Chapter 12 transcription: Failure of Host defenses
Chapter 12 transcription: Failure of Host defenses
If there were only one serotype of pneumococcus, once you got exposed, pneumococcus would be history for you. But the post-translational modifications of the sugar structure of the coat of the pneumococcus is what gives you the 84 different serotypes. If you have antibodies that recognize one, they will not recognize another because these are really distinct. So if someone is infected with the yellow triangles (pg. 1 slide 2) they will make antibodies against that serotype only; if they are infected by the serotype with the blue circles they will not be immune to that, though they are immune to the yellow triangle serotype. The blue circle pneumococcus is so different serologically that they get infected and have to develop a new series of antibodies.
Remember T-cells recognize peptides and T-cells will not be able to distinguish one serotype of pneumococcus from another because the shell of pneumococcus is carbohydrate. The T-cell has to be sensitized by some of the proteins inside and not the carbohydrate in order to tell the B-cell to make antibody. Unless the infection is in the peritoneum, where there are B1 B cells making antibody to very simple carbohydrates, those B1 B cells will make IgM antibody not IgG. So the pneumococcus which normally infects the lung won’t be recognized by any antibodies made by B1 B-cells because those antibodies will not be able to escape the peritoneum.
To make antibodies you need help from a T-cell. There are two different formulations of vaccine against pneumococcus. One is called pneumovax 23 and this is just the carbohydrates, the other is called prevar and it is pneumococcal vaccine against the seven most common carbohydrates, but it is conjugated with protein. Those carbohydrates are physically linked to protein, so that is a much more efficient vaccine. The pneumovax is better at boosting immunity for people who have already been exposed to the multiple serotypes over their life, but as they get older, the elderly are susceptible to pneumonia, so for the for the elderly the carbohydrate only vaccine is effective, but much less so for children.
Influenza is another very flexible organism and as a virus it is an intracellular pathogen, it is an obligate intracellular pathogen. It is released by people coughing and sneezing, so it is free and when it comes into you, it is a free virus, not a cell associated virus like HIV. So there are two glycoproteins for the flu. There is the surface hemagglutinin which is abbreviated HA and there is the surface neuraminidase abbreviated NA, and both are glycoproteins. They are each associated with different serotypes, so we express it as H1N1, H2N2. For humans there are basically 3 hemagglutinin serotypes which can infect people, H1, H2 and H3 and they can mix and match with the neuraminidase, and that is because many viruses have a single unique piece of DNA or RNA. Influenza has eight separate segments of RNA in its genome and it can reassort so that if two viruses that are distinct infect the same cell, when new virus particles are being released, random bits of viral RNA are packaged into them, but reassorment requires two different viruses to infect the same cell.
Influenza is an RNA virus and RNA viruses do not use the hosts proofreading mechanism, because to make DNA, generally, viruses use the hosts DNA machinery and as you learned in molec cell, when you make new DNA copies, those DNA copies are identical and there is proofreading. But RNA viruses use an RNA dependant RNA polymerase and they have to bring their own in because human cells don’t have RNA dependant RNA polymerases. There is no proofreading associated with this, and approximately 1 in 105 nucleotides is a mutant. If this mutant nucleotide has no effect, then it is not selected for, if it is deleterious it is selected against, but if it is a mutant that happens to prevent the binding of host antibody, that is selected for, because that antibody will not bind the mutant virus and it will be able to enter the cells and expand. That is called antigenic drift, and it is a very important phenomenon in the passage of virus over the course of a decade, which is why every year you can get an epidemic of influenza, because the virus has escaped the antibody recognition and can infect some people. Once the virus gets into the individual, the adaptive immune response, the T-cells which kill, whether they are CD4 TH1 cells or CD8 cells, will kill virally infected cells because the internal components even though the HA or NA might drift. For some people, there may be an inapparent infection because they have a good adaptive immune response. That is also the case with reassortments, because when there are reassortments that cause an antigenic shift as opposed to an antigenic drift and so if you have a change in the HA from H1 to H3 then the virus can evade the immune response. In the past, we had huge pandemics that were associated with antigenic shift. In 1918 there was a change from a prior HA to H1, in 1948 there was a change to H2 Has, in 1957 there was another change and in 1968 was the last time there was a change to the H3 HA. Since 1977 there has been cocirculation of the H1 and the H3 virus in populations. However, before then there was only one virus of a serotype. Influenza A viruses, in 1968 was the Hong Kong virus, and it was the prototype virus that changed to H3. Before that was a H2 virus, and before that was an H1. Since 1977 when the Russian flu started co-circulating with the Hong Kong virus there has been both H3 and H1. At the same time we also have a B virus circulating. Influenza B virus has a completely different HA and NA. Influenza B can only infect humans, influenza A can infect virtually any mammalian species as well as avian species. There are also influenza C viruses which cause really mild infections. B viruses are likely to cause mild illness in the elderly and are unlikely to cause serious infections. Because influenza B and influenza A co-circulate and because there are two different serotypes of Influenza A circulating at any time, although one may be dominant in the community, the vaccine against the flu is trivalent. There is a selected virus of the B serotype and two A serotype viruses.
