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FASCINATING FACTOID:
12% of caucasians (Zwickey) are immune to HIV because they are descended from bubonic plague survivors. The Black Death had a 90% death rate and killed 147 million people. It swept Europe 3 times, in the 6th, 14th and 17th centuries. Those who survived (natural selection) don't have a certain chemokine receptor (CCR5) which is necessary for HIV to get into host macrophages. This may explain why some partners of HIV positive people never get the disease even though they do not practice "safe" sex.

notes moved forward from original date 5/25/08
ZWICKEY NOTES NOT INTEGRATED FROM HERE DOWN TO "STRAINS"
Outline
I. Viral Entry
A. Viral Coat
B. Cell Receptors
C. Tropism
D. Viral Fusion
II. Viral Replication
III. Viral Budding
IV. Immune Response to Extracellular Virus
V. Immune Response to Intracellular Virus
VI. Virus Characteristics
VII. Tests for HIV
VIII. Vaccines

HIV infections
I. Viral entry
A virus is completely non-functional without the host cell machinery to make its proteins. Thus, an individual viral particle itself is innocuous. A virus must infect a cell in order to cause damage to the host.
A. Viral Coat
Extracellular protein GP160 (GP=glycoprotein) = gp120 + gp 40
Gp120 Binds to CD4 and a chemokine receptor
B. Cell receptors
There are 2 chemokine receptors that it can bind to
1. CXCR4 on T cells
2. CCR5 on Macrophages and DCs
• Since it binds to both, the cell must have both CD4 and CCR5
• Macrophages and DCs express small levels of CD4, a protein we usually see on T cells, not sure if it is functional
• 12% of caucasians don’t have CCR5!!! Descendants of survivors of the black plague don’t express CCR5
• This is very important because macrophage-tropic virus is sexually transmitted and if you don’t have CCR5 it can't get into your macrophages
C. Tropism
• When a virus gets into your cell and buds off, it takes components from outside of cell with it
• Virus goes in Macrophage, buds off, and takes CD86 and MHC class I and II.
• This virus is now T cell-tropic.
• Virus that buds off the T cell carry with it TCR, CD28, and T cell adhesion molecules.
• This virus is now Macrophage-tropic
• T cell tropic means looking for a T cell; Macrophage tropic means looking for a macrophage
D. Viral Fusion
• After the virus binds to a chemokine receptor and CD4, the second part of the protein (gp 41) gets involved.
• Gp 41 promotes viral fusion.

II. Viral replication
• Virus has everything it needs for replication inside itself
A. Viral components
1. 3 proteins already made in the nucleocapsid core:
• Integrase
• Reverse transcriptase
• Protease
2. Virus has RNA genome
3. Viral process
• Virus enters cell
• Viral transcriptase (called REV – reverse transcriptase) turns RNA into cDNA; Usually RNA from DNA; virus makes cDNA (c-complimentary) from DNA
• After this, integrase integrates the CDNA into host cell genome
• Now it is called a provirus; The provirus will insert into whatever part of the chromosome is unraveled ; Once integrated, it hangs out and doesn’t do anything;
• This is the latent phase; Hangs out till cell gets activated
• When cell gets activated, viral transcription occurs. Virus borrows cells transcription factors from the host
• (mucosal tissue is in a constant state of activation)
4. Viral transcription
• 3 genes (that’s all the virus has)
• Genes called GAG--Structural proteins of viral core
• POL--Enzymes for replication
• ENV--Envelope proteins, GP120 and GP41
• HIV virus makes long chains of these proteins, then chops up the long polypeptides into multiple active proteins
5. Viral Inhibitors
i. Drug being tested that tries to block viral entry (CCR5 inhibitors)
ii. Block reverse transcriptase (Reverse transcriptase inhibitors-
AZT or generic zidovudine)
• Blocks production of provirus
Problems: If virus already integrated this is ineffective
Virus mutates away from this drug with in 4 months
iii. Block protease (Protease inhibitors- Lexiva, Atanzanavir,
Mozenavir, Tipranavir)
Problems: Inhibits human proteases as well
HIV can mutate to avoid protease inhibitors with in 2 days
III. Viral Budding
A. 2 kinds of viruses:
1. Lytic viruses
• Kill the cell they are in. That is how they are released
2. Budding viruses
• Don’t kill cell, instead it buds off.
• The immune response kills the cell
(drawing of budding cell)
• When the virus buds off, it must take all the components it needs
• Integrase, protease, RNA reverse transcriptase
• If the virus doesn’t get all these, it is ineffective
• The body is always making non-productive viruses, but it makes so many productive cells it doesn’t matter
• Any 1 host cell could have as many as 1000 cells budding off of it at a single moment
• The virus also takes some host cell proteins with it and that contributes to tropism
B. Immune Response to budding virus
• Antibody to GP120; if Ab is IgG, Natural Killer Cells, they have Fcγ-3 and ADCC (antibody dependent cellular cytotoxicity) – cell is killed

