AIDS and Other AIDS and Other ImmunodeficiencImmunodeficienc

iesiesBy: Luz Arboleda, Sameer Jain, By: Luz Arboleda, Sameer Jain,

and and

Ranoo Patel.Ranoo Patel.

OverviewOverviewI.I. ImmunodeficiencyImmunodeficiencyII.II. Primary ImmunodeficiencyPrimary ImmunodeficiencyIII.III. Secondary ImmunodeficiencySecondary ImmunodeficiencyIV.IV. AIDSAIDS

i.i. Discovery of AIDSDiscovery of AIDSii.ii. Origin of AIDS VirusOrigin of AIDS Virusiii.iii. Epidemiology & StatisticsEpidemiology & Statisticsiv. HIV-1iv. HIV-1v. Transmission of HIV-1v. Transmission of HIV-1vi. Treatment of HIV/AIDSvi. Treatment of HIV/AIDS

IntroductionIntroduction

The immune system is subject to failure The immune system is subject to failure of some or all of its parts.of some or all of its parts.

If the system is not able to protect the If the system is not able to protect the host from disease-causing agents or host from disease-causing agents or from malignant cells, an from malignant cells, an immunodeficiencyimmunodeficiency results. results.

There are two types of There are two types of immunodeficiency: immunodeficiency: PrimaryPrimary and and secondarysecondary or acquired. or acquired.

Primary immunodeficiencyPrimary immunodeficiency results from a results from a genetic or developmental defect of the genetic or developmental defect of the immune system. The condition is present at immune system. The condition is present at birth, though it may not manifest itself until birth, though it may not manifest itself until later in life.later in life.

Secondary Secondary (acquired)(acquired) immunodeficiency immunodeficiency is the loss of immune function that results is the loss of immune function that results from exposure to various agents. The most from exposure to various agents. The most common example is common example is AIDSAIDS or or acquired acquired immunodeficiency syndromeimmunodeficiency syndrome, which , which results from infection with the HIV-1. or results from infection with the HIV-1. or human immunodeficiency virus 1.human immunodeficiency virus 1.

Primary Primary ImmunodeficienciesImmunodeficiencies

Primary Immunodeficiencies may affect Primary Immunodeficiencies may affect either either adaptiveadaptive ( (T or B cellsT or B cells) or ) or innateinnate ((macrophages or complementmacrophages or complement) immune functions, ) immune functions, which enables us to categorize them which enables us to categorize them according to the type of developmental stage according to the type of developmental stage of the cells involved.of the cells involved.

So, lymphoid cell disorders may affect T cells, So, lymphoid cell disorders may affect T cells, B cells, or, in combined immunodeficiencies, B cells, or, in combined immunodeficiencies, both B and T cells. Myeloid cell disorders both B and T cells. Myeloid cell disorders affect phagocytic function.affect phagocytic function.

Cellular Development in the Cellular Development in the Immune SystemImmune System

Figure 19-1

• Defects in the lymphoid Defects in the lymphoid lineage— lineage— May involve B cells, T cells, or both of these May involve B cells, T cells, or both of these Lineages. B-cell immunodeficiency disordersLineages. B-cell immunodeficiency disorderscause recurrent bacterial infections. T-cell cause recurrent bacterial infections. T-cell deficiency though, can affect both humoral and deficiency though, can affect both humoral and cell-mediated responses.cell-mediated responses.

SCID: SCID: Severe Combined ImmunodeficiencySevere Combined ImmunodeficiencyWAS:WAS: Wiskott - Aldrich syndrome Wiskott - Aldrich syndromeInterferon-Gamma-Receptor DefectInterferon-Gamma-Receptor DefectX-Linked AgammaglobulinemiaX-Linked AgammaglobulinemiaX-Linked Hyper-IgM SyndromeX-Linked Hyper-IgM SyndromeCVI: CVI: Common Variable ImmunodeficiencyCommon Variable ImmunodeficiencyAtaxia TelangiectasiaAtaxia TelangiectasiaImmune Disorders Involving the ThymusImmune Disorders Involving the Thymus

Interaction Between T and Interaction Between T and B CellsB Cells

Defects in cell Defects in cell interaction and interaction and signaling can lead to signaling can lead to severe severe immunodeficiency.immunodeficiency.

A number of primary A number of primary immunodeficiencies immunodeficiencies are rooted in defects are rooted in defects in these interactions. in these interactions. SCID is an example. SCID is an example.

