AIDS - The Quiet Killer

•	AIDS may be the most virulent disease in human history
•	No one has ever truly survived it
•	Once the symptoms of AIDS emerge, the fatality rate is 100%

•	The AIDS epidemic has infected millions of people, and will infect millions more
•	There is no cure for AIDS
•	After all this time, in our age-old struggle with microbes, have we finally met our match?

•	When it comes to AIDS, the most we can do is to slow its inexorable advance through the body
•	Once infected, victims have about eleven years to live…

•	AIDS relies on the fluid route for transmission
•	The virus is carried in the blood or semen
•	You can catch it through sexual contact, or through shared needles
•	Babies can catch it from their mother’s blood in childbirth, or from breast milk

•	The fluid route is one of several dispersal routes that microbes have evolved to exploit
•	In our lecture on microbial strategies, we learned about some of the ways microbes try to breach our defenses, and some of our coevolved counter strategies

•	But getting into our bodies is not enough
•	If a microbe is going to succeed, it also has to find a way to exit the body, so it can infect someone else

•	Diseases like flu, for example, exit by the aerial route
•	Many pathogens travel in aerosols, like Mycobacterium tuberculosis

•	Aerosols are very tiny droplets suspended in air, like a mist of water vapor, produced by sneezing, coughing, or talking
•	This is a very efficient mode of transmission in crowded areas – like hospitals, jails, day-cares, schools…

•	The waste route is another easy way out of the body – exit in feces, or in urine
•	That’s how the microscopic eggs of hookworms leave the body
•	Hantavirus also uses the waste route, exiting in the urine of mice

•	The fluid route offers many opportunities for traveling microbes – they can disperse through saliva, blood, and mucus
•	Rabies, for example travels through the infected saliva of its victims
•	Your mom was right - spitting, or picking your nose, can spread disease!

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That may be why leprosy, or Hansen’s disease, is found in armadillos in the southern states
•	Only humans, chimps, two other primates, and armadillos can catch leprosy
•	The armadillos may have caught it from people blowing their noses into the ground

•	Native southerners, like many people around the world, have an old habit of violently blowing the nose while holding one nostril shut
•	Social graces notwithstanding, this expels the leprosy bacterium into the soil and leaf litter, where it can survive for two to four weeks

•	Armadillos come along, feeding in the dirt and leaf litter, and pick up the bacterium from the mucus
•	Unfortunately, so do young children playing in the dirt, a serious problem in less-developed countries where leprosy is endemic - you can also get leprosy from handling armadillos, or keeping them as pets

•	All of these dispersal routes are effective
•	But one of the most popular microbial highways is the blood route…
•	Microbes that travel in the blood often rely on insect vectors, like mosquitoes, or their technological counterpart, the hypodermic needle

•	But the trifecta for the fluid route is sex - saliva, semen, and sometimes blood are all flowing…
•	Throw in intimate bodily contact, and you have an ideal mode of dispersal and infection – one stop shopping for an opportunistic microbe!

•	So it isn’t surprising that many of the worst diseases that have tormented us are sexually transmitted diseases, or std’s
•	There are nearly 50 std’s, including syphilis, gonorrhea, herpes, and Chlamydia

•	Some, like syphilis, are potent killers
•	Others, like herpes, are mostly annoying, or embarrassing…
•	But none of them holds a candle to AIDS

•	The HIV virus that causes AIDS produces no killer toxins, no violent symptoms 
•	It’s a quiet killer, one that patiently stalks its victim for years…
•	It can take from 6 months to 10 years between the initial infection and the first recognizable symptoms

•	HIV cripples the immune system by striking at its most vulnerable part - the helper T cells, which orchestrate the adaptive immune response

•	Once the HIV virus kills enough helper T cells, the immune system can’t coordinate an attack
•	Every cell in the body becomes a safe haven for the virus

•	It’s a truly deadly and insidious strategy
•	It was only a matter of time before some microbe got lucky and hit upon this particular approach
•	AIDS blundered into a microbial gold mine…

