HIV and AIDS: History of an Infectious Agent
-Early transmission of HIV in Africa was from prostitutes to truck drives which
helped the virus spread throughout the continent
Brazzaville, Congo
◦ 1929
◦ Happened when hunters killed monkey and was contaminated by its blood
◦ HIV & AIDS – Reduction of the immune system
January 10, 1981, Dr. Gottlieb office @ UCLA Medical Center, Los Angeles
Dr Gottlieb( immunologist) in Los Angeles met the 5 patient with HIV/AIDS .
Patient was looking for a job in New York city but couldn’t get one because he
has Labial herpes virus (Cold Sore) on his lips- lasted for half a year.
◦ He had no acquired immunity
◦ Helper T-cells extremely low & antibody production low
◦ 2 weeks later Michael had pneumocystis carinii ( fungal pathogen) pneumonia
(PCP)
◦ In Los Angeles (1967-1978): only 2 cases of PCP in immunocompromised
patients ( taking chemotherapy) 1981, Los Angeles – 5 cases of PCP
◦ All Young
◦ All Homosexual male
Early 1970s: 5 cases/ a year of Kaposi’s sarcoma (KS) in elderly of
Mediterranean background
1981 – 26 cases of Kaposi’s sarcoma
◦ San Francisco and New York
◦ Young
◦ Homosexual male
◦ Aggressive cancer
◦ can move to internal organs
Epidemiology of a New Disease
◦ Two rare diseases:
◦ Opportunistic infection (PCP)
◦ Rare cancer (KS)
◦ Other conditions linked to immunosuppression
Clusters of infected gay men
Concentration within sexually interactive groups
Suggests an infectious agent
Sexually transmitted within the gays
The original name of the disease: Gay-Related Immune Deficiency (GRID)
Gaetan Dugas
◦ was a common partner to many patients
◦ Had over 2500 sexual partners
◦ All were part of the homosexual community
◦ He had slept with 250 partners per year
◦ was a flight attendant
Epidemiology of a new disease Not just in the gay community
◦ Other ways of getting a similar syndrome
◦ Intravenous drug use
could also get HEP from it as well, that why it’s important to use clean syringe &
needles.
◦ Blood transfusions
Druggies would sell their blood to hospitals in order to get money for daily fix, the
blood bank was completely contaminated this way.
◦ Hemophilia A (coagulation factor VIII) The blood from blood banks and use it to
isolate factor VIII to supplement for the patient who does not have enough
(hemophiliacs) ◦ Female sex partners of AIDS-positive, IV drug users and hemophiliacs
A New Name for the Disease: Acquired Immune Deficiency Syndrome (AIDS)
AIDS Statistics (2010)
Sub-Saharan Africa
◦ About 1.9 million new cases of HIV infection per year
◦ 350 000 are children
◦ 1.2 million deaths every year
◦ Approximately 23 million people are infected right now with HIV
◦ 3.1 million are children below the age of 15
◦ Several countries in sub Saharan Africa report infection rates of 20-35%
◦ Significant decrease in life expectancy in African countries in 1995 even though
there was an increase when vaccines were brought to the countries before
Only part of world where females (13 million) are infected almost 20% more than
males (10 million)
Females are infected earlier in life (at around age 20, 1/5 of women are infected)
This is because of gender power, cultural norms, and rape being highly
prevalent.
The "gogo" (Zoolo word for grandmother)
The gogo's are left to take care of several children who have become orphans
due to their parents being infected with the disease. No room in orphanage so
gogo's take care of the children. Friday, 24th January, 2014. Tutorial:
Most children infected with AIDS are infected via sexual activity.
Anti-viral drugs given to mother and baby during and directly after birth reduces
the chance of the baby being infected by 90%.
However, the baby can still be infected through breast milk as anti-viral drugs
cannot be given to the baby for an extended period. Low income mothers will
choose to expose their babies to AIDS through breast milk rather than let them
starve.
January 27 monday (SIDE NOTE: above is JANUARY 22nd wednesday notes,
friday january 24th hasnt been added, i cannot upload them as i was not here for
the class, so if someone has them put them above this)Aids/HIV in western
counties (the US as example)
◦ Over a million ppl diagnosed with aids in US since 81, At least 600 000 of them
died.
◦ Estimated 1.3 million US ppl are infected & 27% are unaware of it
◦ HIV carriers are going up but aids and death from aids is going down.
◦ In US more males infected with aids but in Africa more females, and at an earlier
age.
How are people getting it?