We have discussed original antigenic sin in terms of influenza so there are problems that can arise by making antibody. There are two different vaccines against influenza, there is the sub unit killed virus vaccine which just has HA and NA and no virus, and there is the live attenuated, cold adapted virus called flu mist. Flu mist can actually get in and infect and results in real protection as opposed to just boosting the original antigenic sin antibody. For those who have shots, the nasal spray is much easier.
Flu evades immune responses by mutations and by swapping out the HA and NA. There are other ways that bacteria can evade immune responses, the capsule of the pneumococcus is one, and remember that capsule is anti-phagocytic, so the bacteria is difficult to clear until you can opsonize it. Trypanosomes are parasites have many different surface glycoproteins in their genome and depending upon which is expressed, and they only express one at a time, but they have the potential to express all of them sequentially, and these surface glycoproteins are varied surface glycoproteins, VSGs and by gene conversion events they express one at a time. When the host finally responds to that variant they induce the expression of the next one, and they do so sequentially and that is how they can persist.
Before class started we talked about different kinds of infections. There is the acute infection, influenza is an acute infection. Herpes infections tend to be latent. At one point in your life, you had an acute infection with Herpes Simplex Virus, HSV, and generally this takes place within the first 5 years of life, and generally, 95% of the population, is immune, has had an HSV infection. The nerve which enervates the region in which you have the herpes infection, and that is generally the oral region for HSV-1, and the urogential region for HSV-2, the virus will go up in a retrograde manner to the ganglion which enervates that region. It will set up a latent infection in the neuron, living as an episome, and in many people there is never reactivation. There are other people for whom having some kinds of stresses, and it depends on the indiviual what their precipitating stress is, will have reactivation in the ganglion. The virus will begin to replicate again, and go down and and reinfect the first region of infection, this is what leads to repeated cold sores. If there is genital herpes, people can release the virus into their genital system and if they have unprotected sex, the next person they have sex with can get herpes. Some people have inapparent infections when they release the virus, and so they are not symptomatic. Other times, people have very apparent infections, but that isn’t always the case with genital herpes. So if you get infection with genital herpes, you have persistent infection and the herpes can spread whether you have a visible infection or not.
Herpes I or II of the genital urinary tract is an STD, whereas Herpes in the oral region is a normal infection.
What are the stressers that can turn on the release of virus? The absence of IFNγ in that microenvironment, so when there is a TH2 systemic immunity the virus can be reactivated. For some people reactivation occurs when they get a fever, and every time they get a fever they get “fever blisters” but there is no way of curing the trigeminal ganglion, which is the ganglion or the ganglion which enervates the genital region.
