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AIDS and OtherAIDS and Other
ImmunodeficienciesImmunodeficienciesBy: Luz Arboleda, Sameer Jain, andBy: Luz Arboleda, Sameer Jain, and
Ranoo Patel.Ranoo Patel.
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OverviewOverview
I.I. ImmunodeficiencyImmunodeficiencyII.II. PrimaryImmunodeficiencyPrimaryImmunodeficiency
III.III. SecondaryImmunodeficiencySecondaryImmunodeficiency
IV.
IV. AIDSAIDS
i.i. Discovery of AIDSDiscovery of AIDS
ii.ii. Origin of AIDS VirusOrigin of AIDS Virus
iii.iii. Epidemiology & StatisticsEpidemiology & Statistics
iv. HIViv. HIV--11
v. Transmission of HIVv. Transmission of HIV--11
vi. Treatment of HIV/AIDSvi. Treatment of HIV/AIDS
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IntroductionIntroduction
The immune system is subject to failure ofThe immune system is subject to failure of
some or all of its parts.some or all of its parts.
If the system is not able to protect the hostIf the system is not able to protect the host
from diseasefrom disease--causing agents or from malignantcausing agents or from malignant
cells, ancells, an immunodeficiencyimmunodeficiency results.results.
There are two types of immunodeficiency:There are two types of immunodeficiency:PrimaryPrimaryandand secondarysecondaryor acquired.or acquired.
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Primary ImmunodeficienciesPrimary Immunodeficiencies
PrimaryImmunodeficiencies may affect eitherPrimaryImmunodeficiencies may affect either
adaptiveadaptive ((T or B cellsT or B cells) or) or innateinnate ((macrophages or complementmacrophages or complement))
immune functions, which enables us to categorizeimmune functions, which enables us to categorize
them according to the type of developmental stagethem according to the type of developmental stage
of the cells involved.of the cells involved.
So, lymphoid cell disorders may affect T cells, BSo, lymphoid cell disorders may affect T cells, B
cells, or, in combined immunodeficiencies, both Bcells, or, in combined immunodeficiencies, both B
and T cells. Myeloid cell disorders affect phagocyticand T cells. Myeloid cell disorders affect phagocytic
function.function.
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Cellular Development in the Immune SystemCellular Development in the Immune System
Figure 19-1
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Defects in the lymphoid lineageDefects in the lymphoid lineage
May involve B cells, T cells, or both of theseMay involve B cells, T cells, or both of these
Lineages. BLineages. B--cell immunodeficiency disorderscell immunodeficiency disorders
cause recurrent bacterial infections. Tcause recurrent bacterial infections. T--cellcell
deficiency though, can affect both humoral anddeficiency though, can affect both humoral andcellcell--mediated responses.mediated responses.
SCID:SCID: Severe Combined ImmunodeficiencySevere Combined Immunodeficiency
WAS:WAS: WiskottWiskott --Aldrich syndromeAldrich syndrome
InterferonInterferon--GammaGamma--Receptor DefectReceptor Defect
XX--Linked AgammaglobulinemiaLinked Agammaglobulinemia
XX--Linked HyperLinked Hyper--IgM SyndromeIgM Syndrome
CVI:CVI: Common Variable ImmunodeficiencyCommon Variable Immunodeficiency
Ataxia TelangiectasiaAtaxia Telangiectasia
Immune Disorders Involving the ThymusImmune Disorders Involving the Thymus
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Interaction Between T and B CellsInteraction Between T and B Cells
Defects in cellDefects in cell
interaction and signalinginteraction and signaling
can lead to severecan lead to severe
immunodeficiency.immunodeficiency.
A number of primaryA number of primary
immunodeficiencies areimmunodeficiencies are
rooted in defects inrooted in defects inthese interactions.these interactions.
SCID is an example.SCID is an example.Figure 19-3
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Defects in the myeloid lineageDefects in the myeloid lineage
Defects affect the innate immune functions. MostDefects affect the innate immune functions. Most
of them result in impaired phagocytic processesof them result in impaired phagocytic processes
that are manifested by recurrent microbial infectionthat are manifested by recurrent microbial infection
of greater or lesser severity.of greater or lesser severity.