Figure 19-3

• Defects in the myeloid Defects in the myeloid lineage—lineage— Defects affect the innate immune functions. Most Defects affect the innate immune functions. Most of them result in impaired phagocytic processes of them result in impaired phagocytic processes that are manifested by recurrent microbial infection that are manifested by recurrent microbial infection

of greater or lesser severity.of greater or lesser severity. Reduction in Neutrophil CountReduction in Neutrophil CountCGD: CGD: Chronic Granulomatous DiseaseChronic Granulomatous DiseaseChediak-Higashi SyndromeChediak-Higashi SyndromeLAD: LAD: Leukocyte Adhesion DeficiencyLeukocyte Adhesion Deficiency

• Defects in the Complement Lineage—Defects in the Complement Lineage—Many complement deficiencies are associated with Many complement deficiencies are associated with increased susceptibility to bacterial infections increased susceptibility to bacterial infections and/or immune-complex diseases.and/or immune-complex diseases.

Treatment of Treatment of ImmunodeficiencyImmunodeficiency

Although there are no cures for Although there are no cures for immunodeficiency disorders, there are various immunodeficiency disorders, there are various treatment possibilities. In addition to complete treatment possibilities. In addition to complete isolation from exposure to any microbial agent, isolation from exposure to any microbial agent, treatment options for the immunodeficiencies treatment options for the immunodeficiencies include:include:

1) Replacement of a missing protein1) Replacement of a missing protein

2) Replacement of a missing cell type or 2) Replacement of a missing cell type or lineage lineage

3) Replacement of a missing or defective gene3) Replacement of a missing or defective gene

Secondary Secondary ImmunodeficienciesImmunodeficiencies Loss of immune function that results from Loss of immune function that results from

exposure to various agents.exposure to various agents. Acquired HypogammaglobulinemiaAcquired Hypogammaglobulinemia

Recurrent infection that manifests itself in Recurrent infection that manifests itself in young adults. There are usually very low young adults. There are usually very low levels of total immunoglobulin, though T-cell levels of total immunoglobulin, though T-cell numbers and function may be normal. It is numbers and function may be normal. It is treated with gammaglobulin therapy.treated with gammaglobulin therapy.

Agent-Induced ImmunodeficiencyAgent-Induced ImmunodeficiencyResults from exposure to any of a number of Results from exposure to any of a number of chemical and biological agents that induce an chemical and biological agents that induce an immunodeficient state.immunodeficient state.

AIDS:AIDS: Acquired Immunodeficiency Syndrome Acquired Immunodeficiency Syndrome

Discovery of AIDSDiscovery of AIDS AIDS was first reported in the United States in AIDS was first reported in the United States in

1981 in Los Angeles, New York, and San 1981 in Los Angeles, New York, and San Francisco.Francisco.

The first patients displayed unusual infections The first patients displayed unusual infections by by opportunistic agentsopportunistic agents, such as , such as Pneumocystis cariniiPneumocystis carinii, which causes PCP or , which causes PCP or P. P. cariniicarinii pneumonia, as well as other rare pneumonia, as well as other rare opportunistic infections.opportunistic infections.

Opportunistic agents Opportunistic agents are microorganisms are microorganisms that healthy individuals can harbor with no ill that healthy individuals can harbor with no ill consequences but that cause disease in those consequences but that cause disease in those with impaired immune function.with impaired immune function.

They also displayed They also displayed Kaposi’sKaposi’s sarcomasarcoma—an —an extremely rare skin tumor.extremely rare skin tumor.

Origin of AIDS VirusOrigin of AIDS Virus Within a few years after recognition of AIDS, the causative Within a few years after recognition of AIDS, the causative

agent was discovered to be a agent was discovered to be a retrovirusretrovirus.. Only one other human retrovirus has been described before Only one other human retrovirus has been described before

HIV, the human T-lymphotropic virus I or HTLV-I. HIV, the human T-lymphotropic virus I or HTLV-I. There is also another human virus known as There is also another human virus known as HIV-2HIV-2, which is , which is

less pathogenic than HIV-1. It infects nonhuman primates less pathogenic than HIV-1. It infects nonhuman primates that are not infected by HIV-1. that are not infected by HIV-1.

Viruses related to HIV-1 have been found in nonhuman Viruses related to HIV-1 have been found in nonhuman privates—such as SIV: Simian immunodeficiency virus. privates—such as SIV: Simian immunodeficiency virus. Other animal retroviruses are the Other animal retroviruses are the feline feline and and bovine bovine immunodeficiency virusesimmunodeficiency viruses and the and the mouse leukemia mouse leukemia virus. virus. These don’t yield information pertinent to HIV-1. These don’t yield information pertinent to HIV-1. Only the studies made on chimpanzees when infected with Only the studies made on chimpanzees when infected with HIV-1 can be useful; but they rarely develop AIDS.HIV-1 can be useful; but they rarely develop AIDS.