Women: 75% from opposite gender sex and 25% from
injections/blood Men: 67% same gender sex, 11% opposite gender sex,
14%injections, 8% ?
Gay community and aids: In US men who have sex with men
(MSM) accounted for approx 2/3 of all HIV infections among men even though
only about 7% identify as msm
HIV in body fluid: 18000 blood, 11 000 semen, 7000 vaginal fluid, 4000 amniotic
fluid, 1 saliva
HIV transmission: blood to blood, unprotected sex, mother to child
HIV is NOT transmitted by: physical contact, sneezing/coughing, saliva, toilet,
insect bites.
Safer Sex
◦ The best way to stop HIV being passed on is to use condoms during vaginal, oral
or anal sex if there is any possibility that either partner could have the virus
◦ It can take only a single episode of unprotected sex (ie. not using a condom) with
an infected partner for HIV to be passed on
◦ However HIV is not always passed on the first time
◦ Hence its never too late to start practicing safer sex
◦ It is never too late to get tested for the virus
Drug, Alcohol and HIV ◦ Significantly reduced protection if a person is drunk or high on drugs
◦ Persons under the influence of alcohol and other recreational drugs are more
likely not to use condoms or they don't use them correctly
Approached to HIV Prevention
◦ Education and behavior modification
◦ Safer sex
◦ Condom
» Choose your sexual partners wisely and responsibly when you can make
decisions.
- Avoid mixing drugs/alcohol with sex.
Wednesday January 29
Diagnostic Tests for HIV
◦ If you have antibodies against HIV, it means you have previously been exposed
to HIV
◦ Today: antibody tests are used for screening
◦ It's a quick process - nearly 20 minutes
◦ Old days: many people missed their positive diagnosis because they never
returned for their test results
-Apart from diagnosis (leading to treatment), these tests are a means of
prevention as well (as people diagnosed with the infection are expected to take
precaution and minimize the spread of disease)
From HIV infection to AIDS
There are kind of like two stage: when the infection is chronically subclinical and
when infection become AIDS
(Below is an explanation of what happens during the course of the disease;
derived from the graph shown in class)
◦ Acute infection flu-like detected when one has infection at the chronically
subclinical stage. After firs 6 months (approximately) only do antibodies against
HIV develop. Before that, you can't use antibody (serology tests) to detect the
disease even though the virus is transmittable during the time.
◦ Stage of Chronic infection can last very long
◦ T- Cell production is not stable (up and down) as the t-cells are being killed by
HIV and then reproducing. Overall, T-cell production declines over the course of
the disease.
◦ When T-cells reach the amount of 200 cell/ mm3, the person has AIDS.
HIV Antibodies (serology) Tests
◦ Detect antibodies for HIV
◦ False negative results during the window period ◦ An infected person can transmit HIV to others, without their HIV infection being
detectable using an antibodies test
◦ False positive- cross reaction. Not very common.
◦ Both directions of false negative and and false positive are possible
◦ Confirmation by virus tests (in detail in next section) - will guarantee your results,
much more reliable. A little more expensive but worth it. Antibodies tests were
common in the past but not so much now. Antibodies tests detect after some time
has passed, virus test can tell right away. Sometimes people with HIV are well
treated so that they get negative on the virus test. - Many cases the diagnosis of
HIV is happening cause of the symptoms (which usually occur after the infection
has developed into AIDS), can have certain symptoms that suggested low
immunity which can suggest HIV/AIDS. About 27% ppl with HIV wont have
symptoms and wont know, but usually there are symptoms to help tell ex
pneumonia (PCP one), long-lasting herpes virus or other unusual conditions.
◦ Antibodies go down as immune system breaks down
HIV (virus) Tests
◦ Viral Antigen Test
◦ The test detects the presence of viral proteins (these are simply in the serum and
unattached to anything else)
◦ Nucleic Acid (PCR) Test
◦ Amplify and detect HIV genome sequence
◦ It is important to know the HIV status of the mom: reduces mother newborn
transmission.
◦ When the child is born the child is exposed to the mothers blood and this is when
the child can be infected.
◦ The mother can take certain drugs before birth and it can reduce the child from
getting infected by 50%.
◦ Also as soon as the child is born, give them medication against HIV as well
Mother – Newborn Transmission
◦ The transmission rate from mother to newborn is around 15-50%
◦ May occur during transplacentally route
◦ May occur during the birth process (most cases)
◦ May occur postnatally through breast milk
◦ Greatly reduced by one dose of anti HIV drugs to the mother just before giving
birth and to the newborn, up to 72 hours after birth
◦ Knowing the HIV status of the mom is critical *prevention if better then having to
give treatment!