Reduction in Neutrophil CountReduction in Neutrophil Count
CGD:CGD: Chronic Granulomatous DiseaseChronic Granulomatous Disease
ChediakChediak--Higashi SyndromeHigashi Syndrome
LAD:LAD: Leukocyte Adhesion DeficiencyLeukocyte Adhesion Deficiency
Defects in the Complement LineageDefects in the Complement LineageMany complement deficiencies are associated withMany complement deficiencies are associated with
increased susceptibility to bacterial infectionsincreased susceptibility to bacterial infections
and/
or immuneand/
or immune--complex diseases.complex diseases.
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Treatment of ImmunodeficiencyTreatment of Immunodeficiency
Although there are no cures for immunodeficiencyAlthough there are no cures for immunodeficiency
disorders, there are various treatment possibilities.disorders, there are various treatment possibilities.
In addition to complete isolation from exposure toIn addition to complete isolation from exposure toany microbial agent, treatment options for theany microbial agent, treatment options for the
immunodeficiencies include:immunodeficiencies include:
1) Replacement of a missing protein1) Replacement of a missing protein2) Replacement of a missing cell type or lineage2) Replacement of a missing cell type or lineage
3) Replacement of a missing or defective gene3) Replacement of a missing or defective gene
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Secondary ImmunodeficienciesSecondary Immunodeficiencies
Loss of immune function that results from exposure toLoss of immune function that results from exposure tovarious agents.various agents.
Acquired HypogammaglobulinemiaAcquired Hypogammaglobulinemia
Recurrent infection that manifests itself in young adults.Recurrent infection that manifests itself in young adults.
There are usually very low levels of totalThere are usually very low levels of totalimmunoglobulin, though Timmunoglobulin, though T--cell numbers and functioncell numbers and functionmay be normal. It is treated with gammaglobulinmay be normal. It is treated with gammaglobulintherapy.therapy.
AgentAgent--Induced ImmunodeficiencyInduced ImmunodeficiencyResults from exposure to any of a number of chemicalResults from exposure to any of a number of chemicaland biological agents that induce an immunodeficientand biological agents that induce an immunodeficientstate.state.
AIDS:AIDS: Acquired Immunodeficiency SyndromeAcquired Immunodeficiency Syndrome
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Discovery of AIDSDiscovery of AIDS
AIDS was first reported in the United States in 1981 inAIDS was first reported in the United States in 1981 inLos Angeles, New York, and San Francisco.Los Angeles, New York, and San Francisco.
The first patients displayed unusual infections byThe first patients displayed unusual infections byopportunistic agentsopportunistic agents, such as, such as Pneumocystis cariniiPneumocystis carinii,,which causes PCP orwhich causes PCP or P. cariniiP. cariniipneumonia, as well aspneumonia, as well asother rare opportunistic infections.other rare opportunistic infections.
Opportunistic agentsOpportunistic agents are microorganisms that healthyare microorganisms that healthyindividuals can harbor with no ill consequences but thatindividuals can harbor with no ill consequences but that
cause disease in those with impaired immune function.cause disease in those with impaired immune function. They also displayedThey also displayed KaposisKaposis sarcomasarcomaan extremelyan extremely
rare skin tumor.rare skin tumor.
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Origin of AIDS VirusOrigin of AIDS Virus
Within a few years after recognition of AIDS, the causative agent wasWithin a few years after recognition of AIDS, the causative agent wasdiscovered to be adiscovered to be a retrovirusretrovirus..
Only one other human retrovirus has been described before HIV, theOnly one other human retrovirus has been described before HIV, thehuman Thuman T--lymphotropic virus I or HTLVlymphotropic virus I or HTLV--I.I.