IV. Immune Response to Extracellular Virus
• Microorganisms (whether they are parasites, bacteria or viruses) have a life cycle and the immune response to them can vary depending on where the organism is in its life cycle.
A. The process
1. Before a virus has affected a cell, the particle is floating in the blood, so they are a target for B cells
2. Viral coat is protein so you will make immune response (antibody response)
3. Macrophages have toll receptors that bind to virus
4. Macrophages make IL-12 and drive a Th 1 response
5. B cells make IgG to GP120 and GP41
6. macrophages eat virus
7. Follicular Dendritic Cells in the Lymph node bind to vial particles
• FDC’s are much longer than regular DC’s
• Not APC’s, they are covered with Fc receptors
• FDCs hold on to viral particles and display them for T cells
• Theory: FDCs keep constant antigen around for memory (T Cell)
• Every so often, it lets go of the antigen, and macs eat it
• Think this is contributing in virus reservoir
• When the follicular cell lets go of Ag, the virus can infect another cell
• Fc receptors on macrophage and DC’s allow for more uptake
• However, controversial whether that virus is infectious because it is an endosome

V. Immune Response to Intracellular virus
• Virus can get into macrophage & DC’s in a couple of ways and each way targets a different Ag processing pathway.
A. Infection
• Viral membrane fuses with cell membrane and dumps contents into the cytosol
• Protein in the cytosol → class I (CD8’s)
B. Fc uptake or Phagocytosis
• When virus is taken up through phagocytosis, virus is now in the exogenous pathway in the lysosome → class II (CD4’s)
• Infection triggers “maturation” or “activation” of DC’s & macrophages so that they now express costimulatory molecules!
Professional APC’s!
• These cells activate CD8 T cells to kill all virally infected cells
C. Response when virus is in CD4 T cells
• Virus infects CD4 T cells – no fc uptake: What does that mean?
• MHC Class I pathway
• Virus infects the cell & hangs out integrated in the DNA until T Cell gets activated
• Virus makes protein – it gets presented in MHC I molecules
• You already have activated effector & memory CD8’s specific for HIV in MHC I
• CD8’s recognize MHC/HIV peptide in CD4’s and kill the infected CD4’s.
*What does that mean in terms of future immune responses?
• Everytime a memory T Cell gets activated, it gets killed -→ lose immunological memory
• Everytime a naïve T Cell gets activated, it gets killed

No CD4s means: No more class switching for B’s
No more activation of macrophages to kill :
IMMUNOCOMPRIMISED!
That’s why it is Acquired Immunodeficiency Syndrome
Not AIDS till you get low CD4


VI. Virus Characteristics
With HIV there is different versions
A. HIV I
B. HIV II
Strains A,B,D,E
No stain C anymore cause so virulent that it killed everyone

VII. Tests for HIV



A. Look for antibody
• First people look for Ab to GP120 and GP41
• Do this by using ELISA test (EIA)
• Bind gp120 to bottom of dish
• Label patient’s blood with Ab with color
• If Ab binds then well turns pink
• Can do this test on paper called Western Blot
• GP120 on paper (nitrocellulose paper) than label Ab and drop blood on protein (usually labeled by florescent marker) and if you lay film there is dark spot then your infected (HOME TEST)
B. PCR test
• Measures virus itself (RNA)
• Provirus integrated in DNA
VIII. Vaccines
A. In development
Think of the issues of testing a vaccine
Multiple Strains; Testing the vaccine; Test positive after having had the vaccine




STRAINS
--HIV-1 and HIV-2 are genetically 30% different from each other
--HIV-1 found worldwide, most common everywhere but WEST Africa
--HIV-2 mainly in west Africa
--HIV-2 has A, B, D, E strains which are 5% different from each other
--C strain victims all died, no cases since sometime in the 1990's
--it is possible to be infected with multiple strains
--SIV shares a close sequence homology with HIV-2
--HIV was initially identified by stimulating T cells with IL-2 and looking at the RNA & DNA