A number of viruses have found other ways of avoiding the immune response. We talked earlier, when we discussed innate immunity, about those rapidly growing viruses that needed to shut off innate immune responses. The viruses that persist and set up a longer co-existence with the host, whether it is months or years, have to suppress adaptive immune responses. Among viruses that are capable of these are herpes viruses, Cytomegalovirus, Epstein barr virus, varicella zoster, and there are many others. All of these evade host immune responses. In addition, Pox virus is like vaccinia. If a virus has an Fc receptor, then the virally infected cell will have the antibody facing outwards rather than binding it in a productive way. If the virus encodes a complement receptor, it can be a sponge for those complement factors, could poke holes in the infected cell. If the virus can express a chemokine receptor, that receptor is not one that will induce the migration of that cell in the right direction, but rather it absorbs the chemokine, and that chemokine is not available to recruit neutrophils or macrophages or T-cells to enter that tissue. If the virus encodes a soluble cytokine receptor then it can neutralize the cytokine. As a result that cytokine can’t affect the cells in the immune system or the neighboring cells. Inhibition of signal transduction or inhibition of antigen processing and presentation can also suppress host responses. Many herpes viruses are capable of inhibiting antigen processing and presentation, so someone infected with herpes viruses can’t get the foreign peptide to the outside of the cell. Herpes Epstein-Barr virus encodes a viral IL-10, which it basically stole from a host cell along the way. IL-10 prevents antigen processing and presentation. All of these mechanisms enable viruses like pox and herpes to persist longer and to cause prolonged infection.
There are other things important, and we have talked about the role of TH1 responses in elminating mycobacterial infections, so whether it is TB or leprosy, TH1 responses are essential in providing the capsule around the infected region and in eliminating the infection from infected macrophages. When there are TH2 responses there is more of the bacteria around it can spread from the initial site of infection to other sites, so the balance of TH1 to TH2 response is critical for handling infection with mycobacteria. Individuals who have HIV-1 infections or other immune deficiencies in the T-cell compartment there is a general inability to fight mycobacterial infections and this is one reason why there is a resurgence now of TB in the community of immunodeficient people. Leprosy, unlike TB, is difficult to spread. In the past, before there were antibiotics to treat these things, people were sent away from society, those infected with leprosy were sent to leper colonies and tuberculosis were sent to sanitoriums to keep people away from the general population in the hope that those individuals could cure themselves. This, pg. 4 slide 2, reiterates that people who have an active leprosy infection tend to have a TH2 biased response whereas those who can clear the infection have a TH1 biased response.
In the first lecture, it was said that for any pathway, there can be in immune deficiency, and it depends what it is and how profound it is. If you can’t make an antibody molecule or a TCR you have SCID. If you can’t express class II molecules, and there are several different ways that one wouldn’t be able to express class II molecules, but CIITA, class II transactivator, is a transcription factor in the same family as the NOD molecules, which are intracellular bacterial and viral sensors, and the lack of CIITA results in the inability to make class II molecules. If you can’t load class II molecules with antigen there is another problem. If you don’t make the class II invariant chain you can’t get class II molecules out to the compartment where peptides are loaded. If you don’t have the tyrosine kinase which is involved in signal transduction from antibody to the nucleus then you have an inability to tell the host that the antibody has engaged its specific antigen, and that B-cell will not make secreted antibody. There are many different defects in phagocytes, there can also be complement deficiencies, any one of the complement components can be deficient, and if there is deficiency in a regulatory component of complement then you have too much of the complement cascade and too much inflammation. There are four different complementation groups for ataxia telangiectasia and they result in fewer T-cells, cancer, and many different kinds of respiratory infections. Blooms syndrome is the result of a defective helicase and that is also associated with tumors and respiratory infections. For almost pathway, a deficiency can occur. For some of these things, you can get repeated infections but the host lives, but SCID must be corrected with a bone marrow transplantation.
If you have one of many different deficiencies which result in the failure to produce γ globulins, so BTK deficiency would be among them, then if you take blood from a normal person and an affected individual and you spot them and do electrophoresis to separate the proteins and then put antibody against blood proteins in the middle well and allow it to diffuse, this is a simple immune response assay, you can see that there are no precipitation bands in the γ globulin, but all the other normal blood proteins are found. If someone is γ globulin anemic you can periodically give them γ globulin shots or give them a bone marrow transplant. If you knew the exact gene defect of that individual and you had that gene product cloned, so if you knew the person did not have BTK, the best way to treat the deficiency is to take autologous bone marrow, introduce BTK and put that in, because you will have no incompatibilities and you will not have to suppress the immune system of that individual.
