CLASS: 10:00 11:00 Scribe: Adam Baird

CLASS: 10:00 – 11:00 Scribe: Adam Baird

DATE: November 22, 2010 Proof:

PROFESSOR: AIDS Page 5 of 5

I.  IMMUNOPATHOGENESIS OF HIV DISEASE [S1]

a.  HIV is a worldwide problem.

II.  OVERVIEW OF HIV EMPIDEMIC [S2]

a.  Brief history: HIV and AIDS is a relatively recent medical topic. In 1982, there weren’t any deaths due to HIV.

III.  DEATH RATES IN PERSONS AGED 25-44 YEARS IN THE US [S3]

a.  Over the next 15 years, the death rate in patients skyrocketed (mainly among young adults). It was at this point that effective (highly-active) anti-retroviral drugs were developed. As a result, the death rate of HIV decreased.

IV.  AIDS DIAGNOSES AMONG ADULTS AND ADOLESCENTS [S4]

a.  However, the falling rate in the 1995 timeframe has leveled out. This is the new diagnosis among adults and adolescents.

b.  Notice the different mechanisms for transmission (male-to-male sexual contact, IV drug use, etc.).

c.  Notice that the heterosexual contact mechanism has been steadily growing. Epidemiologic studies in Africa suggest that there is no evidence that transmission rate is higher for heterosexual contact compared to homosexual contact.

V.  A GLOBAL VIEW OF HIV INFECTION [S5]

a.  Notice that different countries show different frequencies of HIV.

b.  Notice that there is rampant disease in Sub-Saharan Africa.

c.  Notice, also, that some of the countries that have low incidence (like India, for example). However, they might not be testing well for HIV. How closely an infection is tested can alter the frequency of reported incidence.

VI.  NO TITLE [S6]

a.  This graph just shows more of the worldwide HIV frequencies.

VII.  NO TITLE [S7]

a.  This map shows the HIV frequency in the US. This shows the prevalence of HIV (the number of people who test positive for HIV).

b.  Overall, HIV prevalence is fairly low in the US (about 0.5%). However, in certain locations, it is substantially higher (like in NYC, DC, etc.).

c.  Black men in DC, for example, have a significantly higher prevalence of HIV.

d.  Men who have sex with men in NYC, for example, have nearly as high of a prevalence of HIV as Africa.

e.  Birmingham has a significant population of HIV-positive people. The UAB clinic sees a high number of HIV-positive patients.

VIII.  LIFE CYCLE OF HIV [S8]

a.  Life Cycle

1.  Viral entry (via CD4 and co-receptors)

2.  Reverse transcription (the virus is made of RNA)

3.  Integration into host chromatin

4.  Transcriptional activation of integrated provirus

5.  Production of viral proteins, particle assembly, and maturation

IX.  HIV PATHOGENESIS: LIFE CYCLE OF HIV [S9]

a.  This is an illustration of the HIV life cycle.

b.  CD4 and two other molecules are needed to attach the virus and then inject the RNA genome. There are two copies that are identical in each virion (which has to be reverse transcribed into DNA). DNA, then, has to get into the nucleus and integrate into the chromosome. An enzyme that is actually part of the virus codes for this process, meaning that it is a good target for therapy (because blocking that enzyme won’t affect the host enzymes). The reverse transcriptase inhibitors were the first class of HIV drugs. There is now a blocker of integration, but that is another target for therapy (although it is not as easy to block as reverse transcription because it’s mediated by the same host-defined factors).

c.  Transcription of the pro-viral DNA into viral RNA occurs, which then makes the proteins of the virus, the capsid proteins, etc. The particles self-assemble and are budded off the membrane and then once it is out, protease (that is also coded for by the virus) clips the capsid protein, making the capsid rearrange it’s 3D structure. This rearrangement is necessary for the virus to attach to other cells and inject the RNA.

d.  The second main class of HIV drugs is called protease inhibitors, which makes newly produced particles not infectious. In 1995, good protease inhibitors were first developed. They were then combined with reverse transcriptase inhibitors. This combination is the current method of HIV therapy.

