aids project (bios 328)

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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

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