There are a number of X-linked immune deficiencies associated with the ability to make antibody, and BTK is one of those, and it is X-linked, and that means that girls do fine, because in half doses, as long as you get only one copy of the mutated gene you can still make antibody and switch classes. However, if you have a male that doesn’t have a function BTK on his x-chromosome, this individual will be gammaglobulin anemic. Women with the mutation will be fine, even though females only use one copy of the x-chromosome it means half the B-cells will be fine but the other half will lack the BTK gene.
During gestation there is transplacental transfer of IgG3 from the mom to the baby and this provides a window of antibody coverage until the body can make its own antibody to challenges. In addition, collostrum will provide IgA antibody, and these maternally transferred antibodies last about 6-9 months. If a baby were infected in utero with something, the babies response would be IgM not IgG, so you could easily tell if the baby encountered the pathogen in utero. After birth the baby will start to respond and at first the response is IgM and then there is class switching, but it takes a while for a baby to mount their own responses, and it takes two weeks for you to make antibody.
There are a number of disorders associated with the failure to develop functional lymph nodes. In mice numerous models can be created by eliminating cytokines and their receptor or chemokines and their receptor. In a normal individual the lymph node has the architecture we are familiar with, there are T-cell rich regions and B-cell rich regions and germinal centers which are characteristic of functional B-cells. In hyper-IgM syndrome you never develop mature B-cells, and they are unable to switch classes and they can’t develop functional germinal centers, so in an individual with hyper-IgM and you do a biopsy of a lymph node you will find an abnormal structure.
Pg. 7 slide 2 reiterates the complement pathways, remember the classical complement is fixed by IgG and IgM, and the mannose binding lectin pathway is turned on by MBL and the alternative pathway is turned on by bacterial and yeast surfaces. All pathways converge at C3 convertase, if you don’t have C3 convertase or C3 you have severe immune problems. C3, C5 and C4 all get cleaved, and they have recruiting small molecules that are inflammatory and bring neutrophils to the site of the infection. The last components of the cascade are the membrane attack complex. Remember that C3 is associated with the C3 receptor which is important for phagocytosis. What is found any complement deficiencies in increased susceptibility to nisseria infections which can be STDs as well as ear infections. If the deficiency is in an upstream molecule there is deficient phagocytosis and recruitment of neutrophils.
There are many different defects of phagocytes, and some of these also affect neutrophils and some affect the ability of T-cells to interact. If adhesion molecules or their ligands missing, then you can’t have cell-cell interactions and you can’t get cells into tissues. Chronic granuloma disease is associated with the inability to get rid of stuff inside the infected macrophages and then you get release of this and new granulomas forming all over. Glucose 6 phosphate dehydrogenase is critical for the respiratory burst and you need a respiratory burst to make the reactive oxygen intermediates which are important for getting rid of intracellular bacteria. Myeloperoxidase is also critical for getting rid of intracellular bacteria. Chediak-Higashi syndrome blocks NK cells as well as phagocytic pathways.
In terms of SCIDs there are several different varieties. There are X-linked SCIDs because the γ chain and JAK and the IL-7 receptor are all found on the X-chromosome, so males are more likely to be affected with these diseases. The γ chain is the common chain of the receptor for many cytokines, not just the IL-2 receptor, and in these cases B-cells, T-cells and NK cells are deficient in the mouse, and in humans NK and T-cells are deficient in the absence of the IL-2 receptor, but B-cells are okay. You can still make a BCR or a TCR, but you can’t divide, signal or differentiate. RAG and Artemis are critical for making B or T cell receptors, and in RAG or Artemis deficient individuals you don’t get B-cells or T-cells. Adenosine deaminase was once thought to be a scavenger enzyme that recycled adenosine, but in the deficient individuals they are completely immunocompromised. In all cases if you know the enzyme that is deficient and you have it, you can transfect the gene into pluripotential stem cells of that individual and get recovery because these are all hematopoetically derived. Otherwise, these individuals live in a bubble because they are susceptible to all infections. In the past they would die before the age of 2 due to infection.
