,000-100,000 occur world-wide)...

Good Question, Ian. :S

If you have a differing opinion/additional info, write your own answer or comment below!

Question 1. A microbial pathogen can be defined as: "An organism capable of causing disease". How good is this definition?

A microbial pathogen can be defined as: "An organism capable of causing disease". How good is this definition?


Draft Phase

Introduction;
Define the key principals in the phrase;

• Microbial Pathogens
• Organisms; Organisms include; viral, fungal, helminth (worms) and protozoan forms of life.

Body;

• What aspects of infectious disease support this definition?
  • Koch's Postulates - identifies the microbe as responsible for causing disease
    • Despite a number of exceptions to Koch's postulates (including anthrax ect); today's definition of microbial pathogens still puts those that don't fit Koch's model at cause of diseases.
  • Microbial pathogens manifest infectious disease.
  • All are capable of causing disease, most rarely do cause disease because of the host's natural defense mechanisms, or through direct competition among other microbes.
  • Opportunistic infections; may only attack when the host is immunocompromised, a new route of entry has occurred or direct competition with other microbes is reduced, can microbes seize the opportunity to enter the body and cause disease.

• What aspects of infectious disease attempt to reject this notion and can they be downplayed to support the original hypothesis?
  • Prions cause diseases and are pathogenic. HOWEVER not considered an 'organism'!
  • It may follow to reason that a number of aspects regarding microbial life are ignored in accepting this hypothesis. i.e. microbes Encounter, Enter, Survive, multiply, cause damage and transmit from host to host... Microbial pathogens all fall under the class of disease causing... To cause disease they need not to be associated with any of these categories. (provide examples)
  • Some microbial pathogens don't cause disease in vectors of a disease e.g. mosquitos... Yes but these microbes are still considered pathogenic through their ability to TRANSMIT.

It is True, it is robust