FACTOIDS
--around since the 1930's
--not sure how we got it
--early infections (1980's) occurred mostly among MSM and IV drug users
--new infections in the US are occurring predominantly among African and Latino females 20-35 years of age
--a retrovirus, it has these enzymes in the virion: reverse transcriptase, integrase and protease
--33.2 million people were infected in 2007
--2.5 million new infections in 2007
--2.1 million people died of aids in 2007
--the number of HIV infected people (that we know of) increased by 400,000 in 2007
--HIV is in the Lentivirus subgroup of Retroviruses, causes "slow" infx with long incubation
--HIV is the most complex of all retroviruses: in addition to teh three typical genes (gag, pol, env) it has 6 regulatory genes (tat, rev, nef, vif, vpr, vpu)
--recommended reading: My Own Country, by a US HIV specialist in the 1980's

TRANSMISSION
--sex (infected lymphocytes in semen contact mucosa, mucosa incl vagina, anus & colon have macrophages, DC's, langerhans cells)
--blood transfusions (whole blood, not plasma, HIV contacts macrophages/DC's in spleen)
--IV drugs
--breast milk? placenta?
--birth
--NO oral trans because lysozyme in saliva kills HIV
--coinfections that greatly increase HIV transmission: syphilis (Treponema pallidum), herpes simplex (HSV-1 and 2), chancroid (Heomophilus ducreyi) and gonorrhea (Neisseria gonorrhoeae)

A STORY: A French Canadian flight attendant travelled around the world and had many MSM lovers. He was HIV positive and spread the infection far and wide. Someone found him and explained to him that he was "patient zero" and causing an explosion of the virus. Apparently he continued the promiscuous behavior for a while but eventually thought better of it and stopped. There's a movie about him: And the Band Played On.

VIRUS STRUCTURE
--RNA dimer inside, and 3 enzymes
--nucleocapsid is cylindrical, made of p7 & p24 from gag gene
--p24 can be measured in serum to detect early infection
--contains +RNA ready for reverse transcription into vDNA
--envelope is spherical and sensitive, can be killed by anything acidic, peanut butter
--protein spikes stick out from envelope
--spikes made of gp160 = shorthand for gp40 (41, 46, stem) plus gp120 (protein blob on tip of spike) (gp = glycoprotein)
--spikes are proteins that mediate viral entry
--gp120 binds CD4 and CCR5, a chemokine receptor
--(CD4 T cells are helper T cells, but other cells incl monocytes, macrophages & DCs also may have CD4)
--chemokine receptors that HIV binds are 2 kinds
----CXCR4 on T cells and some macrophages
----CCR5 on macrophages & DCs)
--GP46 or 41 or 40 induces fusion of membranes (40 has least sugar, 46 has most)
--HIV needs to receptors to bind before it can fuse

VIRAL INVASION
--gp41 promotes viral fusion
--REV = reverse transcriptase turns viral RNA into cDNA (c-complimentary)
--cDNA is integrated into host cell genome, now it is a PROVIRUS
--provirus inserts into whatever part of chromosome is unravelled
--once integrated it hangs out and does nothing: latent
--when cell is activated, viral transcription occurs, using host transcription factors
--mucosal tissue is in a constant state of activation

VIRAL INVASION 2
--1st viral contact is usually with macrophages or DC's in skin/mucosa, virus sees CD4 + second signal, can bind & invade
--only 5% of macrophages have CD4 so this is a slow process, perhaps only one cell for initial contact
--macrophages and DC's have CCR5 a chemokine receptor which is the second signal
--in order to cause an active infection the HIV must infect a macrophage or DC first,
--bubonic plague survivor populations don't have CCR5 and cannot be infected with HIV (small population of Europeans)
--GP120 binds CD4 and CCR5
--CP40 triggers fusion with host membrane (uncoating)
--enzymes and RNA are ejected into host cytoplasm
--reverse transcriptase converts +RNA to DNA "provirus" with linkers on end (integrase) that allow it to insert into host genome
--once in the host genome the viral DNA only makes protein if the host makes protein
--HIV only integrates in host DNA when it is accessible: unwound and less methylated
--teen DNA is more methylated? does this confer some resistance to HIV??
--HIV gets into the genes that are being used at the moment it tries to integrate, often gets into T cell cytokine genes because they're active