So, transplantation, we have talked about this in terms of where the T-cells and where the bone marrow and the parenchymal cells are important. On pg. 9 slide 1 they show a parent giving bone marrow to a child. The parent and the child share one chromosome so the parent has one chromosome that is different, in the child, all of the tissues express the shared MHC as well as the MHC shared with the other parent. The T-cells can only see one of the many MHC molecules and they are educated in the thymus. And in the thymus, the cells that educate are derived from the bone marrow, but your tissue cells have whatever was determined not by bone marrow but the germ cells. The T-cells that recognize the ‘a’ MHC will be unable to recognize any of the cells in the recipients body, because none of the cells express ‘a’ MHC. Only the T-cells educated on ‘b’ MHC will be able to recognize cells in the recipients body. If there were however, a hematopoietic infection or tumor, the ‘a’ restricted T-cells would be able to recognize the cells of the bone marrow. In the case of AIDS, because the T-cells from some chimps could not be infected with the HIV virus, it was proposed that you do bone marrow transplants from chimps and that is completely histoincompatible.
What happens if you put bone marrow in someone, and there isn’t a good match, and you haven’t been careful enough to get rid of all the T-cells in that bone marrow. If you take that stem cell and there is room in the bone marrow for that stem cell to take up residence then you have successful grafting. If there are T-cells in that bone marrow you get graft vs. host disease, and this can be chronic and it can kill. This can be arrested by using cytotoxic drugs that block T-cell differentiation like cyclosporin. Sometimes the host has not been so crippled that it can’t respond to the graft and you get graft rejection or host vs. graft response and if it is a bone marrow transplant you get bone marrow failure.
Your text book devotes far more time to HIV infection than to any other problem, so we will start talking about HIV. HIV is a lethal infection the only thing you can do is to prevent infection. Once individuals are infected, the quality of life and the life span can be enhanced, but ultimately individuals die of HIV associated opportunistic infections or cancers. There are simple ways of preventing infection, safe sex, mutually monogamous sex or the use of barriers. There will never be a good vaccine or a good antiviral cocktail. We are still learning what HIV can do and all the pathways that it uses. It is so different from every other retrovirus and every other virus family.
This slide (pg. 10 slide 1) shows the burden of disease, the number of new cases, and the number of deaths in the year 2006. HIV is a worldwide infection and it likely started in the 1950’s, and probably for many years before that it infected primates in Africa. In Africa, people hunt bush meat and they eat it, whether it is a rhinocerous or a chimpanzee, or whatever other animals, that is what many people eat. During hunts there is blood and scratches and some people may even eat uncooked meat. Basically, SIV slowly adapted to the human host, and then the human host spread this virus among other people. In many areas there is a lot of promiscuity and unsafe sex. And the virus spread rapidly through small villages and then when people from those villages reached the outer areas, it spread through big cities and because this is a global society, it reached the united states. Only after it reached the gay community in San Francisco, was there an explosion of opportunistic infections, including Kaposi sarcoma and pneumocystis carinii, and then HIV reached the radar of the public health community and it was seen that there was a change in the epidemiology of the gay community. It took a while for HIV to be isolated and the nobel prize for physiology and medicine this year was given to the individuals who identified HIV and the identification of the virus HPV. HPV is associated with cervical carcinoma, and there is a very good vaccine that prevents 70% of cervical carcinoma by immunizing prepubescent girls with guardasil.
It took HIV a while to get onto the public health radar and to figure out how it was transmitted. The disease then spread to heterosexual communities and then it became an issue of an STD of an acute infectious disease. HIV is everywhere, though many countries denied its existence for a long time.
We used to pay people to donate blood because there are a lot of people that for one reason or another need blood. There are a lot of people who are having surgery or were in a traumatic accident or they have hemophilia and they need clotting factors and people were not screened for HIV because for a while people were not screened and they did not know how to screen, and hemophiliacs born before 1943 were getting contaminated blood and this resulted in those hemophiliacs dying of HIV, and people who got blood for surgical reasons or platelets because they had cancer and the cancer treatment resulted in clotting disorders were also suddenly developing HIV infections. Then it was found that blood could be tested, though it is only easy to test for the presence of antibody, to test for the presence of HIV virus genomes in the lymphocytes by RTPCR is much more expensive and is not part of standard clearance of blood for transfusion purposes, so only seroconversion, which takes place weeks after infection, is tested for in blood before it is cleared.
