Lecture Notes on HIV/AIDS and other human Pathogens
We know that there are pathogens. Even though the vast preponderance of microbes on the planet are not human pathogens, there are certainly a sufficient number to kill us off if we did not have protection. An excellent example is HIV, which does not directly kill its victims but severely cripples the immune system, allowing other microbes such as mycobacterium tuberculosis to actually kill.
We have two types of defenses. The first is nonspecific (called the innate) resistance. The second system is the specific immune system, and that is centered on the production of antibodies. The first point I want to make is that if you should be penetrated by a microbe, your specific immune system takes about 10-14 days to make a good antibody titer, i.e., if you were not exposed to it before. It does not happen over night.
The innate immune system is layered and consists of physical, chemical and biological barriers. These can overlap, of course. There are very general factors, such as age (old and very young have a weaker immune system) and nutritional status, even socioeconomic status, as poorer people have less access to medical care.
One of the important types of barrier is the physical and mechanical barrier, and these can be intertwined. We need to first entertain two questions: (1) Through what portals can we be infected? and (2) What kind of cells in our body line important tissues such as skin, the respiratory tract, or the intestine? With respect to the first issue, access can occur through the skin, through breathing, mouth or nose, through the mouth via eating and last by sexual transmission. The cells that line these systems are epithelial cells, but mucous membranes and appendages called cilia also play a role in the operation of these physical barriers.
1. The skin. The skin is an important barrier for obvious reasons. One of its important features is that its outer layer is composed of thick, closely packed cells called keratinocytes. This layer is difficult to penetrate. However this is not the only protective property of the skin.
2. There is constant shedding of skin cells and this removes any microbes that are bound to the skin.
3. Skin can be mildly acidic, pH5 to 6, and this in combination with fatty acids (acetate, propionate) produced by commensal staphylococcus can inhibit the growth of or kill microbes that land on the skin.
4. There can be a high concentration of NaCl, and skin can be dry. This condition would disfavor the growth of bacteria in those areas of the skin (low Aw).
5. There are commensals that bind to the skin and this can block pathogens from binding.
I am not going to cover the SALT system .
Another important physical/chemical barrier is the mucous membrane. When we think of mucous, it conjures up the image of sticky and gooey, and that is what it is. Mucous membranes are important for the protection of several systems, including the digestive, urogenital, and respiratory system. I am going to focus only on the latter. It is estimated that we breathe in at least 10,000 microbes per day through the nasal or oral route. What is critical to prevent is the ability of these microbes to reach the lungs, as that could be particularly dangerous (pneumonia).
The mucous is produced by goblet cells, and it lies on stratified squamous epithelium, which is difficult to penetrate. The combination is a formidable one, as the mucous, because of its sticky consistency, can trap microbes. The respiratory tract protective system is an excellent example of a physical/mechanical barrier.
We have hairs in our nasal cavity, and although this is a subject for humor, they serve an important function, which is to trap microbes. Those trapped are in the size range of 10um or larger. Once trapped, the cilia lining the cavity beat toward the pharynx, and the mucous is moved to the mouth and expelled.
Microbes smaller than 10um can bypass the nasal hairs, but many of these get trapped on the mucous on the lower respiratory tract. These are moved away from the lungs by what is called the mucocilliary ladder, which is the combined action of the mucous and the beating of the cilia. Smoking inhibits cilia, resulting in more respiratory infections. Eventually, the microbes are expelled.
Not only does the mucous membrane act as a physical barrier, but it can also be a chemical barrier. Many mucosal surfaces contain lysozyme (cell wall destruction). Lactoferrin is also present. This has significant because it binds iron tightly. As a general rule, free iron is scarce in the human body. This is a defense against pathogens, which need it for their growth.
The Stomach. This is an important barrier to microbes that we consume in food. The pH of the stomach is 2 to 3, which is quite lethal to bacteria. Cells in stationary phase would survive better than log phase cells. This is a barrier that applies to Infectious Dose (ID). Some bacteria have a very low I.D., so even if only a small percent survive the acid, they could go on to cause an infection.
The Gastrointestinal Tract (This pertains primarily to the large intestine). There are 3 mechanisms for removing microbes from this system. 1. Peristalsis, 2. Shedding of cells, 3. Mucous flow. But keep in mind that the large number of commensals can bind to sites on the intestinal epithelium and prevent pathogens from doing so. The production of fatty acids in the colon by resident anaerobes can reach high concentrations, and in combination with a mildly acidic pH can also prevent pathogen proliferation.
I want to begin simply with respect to HIV/AIDS. HIV means human immunodeficiency virus and AIDS means acquired immunodeficiency syndrome. AIDS was first described in 1981, but it is believed to have begun in Africa perhaps 50 years earlier.