VIRAL TRANSCRIPTION
--only three genes to make 13 proteins (unique): pol, env and gag
--long proteins chopped into functional units by a protease brought by the virus
TYPICAL RETROVIRUS GENES
--pol --> 5? replication enzymes (3 essential: REV, protease, integrase)
--env --> 2? envelope proteins (GP120 binds CD4 and GP40 induces fusion)
--gag --> 6? structural proteins, viral core (p24 and p7 for nucleocapsid, p17 for matrix)
--these three genes contain all of the viral info, are chopped up into multiple functional proteins

REGULATOR GENES NEEEDE FOR REPLICATION
--tat --> activates transcription of viral genes (works with nef, too)
--rev --> transport late mRNA's from nucleus to cytoplasm
ACCESSORY GENES (make HIV special: extra sneaky)
--nef --> decreases expression of CD4 and MHC-1 proteins in infected cells (hides and induces cell death of CD8 cells that can't find a second signal)
--vif --> inhibits APOBEC3G enzyme from host that causes hypermutation of invader, thus enhances infectivity by protecting itself from host enzyme
--vpr --> transporter for viral core to get into nucleus
--vpu --> enhances virion release from cell (boosts budding)

VIRAL TROPISM
--HIV propagates by budding off from host cells and taking a piece of membrane (enveloped)
--tropism (attraction) determined by proteins on coat (envelope)
--gets proteins on coat from whatever cell it stole membrane from, which will include the proteins manufactured from viral and host DNA
--if HIV buds from a macrophage it will have MHC-I, MHC-II, CD86 etc---> "T cell tropic"
--if HIV buds from a T cell it will have CD28, TCR, CD4, etc---> "macrophage tropic"
--this explains why HIV alternates between infecting T cells and macrophages
--feline leukemia is not tropic to human cells because it doesn't have the right proteins to activate binding
--attenuation of virus involves forcing it to infect a cell it isn't attracted to: chicken eggs for flu virus vaccine

LATENCY
--when viral DNA is in host genome: stimulate the host-->virus manufactures structural components and more RNA
--example: HIV infects a T cell specific for ragweed-->host makes HIV every spring
--host cell stays inactive-->virus is LATENT
--example: HIV infects a T cell specific for E. bola, host never encounters E. bola and HIV DNA is never read
--latency happens when virus is in T cells and host is not immunologically challenged, so the T cells are not activated
--latency is shorter in Africa due to more infections harder to avoid
--in the US people can stay in latency for many years by avoiding activation of T cells

IMMUNE RESPONSE
--three stages: extracellular (antibody response), intracellular (endocytic) and intracellular (infection)
--HIV must infect macrophage or DC first to have ACTIVE infection, can't activate CD8 T cell without costimulatory molecule (CD86) and CD4 cells don't have CD86 but macrophages do. If an infected CD4 cell presents HIV in MHC-1, it doesn't have CD86 so if a CD8 cell binds it does not get the mandatory second signal and undergoes ANERGY. So need macrophage presenting HIV to get CD8 response, and CD8 response is our best defense against HIV. So I guess "active" infection means with CD8 response???
--when a CD8 cell kills an infected CD4 cell with HIV in MHC-1, it is NOT an autoimmune response (even though it is a self cell killing a self cell) because it is not self antigen
--natural killer cells have Fc gamma receptors, can bind Ab's on infected cells, shoot perforin and granzymes to poke holes & digest infected cell, NK's increased by ashwaganda, happy thoughts, shamanic drumming
--we make antibodies to gp120, if Ab is IgG, NATURAL KILLER cells have Fcgamma-3 and ADCC (antibody dependent cellular cytotoxicity) so they KILL the cell that is budding virus
--macrophages can't kill infected cells, they can only eat opsinized things or dead things after the membrane has flipped
--MAST cells also have FcR gamme but can't respond to human cells
--initial infection, CD4 count dives then recovers as CD8 cells kick in
--when both CD4 and CD8 cells decline--->AIDS
--immune memory is lost at this stage, can be reinfected with things to which one was previously immune
--when CD4 count is under 200, or when certain opportunist infections take hold, Dx: AIDS