There is also another human virus known asThere is also another human virus known as HIVHIV--22, which is less, which is lesspathogenic than HIVpathogenic than HIV--1. It infects nonhuman primates that are not1. It infects nonhuman primates that are not
infected by HIVinfected by HIV--1.1. Viruses related to HIVViruses related to HIV--1 have been found in nonhuman privates1 have been found in nonhuman privatessuch assuch as
SIV: Simian immunodeficiency virus. Other animal retroviruses are theSIV: Simian immunodeficiency virus. Other animal retroviruses are thefelinefeline andand bovine immunodeficiency virusesbovine immunodeficiency viruses and theand the mouse leukemiamouse leukemia
virus.virus. These dont yield information pertinent to HIVThese dont yield information pertinent to HIV--1. Only the1. Only thestudies made on chimpanzees when infected with HIVstudies made on chimpanzees when infected with HIV--1 can be useful;1 can be useful;
but they rarely develop AIDS.but they rarely develop AIDS. Why isnt there a suitable host to study HIVWhy isnt there a suitable host to study HIV--1?1?
a)a) Lack of cellLack of cell--surface receptors required for entry of virus into host.surface receptors required for entry of virus into host.
b)b) Dependence of HIVon hostDependence of HIVon host--cell factors for early events in thecell factors for early events in the
replication process, such as transcription and splicing of viral messages.replication process, such as transcription and splicing of viral messages.
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Epidemiology & StatisticsEpidemiology & Statistics
Since its discovery in 1981, AIDS has increased toSince its discovery in 1981, AIDS has increased to
epidemic proportions.epidemic proportions.
According to the National Centers for Disease ControlAccording to the National Centers for Disease Control
and Prevention (CDC),and Prevention (CDC), 42 million42 million people are estimatedpeople are estimated
to be living with HIV/AIDS. Of these,to be living with HIV/AIDS. Of these, 38.6 million38.6 million
are adults,are adults, 19.2 million19.2 million are women, andare women, and 3.2 million3.2 million areare
children under 15.children under 15.
An estimatedAn estimated 5 million5 million people acquired the humanpeople acquired the human
immunodeficiency virus (HIV) in 2002, includingimmunodeficiency virus (HIV) in 2002, including22
millionmillionwomen andwomen and 800,000800,000 children under 15.children under 15.
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Epidemiology & StatisticsEpidemiology & Statistics
During 2002, AIDS caused the deaths of an estimatedDuring 2002, AIDS caused the deaths of an estimated3.1 million3.1 million people, includingpeople, including1.2 million1.2 millionwomen andwomen and610,000610,000 children under 15.children under 15.
Women are becoming increasingly affected by HIV.Women are becoming increasingly affected by HIV.ApproximatelyApproximately50%50%, or, or 19.2 million19.2 million, of the, of the 38.638.6millionmillion adults living with HIVor AIDS worldwide areadults living with HIVor AIDS worldwide arewomen. Compared to accounting for onlywomen. Compared to accounting for only6%6% of theof the
total cases in 1985.total cases in 1985. The UN predicts that by 2010, more thanThe UN predicts that by 2010, more than 25 million25 million
children will have lost at least one parent to AIDS.children will have lost at least one parent to AIDS.
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Global Estimates of HIV/AIDSGlobal Estimates of HIV/AIDS
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HIVHIV--1 Virus1 Virus
The virus that causes AIDSThe virus that causes AIDS
It is a retrovirus with two copiesIt is a retrovirus with two copies
of single stranded RNA genomeof single stranded RNA genome
It usesIt uses reverse transcriptasereverse transcriptase tototransform its sstransform its ss--RNA genomeRNA genome
into a dsinto a ds--DNA for integrationDNA for integration
into its host genomeinto its host genome
It has marker proteins (gp120)It has marker proteins (gp120)
in the protein coat that allow itin the protein coat that allow it
to recognize specific cells in theto recognize specific cells in the
human bodyhuman body
The protein coat also containsThe protein coat also contains
MHCMHC--I and MHCI and MHC--II moleculesII molecules
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HIVgenomeHIVgenome
gag gene codes for nucleocapsid proteinsgag gene codes for nucleocapsid proteins
env gene codes for envelope glycoproteins, i.e. gp41env gene codes for envelope glycoproteins, i.e. gp41(transmembrane protein) and gp120 (surface protein)(transmembrane protein) and gp120 (surface protein)
pol gene codes for enzymes such as reverse transcriptase,pol gene codes for enzymes such as reverse transcriptase,
protease and integraseprotease and integrase
Other genes code for various activators and accessory proteinsOther genes code for various activators and accessory proteins
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Complete Activation of HIVComplete Activation of HIV
While CD4 is recognized by the virus, it is not sufficient for viral attack; itWhile CD4 is recognized by the virus, it is not sufficient for viral attack; itneeds a costimulatory signal.needs a costimulatory signal.
