HIV/Aids

CD4+ T Cells

Carbohydrate (sugar) Once you produce viral particle, they go and bind to the CD4 receptors in infuse the membrane of the virus with the cell membrane, this is how entry into the cell occurs.

Asymptomatic period

(HIV+)- HIV-I (7-12 years)

Virus reappears in blood

(hidden in lymph nodes before)- lose CD4+ T-cells rapidly= AIDS (< 200 T-cells/ uL of blood or/and one of the several associated illnesses)

Protease Inhibitors

-Norvir/ Ritmavir - Hoffman-LaRoche - Merck developed Indinavir

1981

-first reports in LA to CDC with atypical symptoms for 18-25 male age group - group of young gay males where found to have decreased CD4+ T-cell counts HIV was isolated at Pasteur Institute in France by Luc Montagnier

HIV life cycle

1. HIV is an RNA retrovirus- protein coat surrounding single-stranded RNA- this ss-RNA enters your body and needs to convert to ds-DNAv (viral) 2. Reverse transcriptase transforms ss-RNA to ds-DNAv 3. Integrase makes ds-DNAH (human) and ds-DNAv (asymptomatic period) 4. ds-DNAV transcribed to RNAH 5. RNA is translated to protein (HIV polyprotein) which is not yet functional 6. HIV Protease cuts polyprotein to form viral particles= AIDS

three theories about what most people think HIV formed from

1. It came from chimps because HIV is closest to SIV (98% similarity) which is why we say it is chimps 2. The human entry → there are three leading entries: Human entry: 1900-1950s Human with mouth sore ate raw chimp, people have been eating primates since the beginning of time. 2. Colonial hypothesis: Chimp meat hypothesis with a colonialism: the reason why it started to be bad in the 1950s, because of colonialism in Africa. The jump between chimps and humans. Colonial people came in and they built cities in Africa. Cities are the thing that caused this to explode. Cities are where you got anonymous sex. This disease was always around, but people would die from it and they would be gone. But once you moved into the city. 3. The Earliest case of HIV positive samples comes from the city of democratic of the congo. 1950s OPV testing (oral polio vaccine) Hilary Koprowski at Wilstar wanted government to approve polio vaccine Inadvertently re-extracted SIV Koprowski given right to do vaccine trials wherever he wanted Earliest cases of HIV correspond +/- 20 miles to every place he did OPV trial Started with HIV epidemic Accused western medical communication of releasing worst pandemic The oldest tissue sample that was HIV positive was saved by a colonial doctor during the polio vaccine trials -the only people who saved samples were colonial doctors in that era

Easiest way to stop the disease:

1. Stop having sex. 2. Wear a condom if you are the male. The virus cannot go through latex. The only way you could get it is if the condom ruptured. You might get mononucleosis symptoms at the time of infection (most people do not). Infection occurs almost always by unprotected sex

Phases of HIV

1. infected 2. mononucleosis 3. Asymptomatic period 4. Virus reappears in blood

2 primary diseases recognized

1. pnemonia which was unusual for people with high immune systems 2. cancer - this particular form was called kaposi's sarcoma. This causes horrific skin lesions in the patients. This had not been seen in the U.S by anyone younger than 60. This happens to be would be related to why it showed up in this population and also the government's response to this disease (slow and asinine) because of the populations that would be affected.

What is HIV?

2 studies about HIV. 1. Conducted by Luc Montagnier at Pasteorio and Robert Gallo at NIH. → looked for something in these men that caused their T cells to die. The only agent that has been found is HIV (human immunodeficiency virus) This is a virus you contract only by liquid liquid contact. -It has to be intimate liquid contact for you to contract this virus (in general this exclusively means sexual contact, blood transfusions) Standard dentist latex gloves and condoms protect against HIV Is there any association with the gay population? The sex between men tends to induce more tearing than men having sex with women, naturally results in more blood in one of the two people.