X.  NO TITLE [S10]

a.  This shows the co-receptors.

b.  There are two chemokines (CCR5 and CXCR4). Both can participate (not together, but individually) in binding to the envelope protein GP120 and subsequently, GP41, allowing for a close association for the injection of the nucleic acid material into the cytoplasm of the target cell. There is an inhibitor of this process that can “screw up” the GP41 attachment site. This is also a clinically used HIV drug.

XI.  CHMOKINE CO-RECEPTORS FOR HIV [S11]

a.  There are two co-receptors, CCR5 and CXCR4 (just mentioned).

1.  CCR5 is called “M Tropic” or “non-syncytium inducing” and is usually present in the early stage of the infection.

2.  CXCR4 is called “T Tropic” or “syncytium inducing” and is usually present in the late stage of the disease.

b.  In fact, there are several cases where individuals who were infected with CXCR4, but switched to CCR5 once the virus began to grow.

c.  There are spontaneous mutants of CCR5, particularly from Δ32. Homozygotes with Δ32 mutation appear to be highly resistant against HIV infection (despite the fact that they have a normal CXCR4). It has been speculated that the Δ32 is also protective against cholera. About 1% of Caucasians are homozygotes with the Δ32 mutation. The frequency of the allele is about 15% of the population.

XII.  HIV LATENT INFECTION [S12]

a.  There are two forms of latency of HIV infection.

1.  Pre-Integration Latency

a.  After reverse transcription, but before integration

b.  “Latency” means that the viral DNA is present (so it is no longer sensitive to reverse transcriptase), but the detection of the latent form is dependent upon finding the DNA.

2.  Integrated Latency

a.  Once the virus integrates into the chromosome though, there isn’t a clearance mechanism (other than the transcription of viral proteins, and the viral proteins are either recognized by the immune system or potentially cause direct cell death).

b.  The frequency of a virus sitting in the chromosome (but not transcriptionally active) is very low. But, if therapy is interrupted, that small population can re-ignite the infection and the virus can grow out into uninfected cells. The existence of T-cells that have this form of latency is most likely the reason that highly active therapy does not completely eradicate the virus.

XIII.  HIGH VIRAL MUTATION RATE [S13]

a.  The virus has a very high mutation rate. Almost all of the mutation comes from the reverse transcriptase step (which is not nearly as high fidelity as the DNA polymerases that are involved in copying DNA). It is estimated that are about 1,00 different sequence variants in a single individual at one time.

b.  An infected patient is constantly getting viral mutations. One of these might be resistant to a drug, for example, which can create a significant clinical problem.

c.  In general, there is an inverse relationship of “viral fitness” with how fast it grows and whether it is drug resistant. Wild type viruses grow out when drugs are withdrawn.

d.  Development of drug resistance (because it comes through reverse transcriptase) requires active viral replication. If the virus is not replicating, it doesn’t generate new mutants. This is why a patient who is only partially on drugs can be a bad situation. The best situation for a patient is to be completely on drugs; the next best situation for a patient is to be completely off drugs; the worst situation is for a patient to be partially on drugs, which allows the drugs to select mutations, but not enough drugs to block the replication required to generate mutations.

XIV.  DIAGNOSIS OF HIV INFECTION [S14]

a.  The diagnosis of HIV is not based on the primary symptoms of the infection, but rather, it is based on the development of antibodies to the virus. This, then, can be measured by enzyme immunoassay and then confirmed with a Western Blot; together, this separates the viral proteins by molecular weight and stains them accordingly.

b.  The viral RNA is in the plasma once replication is high. This assay is 5x more expensive than this, and is therefore not really used as a screening tool.

c.  It’s important to know the response to a suspected exposure via a needle stick. If this happens, antiretroviral drugs should be taken. Post-exposure prophylactic ART for about 30 days. This should protect the individual, as it blocks the infection. This actually works pretty well.

XV.  LABORATORY TEST FOR AIDS [S15]

a.  Lab tests for AIDS

1.  Antibody Testing

a.  The antibody is used to diagnose HIV infection

2.  p24 Protein Testing

a.  The viral protein can be measure too, but it’s not very sensitive, so it’s not commonly used.

3.  Viral Load Testing

a.  Viral RNA measures how many virions present in the blood. This is done by PCR-based system (opposed to protein detection) and is very sensitive.

b.  When the viral load is high, it is more infectious and the patient is losing CD4 cells faster. When the viral load is low, everything is relatively better.

c.  When patients are on therapy, the appearance of the virus suggests the development of viral resistance.

d.  Over time, as long as the measurement of viral RNA is low, the patient will be fine; if the viral RNA is high, however, then the patient has developed resistance.