•	HIV stands for human immunodeficiency virus
•	AIDS stands for acquired immunodeficiency syndrome

•	AIDS victims don’t die from AIDS 
•	They die from cancer, or pneumonia, or tuberculosis…
•	They are left defenseless against any and all infectious microbes

•	Because the victim’s body can no longer recognize a cancerous cell, for example, any cancerous growth can be fatal
•	More AIDS victims die of cancer than from any other cause
•	30 to 40% of AIDS victims will develop a malignant tumor

•	In fact, AIDS was first recognized from a cluster of rare cancer cases in 1981
•	An epidemic of Kaposi’s sarcoma swept through the gay community of San Francisco

•	No one suspected it was to signal the start of a global pandemic to rival the 1918 Flu
•	Kaposi’s sarcoma is an unusual type of cancer
•	It’s caused by a virus, HHV8 (human herpesvirus 8)

•	It can occur in skin, or the “skin within” -inside the mouth, or the gastrointestinal or respiratory tracts
•	30% of the first wave of AIDS victims in the 1980’s had Kaposi’s sarcoma
•	It was so common that it was sometimes referred to as AIDS rash

•	As more and more cases were reported, the conspiracy crowd went into a feeding frenzy
•	Because the disease seemed to be confined to the gay community, it was immediately dubbed the gay plague

•	It was a right-wing plot
•	It was a left-wing plot…
•	It was God’s vengeance on homosexuals
•	It was engineered in a secret government lab to wipe out Communists
•	It was designed to kill black Americans

•	As the disease continued to spread, its victims were dubbed the 4H Club – hemophiliacs, heroin addicts, homosexuals and Haitians
•	Unfortunately, because AIDS was incorrectly labeled a homosexual disease, it didn’t get the initial treatment or attention it deserved

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Doctors first called it GRID, for Gay-related Immune Deficiency
•	But as we soon discovered, it was not homosexuality, but promiscuity that caused AIDS to spread like wildfire in San Francisco

•	In the late 1970’s, it was not unusual in San Francisco’s gay underground to have 10 to 30 sexual partners a week, up to 1,000 in a year!
•	As we’ll see in our next lecture, promiscuity selects for the most virulent form of AIDS 

•	Where did this mysterious disease come from?
•	Like so many of our worst diseases, AIDS came out of the jungle…AIDS originated in other primates
•	Many African tribes still hunt and trap monkeys for food, or for sale to the pet trade and biomedical labs

•	Even before AIDS emerged, some experts were warning that frequent human to monkey contact held a deadly potential
•	Those turned out to be prophetic words…
•	Recent genetic analysis place its origins in West Africa, sometime between 1930 and 1950

•	One of the major factors in the emergence of AIDS is deforestation…
•	As African civilization penetrated deeper and deeper into the bush, encounters with primates became more common
•	And as rural populations grew, they became increasingly reliant on “bush meat”

•	The first case of AIDS in America was a 15 year old boy, who died in 1969
•	The most infamous early victim was Gaëtan Dugas, the so-called “patient zero” for AIDS
•	Though not the first victim, this gay flight attendant knowingly spread the disease to over 2,500 sexual partners

•	One of the reasons that AIDS is so deadly is that it’s so new – a scant 50 years have passed since the first cases appeared
•	That’s not much time for the body to evolve a defense
•	And not much time for AIDS to coevolve to a less virulent strain, like syphilis and scarlet fever

•	AIDS is related to a group of primate viruses called SIV’s (simian immunodeficiency virus)
•	There are two species of HIV, HIV-1 and HIV-2
•	HIV-1 is much more virulent, and more highly infective than HIV-2

•	HIV-1 probably originated in African chimps
•	The more recently discovered HIV-2 originated in West Africa, probably in the Sooty Mangabey, and is mostly confined to West Africa today
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The virus may have lived in apes for centuries
•	A 2010 study in Science presents genetic evidence that SIV has existed in monkeys for at least 32,000 years

•	Asian monkeys can get sick from AIDS, but African monkeys are asymptomatic
•	In humans, however, AIDS has become extremely deadly…
•	Now, viruses are strange little creatures to begin with
•	But AIDS is strange, even for a virus!