Once people acquire HIV, CD4 levels drop and the bone marrow tries to keep up, however the course of disease is inexorable, and when it reaches a certain point and the T-cell levels drop the ability of the individuals to fight infections is compromised. Ultimately you see the acquired immunodeficiency, but up until that point people are asymptomatic, and the asymptomatic stage is not really asymptomatic, but it is much less severe than the end stage disease. Individuals feel sick during initial infection because of innate immune responses and the cytokines in the lymph nodes. Either intravenous drug abuse or unprotected sex results in the cells coming in on cells and those cells go to a lymph node. When the HIV is brought to the lymph node you get lymphadenopathy, just like you would have if you had a respiratory infection, but with HIV you get systemic lymphadenopathy. Then the lymph nodes shrink and there are few T-cells around because they have been destroyed. In 1/3 of patients the virus on macrophages crosses the blood brain barrier and you then get neuroaids with behavioral and functional changes in the brain. The blood brain barrier prevents the highly active anti retroviral drugs from crossing blood brain barrier but you can diminish the virus in the periphery but you can’t change the course of disease in the brain.
Pg. 11 slide 2 shows what the virus looks like. It has a glycoprotein and it has a group antigen, which in other viruses would be called a matrix or membrane protein, it has two identical pieces of RNA and the RNA has a nucleocapsid. RNA viruses must have a nucleocapsid. In some cases you have free virus, but in few cases do you have free virus. Mostly you have T-cells that are infected, and these T-cells go to lymph nodes. That glycoprotein is a fusion molecule and the virus doesn’t ever have to leave infected cells because in a lymph node there is no space between T-cells, and the virus leaves one cell, fuses with the next cell over and infects that cell. So even if you had antibody against the incoming virus, it is never free to be neutralized by the antibody. In some cases dendritic cells find through the DC sign molecule free virus and bring the virus to lymph nodes where it infects CD4 cells. CD4 is the viral receptor along with the co-receptor and several different complement receptors.
Some people in the gay community took tremendous excitement when they learned that there were some individuals who had a delayed course of disease when they had some complement receptor genetic defects, but those people ultimately develop AIDS, it just takes longer. As you can see ( pg. 12 slide 2) there is CCR5, CCR2, CXCL 12, CXCL6, and these are all different receptors that HIV uses to enter cells, and for those individuals that have a deletion in any of those receptor genes, have delayed onset of AIDS and it can prevent lymphoma. If you are infected with AIDS and persist in risky behavior, you can be doubly infected with another strain of the HIV virus.
In some cases, the cytokine or chemokine deficiency accelerates AIDS, and in all cases, people can get infected and develop disease. The absence of IL-10 might be able to limit infection and depending upon your histocompatability molecules you either develop efficienct CTLs rapidly, or not. But, HIV is an RNA virus, it is a retrovirus, and it goes from an RNA genome to an RNA-DNA hybrid, and that becomes a DNA genome. The RNA stage is full of mutations, and the reverse transcription persists in making more mutations. The virus, once it gets into a cell, can make a variety of daughter viruses, which may be able better able to infect those cells that have a deletion in the chemokine receptor, or go from T-cell infection to macrophage infections, to microglial infections, to dendritic cell infection, or to not bind HLA molecules, so you can’t get CTLs which recognize that peptide or which can evade the ability of the highly active antiretroviral drugs which inactivate the virus. So, the virus binds to CD4 and the chemokine co-receptor, it fuses on the cell surface, it doesn’t need the acidification of the endosome, and it gets into the cell. This is what happens in tissue culture, in vivo life an infected cell fuses with a healthy cell and transmits the virus. Then the genome undergoes reverse transcription and you get a cDNA and this cDNA goes an intercolates into the host DNA, and this cell is forever latently infected with HIV, it may not go on at that moment to be productively infected, but it will always have the virus. The provirus gets turned on by NFκB, virtually every signaling pathway we have talked about, has NFκB involved. So if you have that latently infected cell in a lymph node, because of a third party response in the vicinity, you get the release of TNF, which will bind the receptor on the infected cell, cause the signal transduction cascade which will result in the production of NFκB and NFκB will then induce transcription and translation of HIV genes. When the provirus is sitting in the cell it is inaccessible to any of the anti retroviral drugs because it is not being actively produced. If you want to have a drug that will target the reverse transcriptase, the reverse transcriptase must be active, and that is only when the virus infects a new cell. If you want to target a protease, that is when new virus is being produced. If you want to target the receptor, that is between cells, but it is very difficult to bind that receptor. There have been many failed vaccines. They thought a soluble CD4 would work, the virus used in tame lab experiments is very different from field isolates, and the vaccine worked in the lab, but it did not work in the population.