There are two major types of HIV that we are aware of: HIV-1 and HIV-2. Despite conspiracy theories, such as the government created this virus, the evidence on the basis
of DNA sequencing is that the HIV-1 can be traced to a virus in the chimpanzee referred to as SIVcpz. The ancestry of HIV-2 has been linked to another SIV, this one from a monkey found in West Africa called a sooty mangabey (SIVsm).
This is an important lesson because it shows that primates have a similar virus, SIV or simian immunodeficiency virus. We know that a given simian is resistant to its own SIV, but if infected with an SIV from a different primate, it will develop an HIV-like disease.
Three statistics: (1) Currently (2007) it is estimated that 33 million people are living with AIDS. (2) 6,000 people die per day from this disease. (3) 6,800 people become infected daily. Globally, the worst-case scenario is Sub-Saharan Africa and Southeast Asia. In Africa many children have become orphans because of this disease.
Of HIV-1 and HIV-2, it is HIV-1 which is far more virulent. DNA sequencing has shown that there are different lineages of HIV-1, which trace to various SIVcpz lineages, but it is group M that accounts for the global pandemic.
It will now be instructive to view HIV-1, which is a retrovirus (see figure 37.8). This is an enveloped virus, but let’s consider the nucleocapsid. It is an RNA virus with 2 strands of RNA. There are two proteins present in the virus that should be noted. One is reverse transcriptase, and the second is integrase. So these do not have to be made when the virus initially infects a cell. Two other proteins that I want to mention now are gp120 and gp41, which together create a mushroom-like structure on the surface of the virus, gp = glycoprotein. Gp120 is referred to as Envelope. It is important because it is the virus ligand that binds to a receptor on target cells. In reality there are 2 receptors (co-receptors): one is the CD4+ protein and the other is a chemokine receptor CCR5 or CXCR4. The CD4+ protein is present on TH cells and T-memory cells, macrophages and dendritic cells. There are central to antigen presentation and the stimulation of B-cells to make antibodies and to the activation of Tc.
Amazingly, it has been found that there are individuals who are HIV-resistant and they have two mutant copies of CCR5. This resistance shows a distinct ethnic distribution and it is only northern Europeans and western Asians who are resistant. If a person is heterozygous for the CCR5 gene, +/-, there is a delay in getting the full-blown disease, but it will happen. There are also people who are celled elite controllers because they can have the virus, but do not become ill. We need to learn why.
When a person is infected, the gp120 (Envelope) binds to the co-receptors. Once solid contact has been made, the gp 41 (a fusin) is needed for the virus to fuse with the cytoplasmic membrane of the host cell and enter. The virus will uncoat and release the RNA genome, which is then converted to a dsDNA by reverse transcriptase. The DNA with the help of integrase will make its way into the nucleus and integrate into a provirus state. It can remain in that state for a long time. It has been estimated that in dormant T-memory cells the provirus state can last for 5 decades. If the cell in which the provirus state should go into a replicative phase, the provirus will produce mRNA and RNA to create new HIV virions.
How can we detect the presence of HIV? There are two means: (1) by detecting antibodies using an ELISA or Western blotting, and (2) detecting viral RNA via RT-PCR. For screening, ELISA is sensitive but is subject to false positives, so confirmation via Western blotting (of the presence of HIV antibodies) is desired. PCR is more sensitive and a patient needs to be monitored to understand his/her amount of virus (called viral load) or virus titer.
What is the clinical perspective? (see lecture for diagram)
If an individual is infected and not treated, then on average symptoms will be experienced in 2-8 weeks. This is referred to as the acute stage. The virus titer spikes at high levels and in this state this person will experience flu-like symptoms. So he/she might have fever, headaches, weight-loss and lymph node enlargement. But at this stage the immune system is functioning and the viral titer drops down to a low level. In an untreated person, this level can remain low for a number of years. The CD4+ level in a healthy person is stated as 800-1000 cells/ul. As long as the CD4+ population remains above 400 cells/ul the infected person is alright. When this cell population drops to 400 or below, especially 200 or below, then there is insufficient immune system power to curb the virus’ replication and it increases again to a high titer. The patient will experience opportunistic infections and a particularly dangerous one is to contract TB. There are vicious strains of TB in existence, which have multiple drug-resistance (see if you are curious). See also Table 37.3 for opportunistic infections.
So, on the average, in an untreated patient, it takes 8-10 years to progress to this state. In people who have high-risk sex (multiple partners), this can easily progress in ˝ the time as they may contract other pathogens. The best example if Kaposi’s sarcoma -- a cancer caused by human herpes virus 8.