•	Many biologists don’t even think viruses are alive
•	They aren’t even usually considered organisms, strictly speaking, because they’re not made from cells, and can’t reproduce on their own
•	A virus must enter a cell, and use the cell’s machinery to make copies of itself

•	Viruses are incredibly diverse
•	There are probably millions of different viruses, but we only know about a few thousand!

•	Their average size is about 100 nanometers, which is ultra tiny - 1 inch = 25,400,000 nm
•	A quarter of a million viruses laid end to end would barely fill an inch
•	The adenovirus, one of the causes of the common cold is so minute that it would take well over 2 million of them to equal an inch

•	Viruses are so small, that if you put one next to a bacterium, the bacterium would tower over it, like a human being standing next to the Statue of Liberty!
•	Viruses are truly, as Pasteur remarked in his hunt for the cause of rabies, “a microbe of infinite smallness”

•	And their abundance is simply staggering
•	There are an estimated 4 x 1030 viruses in the ocean!
•	If all the viruses in the ocean alone were placed end to end, they would stretch from one end of the galaxy to the other – 100 times!

•	Viruses usually consist of strands of either RNA or DNA, wrapped in a protein coat called a capsid (we’ll learn more about RNA and DNA in a moment!)
•	Every type of virus is coded to attach to a particular type of cell – so viruses can target specific tissues and organs

•	A virus attacks by
>	Attaching to the outside of the cell
>	Injecting its genetic code into the cell
>	Taking over the cells machinery
>	Using the cell to make more viruses

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The ultimate origin of viruses is a complete mystery, though there are three main hypotheses:
>	Cellular origin hypothesis
>	Coevolution hypothesis
>	Degeneracy hypothesis

•	The cellular origin hypothesis, also known as the vagrancy hypothesis, claims that viruses are rogue bits of genetic material that escaped from intact cells, maybe in the form of plasmids

•	The coevolution hypothesis suggests that viruses simply coevolved with cells from the very beginning
•	Viroids, little bits of viral-like RNA that lack a protein coat, suggest that early forms of “free-floating” RNA could have developed into the tiny parasites we call viruses

•	And finally the degeneracy hypothesis, or regressive hypothesis, claims that viruses are simply degenerate cells
•	Viruses are cells that became so specialized as parasites, they gradually lost all the genes they needed to survive outside of a living cell

•	Chlamydia and Rickettsia bacteria support the degeneracy hypothesis
•	Both are living cells, but neither can survive outside of the cells they parasitize

•	AIDS is a type of virus called a retrovirus
•	A retrovirus is made of RNA – a single strand of sugar and phosphate molecules, attached to which are a series of 4 different kinds of molecules called nucleotides

•	Retroviruses are curious little creatures
•	A DNA virus, like an adenovirus, injects its DNA into the host cell, where it crosses into the nucleus and starts issuing instructions, using the cell’s own factory to carry them out
•	But it remains physically separate from the host cells’ DNA, and eventually degrades

•	An RNA virus, like flu, or West Nile, only needs to get into the cytoplasm, the cell’s factory floor, where it can directly hijack the process of making proteins, circumventing the host’s DNA 
•	A retrovirus, on the other hand, takes a more circuitous route…

•	Using an enzyme called reverse transcriptase (RT), retroviruses stitch their RNA into the host cell’s DNA
•	When that DNA is later transcribed, or read, the instructions added by the virus will also be read, and then the virus can take over - much the same way that a computer virus works (which, by the way, is precisely why we call them that!)
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To make matters worse, because its RNA is now an integral part of the host’s DNA, when the host cell reproduces, it can pass that viral RNA on to all its daughter cells
•	Even if the immune system kills every single active virus in the body, the instructions for making more will live on

•	This integration of viral and host DNA is unique to retroviruses
•	Even if the virus eventually goes extinct, some of its genes will survive
•	But unless the virus infects a germ cell, a cell that makes eggs or sperm, its viral genes won’t be directly inherited