4.  CD4 Testing

a.  CD4 testing measures disease progression.

b.  The classic analogy: HIV is like a train, headed for a cliff. The viral load measure how fast the train is moving. The CD4 count measure how close the train is from the cliff.

c.  Example: If there is a high viral load, but a high CD4 count, the train is moving fast but it’s relatively far from the cliff.

5.  Genotypic Resistance Testing

a.  If drug resistance seems to develop, there are several ways that the resistance can be measured, which can serve as guidance for another drug to try.

XVI.  OCCUPATIONAL EXPOSURE TO HIV [S16]

a.  Universal caution should be used when handling any form of human bodily fluid.

b.  Early treatment has substantial benefits, but the time after infection is critical. If proper steps are taken within 3 days of exposure, treatment will likely be fairly effective. Any time longer than 3 days will allow the virus to “already get running”.

XVII.  THREE PHASES OF HIV DISEASE [S17]

a.  There are 3 phases of HIV disease. Only the end stage is called AIDS.

1.  Acute Infection Syndrome

a.  Somewhat like the flu.

b.  Only about 50% of the people infected have any symptoms. Many are asymptomatic during this first phase.

c.  People may get a sore throat, for example, but it will go away.

2.  Clinical Latent Disease

a.  The virus is actively replicating

b.  There aren’t any clinical manifestations though; people infected usually don’t “feel sick”.

c.  15 – 20 years ago, before antiretroviral therapy, people were dated as to when they were infected. This could help identify how long it took the patient to get sick (because the initial date of infection was approximately known). Today, it’s known that it takes 8 – 10 years (median) for people to go from the initial infection to the in-stage disease. During this time, they are infectious to other people. If the virus infected people and immediately killed people, it would not be an epidemic (because the virus couldn’t spread). This long clinical latent phase is what makes HIV so contagious.

3.  End Stage Disease (AIDS)

a.  Occurs when CD4 count falls below 200.

b.  Often, the viral load increases from what it initially was.

c.  After this occurs, the immune system begins to collapse (because there aren’t any available CD4 cells to direct the other cells) and opportunistic infections may result.

d.  Once a patient enters this last phase (untreated), the life span is 18 months – 2 years.

XVIII.  NO TITLE [S18]

a.  This graph simply illustrates the three phases of HIV disease.

b.  This was developed in 1993. It characterizes the primary infection episode, shows the clinically latent phase of the disease (notice the CD4 count slowly falling), and the viral load (notice that it is basically stable).

c.  It then shows where the CD4 counts falls even faster, the viral loads increases, and then death occurs.

XIX.  NO TITLE [S19]

a.  A dangerous issue: blood donation.

b.  Today, the viral antibody in blood to be transfused is measured. Any units that have HIV antibodies are excluded from donating to someone else. The problem: between infection and the time that antibodies develop is about a month. During this period, the virus is present in the blood, but there aren’t any antibodies (because the patient hasn’t developed a sufficient immune response to detect it yet). So, the virus could be in the blood yet without showing up during testing; this could lead to clearance for donation to another person, which could harm the acceptor. This rate, however, is relatively low (at an estimated 1 in 1,000,000,000 transfusions might be infected with HIV). Another complication: general anesthesia (at an estimated 1 in 10,000 might cause complications). For these reasons, many precautions are taken.

XX.  AIDS-DEFINING OPPORTUNISTIC INFECTIONS AND NEOPLASMS IN HIV INFECTION [S20]

a.  Here are some of the infections that happen in an opportunistic fashion when the immune system collapses (from HIV). These are infections that are primarily controlled by T-cells (which are killed off in HIV infections).

1.  Protozoal and Helminthic Infections

2.  Fungal Infections

a.  Of particular importance: Candidiasis (esophageal, tracheal, or pulmonary)

i.  Candidia is present in our mouths now, but we have enough of an immune response that an infection doesn’t occur. When the immune system is low (due to HIV, for example), this infection may occur.

b.  Of particular importance: Cryptococcosis (CNS infection)

i.  Very serious infection

ii.  Is not a problem with immune-healthy patients