T cells: coreceptor is CXCR4, which also acts as a receptor for the chemokineT cells: coreceptor is CXCR4, which also acts as a receptor for the chemokineSDFSDF--1; there is competitive inhibition between chemokine and HIVfor1; there is competitive inhibition between chemokine and HIVforbinding; the HIVstrain is called Tbinding; the HIVstrain is called T--tropictropic
Monocytes: coreceptor is CCR5, which is a receptor for chemokines, whichMonocytes: coreceptor is CCR5, which is a receptor for chemokines, whichalso act as competitive inhibitors to HIV; the HIVstrain is called Malso act as competitive inhibitors to HIV; the HIVstrain is called M--tropictropic
TT--tropic HIVstrains cause syncytia: formation of giant cells as a result oftropic HIVstrains cause syncytia: formation of giant cells as a result of
fusion of cells via the gp120 protein on viral coats.fusion of cells via the gp120 protein on viral coats.
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Infection of Human Cell with HIVInfection of Human Cell with HIV
HIVgp120 surface protein bindsHIVgp120 surface protein bindsCD4 on target cellCD4 on target cell
Transmembrane component, gp41,Transmembrane component, gp41,binds coreceptor CXCR4 tobinds coreceptor CXCR4 toenhance fusionenhance fusion
Viral genome and other proteins areViral genome and other proteins areable to enter the cell viaable to enter the cell vianucleocapsidnucleocapsid
RT transcribes the ssRNA genomeRT transcribes the ssRNA genome
The next DNA strand is made,The next DNA strand is made,
making a double strandedD
NAmaking a double strandedD
NAmolecule called a provirusmolecule called a provirus
The dsDNA is transferred to theThe dsDNA is transferred to thenucleus to be added to the hostnucleus to be added to the hostgenome via the viral integrasegenome via the viral integraseprotein at HIVLTR sitesprotein at HIVLTR sites
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HIVInfected THIVInfected T--CellCell
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Overview ofOverview of
InfectionInfection The viral load is kept at a steady state; halfThe viral load is kept at a steady state; half
life for infected cells is roughly1.5 dayslife for infected cells is roughly1.5 days
In addition to these lytic cells, there areIn addition to these lytic cells, there are
small numbers of latent cells that cansmall numbers of latent cells that can
persist for long periods of timepersist for long periods of time Diagnosis for AIDS includes finding theDiagnosis for AIDS includes finding the
HIVvirus in the patient,
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Testing for HIVTesting for HIV EnzymeEnzyme--linked immunosorbent assay (ELISA).linked immunosorbent assay (ELISA).ThisThis
screening test is usually the first test used to detect infection withscreening test is usually the first test used to detect infection withHIV. If antibodies to HIVare present (positive result), the test isHIV. If antibodies to HIVare present (positive result), the test isusually repeated.usually repeated.
Western blot.Western blot.This test requires high technical skills. It is moreThis test requires high technical skills. It is moredifficult than the ELISA to perform and interpret accurately, butdifficult than the ELISA to perform and interpret accurately, butit is less likely to give a falseit is less likely to give a false--positive result because it canpositive result because it candistinguish HIVantibodies from other antibodies that may reactdistinguish HIVantibodies from other antibodies that may reactto the ELISA. A Western blot is usually done to confirm theto the ELISA. A Western blot is usually done to confirm theresults of two positive ELISA tests.results of two positive ELISA tests.