HIV

A disease that came to light in the U.S in 1981 (this is its genesis year) This is not when the disease first infected humans, but first time humans became aware of disease because of the quirks or efficiencies of the U.S government

AIDS

AIDS is a technical definiton: 1. You have less than 200 t cells per microliter of blood This would mean you are positive for AIDS at that point. If you have AIDS you will die. 2. You can be any of these 2 conditions. You have an associated opportunistic infection and you are HIV positive

4th phase

Aids, when you will die

Truvada effectiveness

Giled (the company that markets it) says it is up to 100% effectiveness, but there are studies out there that have reported 49% effectiveness under the same dosage levels. The largest study undertaken was actually in Thailand. Thailand as a government has a huge problem. 12% of the overall 33 of men who were taking it 4 times a week took it everyday. The overall numbers in the Thai study: protection was closer to 50% , this explains these numbers. Most studies are reporting 49 or 50% effectiveness, because most men are not taking it enough for it to be effective. If someone tells you that you are on Truvada and you can have sex with them, you should run.

Where did this disease come from?

HIV - what is its source? All primates are infected with a similar virus Our closest friends in the animal community. All primates have SIV (simian immunodeficiency virus) - We believe that HIV is trying to mutate it. The most rapid mutate organism we've ever seen. What we think it has happened, it has entered humans relatively recently. It was SIV from a particular primate (from Chimps)

Hoffman

Hoffman-LaRoche developed Saquinavir edegraded too quickly, needs to be taken with Norvir

HIV positive women

In 80% of HIV positive women, it protects fetuses. So if a woman becomes pregnant and she is HIV positive, that woman will be put on AZT so the child has a 20% chance of being born HIV positive, without HIV the child will be 55-80% likely to have HIV Almost every pregnant woman will be put on AZT because it reduces babies risk of getting HIV

Why are young people losing these t cells?

In the U.S that disease would come under a name that stands for AIDS (immune deficiency syndrome) in other parts of the world the name is called GRID - GRID: gay related immune deficiency disease We believe today that GRID is no longer used because AIDS can be gotten by anybody

Truvada

In the gay community, many have received the message they think this drug can protect from HIV with unprotected sex with this drug, and this drug acts as protection against HIV. -This drug is not 100% effective.

Why/how was HIV discovered?

It was discovered largely because center of disease control prevention in Atlanta has required or requested doctors and hospitals to forward to them unusual medical cases they come across (mainly this is hospitals doing it) - Hospitals are supposed to notify the CDC of this, or a communicable diseases... It BEGAN by a spurious report 1981 in los angeles → there were 5 young men that would be hospitalized in that hospital for what was considered unusual diseases for people in their early 20's -

First report on tv about HIV

It was on NBC - Most of this report spends its time talking about the lifestyles of gay men -Showed a man who led a lifestyle that was active

Integrase Inhibitors:

Mmerk insentress: Internal number was MK0518 Drug companies switched to patients developing copies of HIV in their blood and death would ensue, then you give them this isentress and you ask if this would reduce the number of HIV particles in their bloodstream During this trial, they took men with greater than 1000 copies of HIV per mill, when they went on isentress it reduced to below 400 copies/mil in 79% of men.

Mmerk Isentress:

Most would say this was a successful clinical trial. There was one problem, for patients that took sugar pill the placebo reduced it in 43% of the men. This is known as the placebo effect. - This is when they assume they are getting an active drug, this is what doctors famously call the placebo effect. In the case of merck there was not enough of a difference between the sugar pill and isentress, and the MK0518, it means there were at least 517 other drugs merck was working on in that same study before they got to this drug. *this is part of reason drugs are very expensive the other 517 drugs never saw the light of day. All the money invested in this program went to nothing, mechanism for paying for it is that you charge high amounts of money to pay for all the other development that lead nowhere. The few that are successful (the ratio is 1-10,000) pay for the ones that were not successful U.S is paying for the highest prices of drugs, means we are funding directly the world's drug development. Canada is funding much less

HIV Drug Targets:

Reverse Transcriptase Inhibitors (RTI) Aziodothymidine (AZT) developed in the 1950s 1st developed as an anticancer drug- completely ineffective AZT showed no increase in life expectancy, though patients on it may experience a healthier life during their time on AZT It prevented the transmittance of HIV from pregnant women to their fetus up to 80% ddI- no increase in life expectancy

Norvir/Ritmavir

Ritmavir (successful) Developed by Abbott Labs (Dale Kempf) First ever computer designed drug Combined with AZT, inhibited liver enzymes

Emtricitabine

Sold as a package as truvada or PrEP

3rd period:

The latency period → the virus has gone into their body, they show no problems with their t cells everything is fine they are having sex unprotected, they don't know they are HIV positive and they are spreading the disease to other people

first 5 men discovered with HIV

The first 5 men that would be discovered with these rare communicable diseases were all active homosexuals. That is the characteristic they share.