Unlike other retroviruses where you have a group antigen, a polymerase and an envelope, HIV has all of these other genes that have profound effects on the way the virus interacts with cells and the way the virus suppresses immune responses.
It takes 4-8 weeks after infection, to mount any immune response. CTL, and those CTLs are around as long as T-cells are around, but the virus can escape CTL recognition by switching the epitopes that are bound to the MHC.
Individuals with HIV don’t die of HIV but they die of things associated with the loss of immune responses. Normal individuals don’t get opportunistic infections, normal immune responses can deal with these things. Pneumocystis carinii was one of the first opportunistic infections recognized, along with Karposi’s sarcoma. So these were the first flags of the infection, and normal people don’t get this disease. TB requires functioning T-cells, toxoplasma infections, serious herpes infections or cancers; all of these can kill individuals with AIDS. In Africa, HIV was called slim disease, because people developed diarrhea and died of dehydration. Here, people who are getting good medical care are able to use electrolyte replacement to deal with diarrhea, but without good water, diarrhea is problem. As you know, in Africa several communities have been wiped out, the middle class is gone in many areas, and there are many orphans with HIV, who got it from their mothers transplacentally. HIV can also be transmitted in breast milk. Newborns are often given HAART treatment as soon as they’re born, and pregnant women can be given HAART treatment to prevent transplacental passage but it won’t prevent breast milk passage because there are leptocytes in breast milk.
In an individual, HAART treatment does work for those cells that are actively producing the virus, and there had been a theory proposed by Bruce walker, to have people immunize themselves against the virus. Administer HAART treatment, and then stop and allow the virus to come back when they have a somewhat intact immune system, let them immunize themselves, and lets go through sequential times, and he extended the period of time before you saw a lot of virus in blood, but ultimately people did get AIDS. The man who did this was also able to document in those people the superinfections, for people who continued high risk behaviors.
This (pg. 18 slide 1) is where the antiretroviral drugs are able to block but they are not great, and because this is an RNA dependent RNA polymerase, you get mutants and you can escape from any antiretroviral drug therapy.
Because this is an RNA virus which is constantly undergoing mutation, you are going to select more aggressive viruses or sometimes, attenuated viruses. There was a study done by Oxford of long term survivors who were prostitutes in Africa and they had attenuated virus, but that attenuated virus can undergo mutation and become more aggressive. But all the viruses in individuals treated with antiretroviral drugs ultimately become resistant to the drug therapy.
For a bacterial infection, the infection can be cured, with a course of antibiotics. But you can’t cure HIV infections. Now an individual, over the course of infection, has a virus that is constantly changing. So the virus they were infected with is really different antigenically from the virus later, so any monoclonal antibody treatment or T-cell vaccine will not work because the virus is constantly changing. Once the virus is in a community, if it infects 100 people, you can have 100 different viruses. To make a vaccine, you can’t anticipate all of the diversity. There are also 8 different serotypes of the virus circulating. There will never be a vaccine, the only treatment is prevention.
Many drugs that are in use can affects on your other cells, and that is one reason why people find them so toxic. They are also very expensive.
If you destroy your CD4 cells it is hard to make antibody it is hard to help CD8 cells and it is hard to get rid of many infections, but people won’t have problems with delayed hypersensitivities like poison ivy.