Indirect fluorescent antibody (IFA).Indirect fluorescent antibody (IFA).This test also detectsThis test also detectsantibodies made to fight an HIV infection. Like a Western blotantibodies made to fight an HIV infection. Like a Western blot
test, it is used to confirm the results of an ELISA.test, it is used to confirm the results of an ELISA. Polymerase Chain ReactionPolymerase Chain Reaction (PCR).(PCR).This test detects the RNAThis test detects the RNA
of HIV, rather than detecting antibodies to HIV. Therefore,of HIV, rather than detecting antibodies to HIV. Therefore,PCR can reveal an HIV infection before antibodies can bePCR can reveal an HIV infection before antibodies can bedetected. PCR can also accurately determine whether a babydetected. PCR can also accurately determine whether a babyborn to an infected mother has HIV.born to an infected mother has HIV.
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Immunological problems associatedImmunological problems associated
with HIV infectionwith HIV infection
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Other Immune EvasionsOther Immune Evasions
Mechanisms of HIVMechanisms of HIV TTCC cells are able to generate a response for years until finally theycells are able to generate a response for years until finally they
are no longer effective against HIVare no longer effective against HIV The HIVpeptides that act as epitopes to the MHC I molecules mutate atThe HIVpeptides that act as epitopes to the MHC I molecules mutate at
a high rate and the Ta high rate and the TCC cells are not able to keep upcells are not able to keep up
Some HLA haplotypes are more susceptible to HIVattack thanSome HLA haplotypes are more susceptible to HIVattack than
othersothers HIVgene products have functions in addition to viralHIVgene products have functions in addition to viral
replication functions; some are able to down regulate host cellreplication functions; some are able to down regulate host cellMHCMHC--I expression so fewer peptides are presented to theI expression so fewer peptides are presented to thedefense mechanismsdefense mechanisms Tat represses transcription of MHCTat represses transcription of MHC--II
Vpu keeps MHCVpu keeps MHC--I molecules from leaving the endoplasmic reticulumI molecules from leaving the endoplasmic reticulum
Nef selectively internalizes some MHCNef selectively internalizes some MHC--I molecules from the plasmaI molecules from the plasmamembrane, so that the cells have fewer MHC molecules in total. It leavesmembrane, so that the cells have fewer MHC molecules in total. It leavesthe MHCthe MHC--I molecules that will help prevent lysis by NK cells.I molecules that will help prevent lysis by NK cells.
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3 Points In HIVCell Cycle Where Replication Can be Stopped3 Points In HIVCell Cycle Where Replication Can be Stopped Nucleoside Reverse Transcriptase Inhibitors (NRTIs)Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
NonNon--Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Protease InhibitorsProtease Inhibitors
All 3 of these treatments are usually prescribed at once. Known as HAART, theAll 3 of these treatments are usually prescribed at once. Known as HAART, the
combination of all 3 fights the ability of the virus to rapidly mutate.combination of all 3 fights the ability of the virus to rapidly mutate.
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Reverse Transcriptase InhibitorsReverse Transcriptase Inhibitors
Reverse Transcriptase Inhibitors interfere with theReverse Transcriptase Inhibitors interfere with thereverse transcriptase (RT) enzyme that HIVneeds toreverse transcriptase (RT) enzyme that HIVneeds tomake copies of itself. There are 2 types of inhibitorsmake copies of itself. There are 2 types of inhibitors
each working differently.each working differently.Type 1:Type 1: NRTIsNRTIs nucleoside drugs provide faultyDNAnucleoside drugs provide faultyDNA
building blocks, stopping the DNA chain the virus uses to makebuilding blocks, stopping the DNA chain the virus uses to makecopies of itself.copies of itself.