Why this showed up in the male gay population

This is a virus, it is called an RNA retrovirus. An RNA virus is a corporate made of proteins, inside is a single stranded RNA molecule. It is considered more stable. RNA based organisms are viewed as most biologists as the oldest things on this planet. They have been here forever, which begs the question why 1981 it was first seen. It was because of our government's ability to detect things that other people ignored so people just died. In Kenya, they don't have death or birth certificates in Kenya. This government tracked that and discovered the disease because of that. 99% of scientists who are worth their salt considered this the causative agent of aids. Why are there some people who doubt this? Thabo Mhek → second free president. Nelson mandela's last son died of aids. The only living heir's of mandela are his daughter. This disease personally affected his family. He knew that aids was caused by HIV. Thabo told country that poverty causes aids, the only way you could solve aids was to solve poverty. So AIDS is more pertinent in poorer countries. One simple biological problem → the way you usually test someone for it, you inject a perfectly healthy organism and you inject it into them to see if this develops

Three targets for drug companies

Three original targets:to kill 1. Reverse transcriptase (that enzyme) 2. Intograse 3. HIV Protease

Lawrence Altman

Wrote infamous article, spread to NY and also quickly to Chicago. He talks about a rare cancer seen in homosexuals. The disease is completely related in the public's eye to being gay. It is gay men who get this disease and it is something in their lifestyle.

more about AIDS

You can only get aids from humans. So people who say it is not the causative agent say that not everybody who is HIV positive has died of aids. - Over 50% of people who have contracted HIV have gone on to die of AIDS. the only other known retrovirus is cause by HTL virus 1, you have a risk of getting cancer of only 15% in your life. - The infection occurs almost always by unprotected sex.

The first enzyme

an enzyme called reverse transcriptase → ssRNA → dsDNA (this is the first step) Once it has double stranded DNA (viral DNA) that is separate than your body's DNA It will need to insert it into the double stranded DNA When the polyprotein starts to be cleaved...

Merck

developed Indinavir Did not inhibit liver enzymes, taken with Norvir

More on HIV

disease will be discovered as an immune deficiency → a specific type of immune cell is affected by the disease. Many people in BIO call these the helper T cells, their job is to engulf foreign cells and kill. That is the job of the T cells in your immune system. - You are constantly under assault by bacteria

HIV origin theories

earliest HIV+ sample from Congo in 1959 - related to SIV (Simian Immunodeficiency Virus)- present in every primate (unaffected by it) 1st theory: could have been transmitted to humans from eating uncooked, contaminated chimp meat 2. colonial cities could have made HIV "appear" 3. Edward Hooper (1940s) suggested in his book "The River" that development of the OPV by Hilary Koprowski caused HIV During testing of vaccine in chimps, SIV could have been extracted WISTAR did eventually produce samples that were HIV- from people who received the OPV, but no HIV+ sample earlier than this date has been produced so this theory cannot be completely ruled out until that point Most scientists do not believe this is true- because theoretical studies have suggested that HIV developed before the 1940s

HIV

first case was because it came up as a rare cancer seen in homosexuals - a disease that has become a feared disease of people around our age.

Infected

liquid to liquid transfer

Mononucleosis like symptoms

mono, rare

South African's and Aids

over 85% of them know their HIV status. Done by the companies of South Africa have all their employees are regularly tested, testing them so they can get them medicine and make them aware they are HIV positive.

The integrase inhibitor:

used in combinatorial therapy, used with other drugs - Used in combination with RTIs (reverse transcriptase and protease inhibitors) and reasonably effective

Tenofovir

used with patients associated with risks of being a gay male