ZWICKEY VERSION OF THREE STAGES
STAGE 1: Antibody response to EXTRACELLULAR virus
--immune response to any invader may vary depending on where organism is in its life cycle
--before a virus has affected a cell it is floating in the blood and is a target for B cells
--B cells make antibodies to proteins in viral coat
--seroconversion = the change of a patient's serologic test results from negative to positive, indicating development of antibodies in response to infection or immunization
--macrophages have TLR's that bind to the virus
--macrophages make IL-12 and drive a Th1 response
--B cells make IgG to gp120 and gp41
--macrophage eats virus
--follicular dendritic cells in LN bind viral particles
--extracellular virus can be bound by antibodies, with three effects
--1) Ab binding covers viral GP120 so it can't bind to T cells and induce fusion
--2) Ab binding also opsinizes, so macrophages will phagocytize virus & present it in MHC-2 (this is stage 2)
--3) Ab's activate the compliment cascade
--problem Ab response: GP120 is highly mutatable, so as soon as we mount an Ab response, it changes
--somatic hypermutation (our B cells attempt to change the Ab to keep up with antigen change) isn't fast enough
--there is no T cell response so B cells will make IgM
STAGE 2: Fc UPTAKE or PHAGOCYTOSIS of virus
--when a virus is taken up through phagocytosis, the virus is in the exogenous pathway in teh lysosome --> MHC-2 --> CD4 response
--infection triggers "maturation" or "activation" of DC's and macrophages so that they now express costimulatory molecules and are acting as professional APC's ==> activate CD8 cells to kill all virally infected cells
--phagocytosis of HIV and presentation in MHC-2 (Ii invariant chain keeps MHC-2 from binding other protein in ER, it gets the HIV protein inside the phagolysosome)
--T cell (with CD4, HIV specific) recognizes, binds, divides, makes Th1 cytokines (IFNgamma, TNFalpha, IL2, GM-CSF) --> B cell class switches to IgG (usual response time to an antigen is about 2 weeks but HIV can take 6 months), more on IgG effects below
STAGE 3: INFECTION of macrophages, B & T cells
--viral membrane fuses with cell membrane, dumps contents in cytosol --> MHC-1 --> CD8 response
--HIV can directly infect 5% of macrophages because they can have CCR5 and 5% have CD4
--"low frequency event" "takes a while"
--HIV gets into cytoplasm by inducing membrane fusion, invades nucleus, macrophage makes viral proteins which get ubiquinated (marked as trash) then degraded in a proteasome, transported via TAP into ER lumen, installed in MHC-1 and presented --> travel to lymph node, continues to bud off HIV --> activate CD8 T cell specific to HIV
--if sexually transmitted the lymph node involved is often inguinal sometimes mesenteric
--HIV rarely latent in macrophage or DC because they are very active all the time
--there will be lots of MHC-1 with virus on an infected macrophage
--RESPONSE WHEN VIRUS IS IN CD4 T CELLS: no Fc uptake ???, MHC-1 pathway, no costim, so when a CD8 cell recognizes the virus being presented in MHC-1 there is no second signal and it undergoes ANERGY which causes a LOSS OF IMMUNOLOGICAL MEMORY (every time a naive T cell gets activated, it gets killed) --> No CD4's means no more class switching for B cells, no more activation of macrophages to kill, IMMUNOCOMPROMISED!!! Not AIDS until low CD4.

IgG EFFECTS: FOLLICULAR DENDRITIC CELLS
--longer than regular DC's
--not APC's, they don't have MHC-2
--fDC's hold onto viral particles and display them for T cells
--When Th1 response makes B cells switch to IgG, follicular DC's come into play
--possible function of fDC's in immune response: maintain immune MEMORY
--fDC's are not related to DC's, not from macrophages
--fDC's are named thusly because they have long dendrites
--they are not phagocytic
--they are covered in many FcR gamma, that is receptors for IgG
--bind & release
--sometimes lets go of viral particle, macrophage can EAT it-->new infx??
--Zwickey says controversial if this causes infx because virus is in endosome???? How?
--the IgG's can be bound to HIV virus
--thus fDC's serve as a reservoir of HIV: a person can test negatively for both antibodies and viral load, and still have recurrent infection
--stress kills fDC's, and when they die we lose all lymph node structure
--in mice, increased CRH --> increased cortisol --> kills fDC's

BONNAH VERSION OF THREE STAGES
--early acute stage: 2-4 weeks after infection, 87% report mono-like infx with fever, lethargy, sore throat, generalized lymphadenopathy, 13% have no early acute symptoms. May also see maculopapuular rash on trunk, arms, legs. Leukopenia occurs (he says CD4 count is normal, I think he's wrong, so I wonder which WBC's he means?) Person can transmit infx. Ab's appear 10-14 days after infx ("seroconversion"), this stage ends when CD8 cells increase.
--middle latent cells
--late immunodeficient stage (CD4 and CD8 cells in decline)