Type 2:Type 2: NNRTIsNNRTIs-- nonnon--nucleoside RT inhibitors bind RTnucleoside RT inhibitors bind RTso the virus cannot carry out its copying functionso the virus cannot carry out its copying function
Examples Include: AZT, 3TC, Combivir, NevirapineExamples Include: AZT, 3TC, Combivir, Nevirapine
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Protease InhibitorsProtease Inhibitors
Protease InhibitorsProtease Inhibitors (PI), discovered in 1995, block the(PI), discovered in 1995, block theprotease enzyme. When protease is blocked, HIVprotease enzyme. When protease is blocked, HIVmakes copies of itself that cant infect new cells.makes copies of itself that cant infect new cells.
PI Side EffectsPI Side Effects: PIs can cause high blood sugar and: PIs can cause high blood sugar andconsequently diabetes. Another main concern isconsequently diabetes. Another main concern islipodystrophy, where your body absorbs fats andlipodystrophy, where your body absorbs fats and
nutrients in an irregular manner. Latent HIVcan hidenutrients in an irregular manner. Latent HIVcan hideout in these fat cells.out in these fat cells.
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Death rateDeath rate
Death rates per 100,000 population from leading causes of death
among persons 2544 years old, United States, 19872000
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What does the future hold?What does the future hold?
Scientists are working on more potent protease inhibitors,Scientists are working on more potent protease inhibitors,
less toxic RT inhibitors, as well as 2 new classes of drugs:less toxic RT inhibitors, as well as 2 new classes of drugs:
**Fusion InhibitorsFusion Inhibitors-- Drugs which act to block HIVDrugs which act to block HIV
before it enters the human immune cell. This class of drugsbefore it enters the human immune cell. This class of drugsworks to stop HIVreplication at an earlier stage.works to stop HIVreplication at an earlier stage.
**Integrase InhibitorsIntegrase Inhibitors--Aim to block the integrationAim to block the integrationof the viruss DNA into the cells chromosome. 2 differentof the viruss DNA into the cells chromosome. 2 different
integrase inhibitors are currently in human trials.integrase inhibitors are currently in human trials.
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Can HIVbe Vaccinated Against?Can HIVbe Vaccinated Against?
ChallengesChallenges--HIVthrives in the presence ofHIVthrives in the presence of
circulating antibodies directedcirculating antibodies directed
against it.against it.
-- HIV integrates itself into the host genomeHIV integrates itself into the host genomeand may stay dormant for years. All retroviruses prove difficult toand may stay dormant for years. All retroviruses prove difficult toremoveremove
--HIVmutates and can show up to 10HIVmutates and can show up to 1099virusesvirusesper day, while the common cold with 100 subtypes has proven toper day, while the common cold with 100 subtypes has proven todifficult to make a vaccine fordifficult to make a vaccine for
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Summary of HIVtransmissionSummary of HIVtransmission
HIVis a retrovirus with a single stranded RNAHIVis a retrovirus with a single stranded RNAgenome; it is the virus that causes AIDSgenome; it is the virus that causes AIDS
There are two major strains of HIVthat infect T cellsThere are two major strains of HIVthat infect T cells
or monocytesor monocytes The gp120 interacts with CD4 on the host cell, butThe gp120 interacts with CD4 on the host cell, but
there are coreceptors that are necessary for attackthere are coreceptors that are necessary for attack
The viral load of the plasma is a good indicator of theThe viral load of the plasma is a good indicator of the
disease coursedisease course Many secondary diseases can afflict the patient from theMany secondary diseases can afflict the patient from the
lowered immunity that results from AIDSlowered immunity that results from AIDS
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HIV/AIDS Therapy SummaryHIV/AIDS Therapy Summary
3 primary methods to battle HIV/AIDS3 primary methods to battle HIV/AIDS
-- NRTIs, NNRTIs, PIsNRTIs, NNRTIs, PIs
All 3 combine to form HAART which has proven to beAll 3 combine to form HAART which has proven to bemuch more effective against HIVs mutations.much more effective against HIVs mutations.
New drugs which eliminate side effects or targetNew drugs which eliminate side effects or targetdifferent steps in the replication process are underdifferent steps in the replication process are undertesting.testing.
For now a vaccine still seems to be a pipe dreamFor now a vaccine still seems to be a pipe dream