Why do CD4+ cells die? These are T-helpers, T-memory cells, even macrophages and dendritic cells. Researchers say that T-memory cells are a prime target of HIV-1. You can appreciate that loss of T-helpers and antigen presenting cells (macrophages and dendritic cells) would cripple the inmmune system as B-cells and TC cells depend on these processes for full activation.
The HIV can replicate only if it goes into a provirus state, consequently some people view it as a mobile genetic element. When HIV integrates, it does so randomly into the human genome. One way in which the virus kills is that when it replicates, it produces enough progeny that they kill the host cell (called a cytopathic effect). A second proposed means is that later in the disease, the HIV forces the formation of what are called syncytial cells. These are giant multinucleate cells, and I am presuming they go into apoptosis. In a lecture I just heard from Dr. Marie-Lise Gougeon of the Pasteur Institute in Paris, a different possible mechanism was proposed. New evidence has shown, at the time of the acute phase or shortly thereafter, that the intestinal mucosa (the epithelial cells) is severely damaged if not destroyed. The bacteria inside the colon die to some extent (normal) and the LPS that is released escapes through the damaged epithelium into the blood. The LPS interacts with CD4+ cells and forces them into apoptosis.
What can we do about HIV? We can try a global sociological approach. Abstinence or safe sex, education, needle exchange. If we can affect behavior we can stop the disease.
Vaccination – This has been a miserable failure thus far, and no vaccines are on the horizon. Why do vaccines fail? The major reason for this is that the virus mutates at a very high rate. The RT does not proof read when it makes DNA. Consequently, it makes mistakes and the DNA has on average one mutation/genome of HIV. The gp120 gene, whose product would be a good target, appears to hypermutate. Vaccines aimed at this target have failed for this reason. In reality, type M HIV-1 has mutated into various strains called clades. Vaccines have also been developed to try to boost the production of Tc cells, but this approach has also failed.
Drugs – A pharmacological, that is, drug approach has been much more successful. But I need to emphasize that this is not a cure; it is management of the disease. This therapy is called HAART, highly active anti-retroviral therapy. This is a 3-drug cocktail and we now have five types of drugs, meaning different targets that are available. The classic cocktail contains two types of reverse transcriptase inhibitors and a protease inhibitor.
1. Nucleoside Reverse Transcriptase inhibitors -- block DNA synthesis.
2. Non-nucleoside Reverse Transcriptase inhibitors -- bind to RT and inhibit it.
3. Protease inhibitors – block assembly of virus.
Two newer types are:
4. A gp41 fusin inhibitor – blocks entry of virus; and
5. Integrase inhibitors – block provirus formation.
This regimen is not always easy to take and many cannot tolerate it. But I understand that some of the newer drugs are less toxic. Protease inhibitors can have bad side effects, which cause redistribution of lipid in the body. Patients have been known to develop diabetes because of this or have fatal heart attacks. The drug cocktail treatment began in 1995 and so the longest anyone has been on it is 13 years. We don’t know how safe it is for long durations.
Why 3 drugs? There are two reasons for this. Each inhibitor type acts differently, so bio-chemically, three different modes of action are involved and likely to work more effectively than one. But the major reason is genetic. As stated before, the virus mutates at a high rate. It becomes resistant to one drug quickly. Let us suppose that the mutation rate for one gene is 10-7. Then for three genes it would be multiplicative 10-7 x 10-7 x 10-7 or 10-21. Thus, there is a low probability that a strain would develop that is genetically resistant to three inhibitors simultaneously.
I want to emphasize that the drugs reduce the virus titers to extremely low, essentially undetectable levels. But if the patient is withdrawn from the drugs, the virus always comes back. The question is, then, where is the virus hiding. There may be 3 sites. It is known that macrophages can cross the blood-brain area and enter the brain. An infected macrophage in the brain would be safe from the immune system. We do not know if the virus can get out of the brain. We do know that HIV patients can develop dementia because of this. Second, virus may be produced at a low level by macrophages and dendritic cells in lymph nodes and the intestine. This makes it harder for drugs to reach. Third, the best reservoir may be memory T-cells that are non-mitotic. So one hope is that if drugs can be developed to combat these reservoirs, we could cure this disease.
References. Edition #7 Chapter 37, p926-931.
Watkins, D. I. (2008) The Vaccine Search Goes On. Scientific American, 299:69-77.
Stevenson, M. (2008) Can HIV Be Cured? Scientific American, 299:78-83.
I love Africa
Re: Lecture Notes on HIV/AIDS and other human Pathogens
are you a medical student? that was a great post. I really enjoyed reading it. thanks very much for sharing
"Wood already touched by fire, is not hard to set alight"...An African proverb.
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