DIAGNOSIS
--testing for Ab's
--first check for anti-gp120 and anti-gp41, using ELISA test (EIA)
----bind gp120 to bottom of dish, label pt's blood w/ Ab w/ color, if Ab binds then well turns pink, can do this test on paper called Western Blot, GP120 on paper (nitrocellulose paper) then label Ab and drop blood on protein (usually labeled by flourescent marker) and if you lay film there is dark spot then you're infected (HOME TEST)
--PCR TEST: measures virus itself (RNA) or provirus integrated in DNA
--both CD4 and CD8 cells decline--->AIDS
--allergies gone
--CD4 count under 200
--opportunist infections

OPPORTUNIST RUNDOWN
--Lungs: pneumo & TB due to Pneumocystis carinii, HCMV, Mycobacterium tuberculosis
--Mouth & Esophagus: thrush, hairy leukoplakia, ulcers, esophagitis due to Candida albicans, Epstein Barr Virus, HSV-1, Histoplasma capsulatum, HCMV
--Intestines: diarrhea due to HCMV, Salmonella, Shigella, Cryptosporidium parvum, Giardia lamblia
--CNS: meningitis (Crytosporidium neoformans), brain abscesses (Toxoplasma gondii), progressive multifocal leukoencephalopathy (JC virus)
--Eye: retinities (HCMV)
--Skin: karposi's sarcoma (HHV8), Zoster (Varicella-zoster virus), Subcu nodules (Cryptococcus again)
--Reticuloendothelial sys: lymphadenopathy or splenomegaly due to Mycobacterium avium complex and/or EBV

TREATMENTS/DEFENSES
--our native CD8 "killer" T cells kill infected CD4's
--the infection HAS BEEN CLEARED by some individuals
--note: as CD4 cell population decreases, allergies go away
--other things that decrease CD4 numbers: stress, diet, radiation
--Saint John's wort --> downregulates chemokine receptors-->reduced fusion, reduced replication, also increased photosensitivity, increased detox pathways --> decrease drug effects (can't mix StJW w/ triple drug cocktail)
TRIPLE DRUG COCKTAIL: ADT and two protease inhibitors
--cost: $1140/mo wholesale in US
--have to keep rotating drugs to keep HIV busy
--manufacturers claim it extends lifespan up to 20 years, this is debatable
AZT = reverse transcriptase inhibitor
--blocking reverse transcriptase blocks the production of the provirus but if virus is already integrated this is ineffective (must use early in infx)
--inhibits HTERT --> won't get cancer
--takes 1-3 (Bonnah) 4 (Zwickey) months for HIV to evolve away from this drug
--kills host stem cells too
--other reverse transcriptase inhibitors: ZDV aka Zidovudine, Retrovir, Didanosine
PROTEASE INHIBITORS
--lexiva, atanzanavir, mozenavir, tipranavir (I am not going to capitalize prescription brand names anymore, but you may notice I have started capitalizing Christian again)
--problem: inhibits human proteases as well (junk proteins accumulate in cells)
--HIV can mutate in 2 days to circumvent protease inhibitor, that's why we give 2 at a time, slows it down
--it takes only a single amino acid substitution to avoid protease inhibitor
--decrease host ability to fight infections
--proteases are usually contained in lysosomes
HAART = Highly Active Anti-Retroviral Therapy (not explained but in Bonnah notes)
--inhibit proviral synthesis (inhibit reverse transcriptase)
--nucleoside & non-nucleoside inhibitors
--protease inhibitors

TREATMENT FAILURES
--drugs to block CCR5 (stop viral entry) don't work
--fusion inhibitors haven't worked yet

VACCINES
--vaccines not effective so far, need live virus in vaccine to get CD8 response and nobody wants to take it
--multiple strains
--would test positive after having vaccine

THOSE WHO ASSERT THAT HIV DOES NOT CAUSE AIDS USE THESE ARGUMENTS
--other things cause immune deficiency
--long time lag weakens psychological link
--never proven by Koch's postulates (this is in fact false, though no one volunteered to be innoculated with the virus there have been enough accidental innoculations to study)
--Peter Duesberg at Berkeley is main scientist asserting this: http://www.duesberg.com/

THE BAD NEWS
--This virus will never go away unless everyone who is infected dies.

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