•	A big part of our cellular heritage is what we call “junk” DNA
•	It doesn’t code for anything useful, at least as far as we know
•	It consists of genes, or fragments of genes, that are just old evolutionary baggage, including many fragments of ancient retrovirus genes

•	There are many types of retrovirus, including Hepatitis B and the Rous Sarcoma virus
•	Sheep, mice, monkeys, guinea pigs, birds, snakes, and cows also suffer from retroviruses 
•	Cats are prone to two deadly retroviruses, Feline Leukemia Virus (FeLV) and Feline Immune Deficiency Virus (feline AIDS!)

•	AIDS, like all the retroviruses, uses reverse transcriptase to take over the cells it infects
•	The “ase” ending of reverse transcriptase, incidentally, tells us that it’s a special kind of protein called an enzyme
•	Enzymes are a type of molecule called a catalyst

•	Catalysts can affect the course of a chemical reaction without being changed by it themselves
•	Which sounds like a pretty tricky thing to do - but it’s like putting puzzle pieces together…

•	If two molecules happen to bump into one another at random, and happen to be facing the right way, they might join together, or be torn apart, in a chemical reaction
•	Enzymes make sure that this will happen, over and over again…

•	Catalysts like enzymes have molecular “docking ports”, or binding sites, that have just the right shape, and just the right pattern of electrical charges on their surface, to latch onto certain molecules
•	By bringing two molecules together, one in each binding site, and holding them in just the right orientation, the catalyst or enzyme allows them to react

•	The docked molecules then drift away, and the enzyme is free to catalyze another reaction
•	Enzymes can put things together, and they can also break things apart

•	This makes enzymes the perfect type of molecule to control the mind-boggling number of inter-related chemical reactions that keep us all alive and well

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In fact, most of what your genes actually code for is a lengthy list of recipes for making different kinds of enzymes
•	And unfortunately, enzymes provide viruses with a lever that is so well-placed, it can be used to topple human empires…

•	Transcriptase reads the sequence of nucleotides in DNA, mapping it onto a single strand of nucleotides called messenger RNA (mRNA)
•	Messenger RNA carries those instructions out to the cytoplasm, the “factory floor” of the cell, where other types of RNA will read the coded instructions and use them to assemble a protein

•	Now we can appreciate the genetic strategy of retroviruses like AIDS
•	Retroviruses flip the normal process of protein synthesis around…
•	Instead of turning DNA into RNA to make proteins, they turn the viral RNA into DNA, which other viral enzymes will then stitch into the cells own DNA in the cell’s nucleus!

•	So when that stretch of DNA is finally read later on, the code words will be new ones, codons that code for making the proteins that will be assembled into a new virus
•	A very elegant act of piracy…

•	So with all this new information under our belt, we can finally take a close up look at HIV and see what makes it tick…
•	The virus contains nine tiny genes, on two strands of RNA
•	Six of them code for proteins that help the virus to reproduce inside the cell, and to infect other cells

•	The remaining three genes code for making 3 larger proteins, which are then snipped into 8 smaller functional proteins by an enzyme called protease
•	The first big protein (called gag) breaks into 3 proteins used to build the virus, p17, p18 and p24

•	The second (called env) breaks into two proteins called gp120 and gp41
•	These two proteins are the proteins that help the virus fuse to cells
•	We’ll talk more about them in our next lecture

•	The third big protein (called pol), breaks into the starter kit of key enzymes that the newly made virus will need to restart its life cycle in a new cell – reverse transcriptase, protease (the scissors), and integrase
•	Integrase is aptly named, it stitches the viral DNA, made by reverse transcriptase, into the host’s DNA
•	As we will see later on, one of the most promising strategies for fighting AIDS is to attack or disable one or more of these three critical viral enzymes
•	In our next lecture we’ll see how AIDS enters and exits cells, and learn how it disables the immune system
•	We’ll consider the extent of the pandemic, and explore the avenues of research that might someday, we can only hope and pray, lead to a cure…