- It is illegal to give HIV drugs without the permission of the mother
◦ HIV is directly related to certain types of cancer
◦ HIV mutates more than any other virus
◦ Huge amount of variability - for this reason people can't take just ONE drug, must
take MANY at once
Side effects of drugs: changing distribution of fat in the body, diarrhea, nausea
etc. Friday. January 31
The structure of HIV: nucleic acid genome: Rna (Diploid)The virus enters the cell with several enzymes: reverse transcriptase, integrase, and protease.
Protein coatLipid envelopGP120 attachment protein
◦ Drugs for AIDS Treatment
◦ Existing and potential drugs for AIDS are based on unique enzymatic activities of
the HIV in HIV infected cells.
◦ Drugs can inhibit;
◦ 1. Fusion of viral cells with healthy cells
◦ 2. Integrase activity
◦ 3. Reverse transcriptase
◦ 4. Protease activity
HIV flow of info: DNA >(transcription)>RNA >(translation)>Protein . This is the
normal wayReverse transcriptase (RT) Is Rna>Dna.VIDEO(Missed a lot of the
info): HIV enters helper T-cells by binding its gp120 to the glycoprotein CD4 of
the helper T-cell. The binding to CD4 causes CCR5 to change. The virus must
bind to both before entering the host cell. Reverse transcriptase creates single
stranded DNA from RNA. The single stranded DNA is then picked up by host cell
polymerase which forms the double stranded DNA. Due to the lack of proof
reading mechanism, the DNA contains a high amount of mutation.
We can try to stop the interaction between virus and co-receptor, several drugs
that can bind to co-receptor and cover it so virus cant bind to it so it cant get in
the cell.
Sometimes the virus is enveloped and when its membrane fuses with cell
membrane the virus gets in, there are drugs to stop this.. Integrase enables
integration of viral dna into cellular dna. There are drugs that can inhibit the
integrase which are very useful drugs.Virus is present in genome. Memory cells
can stay in your system for a lifetime. When the memory cells replicate, the
daughter cells will contain viral genome.
That's why people with hiv have it for life because somewhere in our body, there
are infected memory cells. They just haven't been activated.Virus makes
mRNAs which leaves nucleus and is translated(not a good stage to make drugs
against, because we will be fighting our own ribosome). A single genome codes
for a long protein chain which consists of several enzymes. It is activated when
the protein is separated into the corresponding enzymes. Protease is the enzyme
responsible for cleaving polypeptides into functional protein.
. Anti HIV chemotherapy
HAART: highly active anti retroviral therapy
◦ Not only one drug against HIV. In order to use drugs against a virus which is mutated so much we need to use several drugs which stop the virus at different
stages. HAART : use of drug combos. Often 2 reverse transcriptase inhibitors
and 1 protease inhibitor which both are inhibitors of viral enzymes.Animation:
Substates molecules bind to the active site of a molecule. Enzyme substrate-
complex occurs, catalyses occur which releases the product(substrate molecule).
Substrates need to fit the enzyme binding site.
◦ Competitive inhibitors: a substrate that binds to enzyme, preventing other
substrates to use the enzyme.
◦ Non competitive inhibitors: a substrate that binds to allosteric sites, changing the
enzyme and preventing/ slowing the enzyme from catalyzing.AZT: an inhibitor for
HIV replicationAZT is similar to thymidine except difference is no OH.Acts as
chain terminator. As a result, RT often will confuse Thymidine with AZT. Viral
reverse transcriptase is 100 times more susceptible in inhibition by AZT than pst
cellular dna polymeraseAnimations(maybe wrong, was trying to type
quick):Treatment of Hiv: reverse transcriptase binds to Hiv RNA, you add azt and
integrates in the dna. When azt integrates into the virus dna strand that will be
the end of the dna, no more nucleotides can be added to dnaNucleotide-like
competitive RT inhibitors: thymidine, azt, and 3tc.
◦ 3tc made as a drug against hiv and a modification of azt, also ended up being a
drug successful against hepatitis b. works better on hep then hiv.
Nevirapine: an AIDS drug
Non-nucleoside Non-competitive RT inhibitors
◦ Good blocker of mother to child transmission
◦ Single dose before delivery to the mom and by 72 hours after delivery to the
newborn reduced HIV transmission by 50%
◦ Combination therapy with AZT Resistance mutations are not likely to be at multiple sites
Works at very low concentrations
Minimal toxicity
Protease Inhibitors
Retrovirus: HIV
Drug Design
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