Why isn’t there a suitable host to study HIV-1?Why isn’t there a suitable host to study HIV-1?a) a) Lack of cell-surface receptors required for entry of virus Lack of cell-surface receptors required for entry of virus into host. into host. b)b) Dependence of HIV on host-cell factors for early events in Dependence of HIV on host-cell factors for early events in the the

replication process, such as transcription and splicing of replication process, such as transcription and splicing of viral messages.viral messages.

Epidemiology & Epidemiology & StatisticsStatistics

Since its discovery in 1981, AIDS has Since its discovery in 1981, AIDS has increased to epidemic proportions.increased to epidemic proportions.

According to the National Centers for Disease According to the National Centers for Disease Control and Prevention (CDC), Control and Prevention (CDC), 42 million42 million people are estimated to be living with people are estimated to be living with HIV/AIDS. Of these, HIV/AIDS. Of these, 38.6 million38.6 million are adults, are adults, 19.2 million19.2 million are women, and are women, and 3.2 million3.2 million are are children under 15. children under 15.

An estimated An estimated 5 million5 million people acquired the people acquired the human immunodeficiency virus (HIV) in 2002, human immunodeficiency virus (HIV) in 2002, including including 2 million2 million women and women and 800,000 800,000 children under 15. children under 15.

Epidemiology & Epidemiology & StatisticsStatistics

During 2002, AIDS caused the deaths of an During 2002, AIDS caused the deaths of an estimatedestimated 3.1 million 3.1 million people, including people, including 1.2 1.2 millionmillion women and women and 610,000610,000 children under 15. children under 15.

Women are becoming increasingly affected by Women are becoming increasingly affected by HIV. Approximately HIV. Approximately 50%50%, or, or 19.2 million 19.2 million, of the , of the 38.6 million38.6 million adults living with HIV or AIDS adults living with HIV or AIDS worldwide are women. Compared to accounting worldwide are women. Compared to accounting for only for only 6%6% of the total cases in 1985. of the total cases in 1985.

The UN predicts that by 2010, more than The UN predicts that by 2010, more than 25 25 millionmillion children will have lost at least one children will have lost at least one parent to AIDS.parent to AIDS.

Global Estimates of Global Estimates of HIV/AIDSHIV/AIDS

HIV-1 VirusHIV-1 Virus

The virus that causes AIDSThe virus that causes AIDS It is a retrovirus with two It is a retrovirus with two

copies of single stranded copies of single stranded RNA genomeRNA genome

It uses It uses reverse reverse transcriptasetranscriptase to transform to transform its ss-RNA genome into a its ss-RNA genome into a ds-DNA for integration into ds-DNA for integration into its host genomeits host genome

It has marker proteins It has marker proteins (gp120) in the protein coat (gp120) in the protein coat that allow it to recognize that allow it to recognize specific cells in the human specific cells in the human bodybody

The protein coat also The protein coat also contains MHC-I and MHC-contains MHC-I and MHC-II moleculesII molecules

HIV genomeHIV genome

gag gene codes for nucleocapsid proteinsgag gene codes for nucleocapsid proteins env gene codes for envelope glycoproteins, i.e. gp41 env 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 pol gene codes for enzymes such as reverse

transcriptase, protease and integrasetranscriptase, protease and integrase Other genes code for various activators and Other genes code for various activators and

accessory proteinsaccessory proteins

Complete Activation of Complete Activation of HIVHIV

While CD4 is recognized by the virus, it is not sufficient for viral While CD4 is recognized by the virus, it is not sufficient for viral attack; it needs a costimulatory signal.attack; it needs a costimulatory signal.

T cells: coreceptor is CXCR4, which also acts as a receptor for T cells: coreceptor is CXCR4, which also acts as a receptor for the chemokine SDF-1; there is competitive inhibition between the chemokine SDF-1; there is competitive inhibition between chemokine and HIV for binding; the HIV strain is called T-tropicchemokine and HIV for binding; the HIV strain is called T-tropic

Monocytes: coreceptor is CCR5, which is a receptor for Monocytes: coreceptor is CCR5, which is a receptor for chemokines, which also act as competitive inhibitors to HIV; the chemokines, which also act as competitive inhibitors to HIV; the HIV strain is called M-tropicHIV strain is called M-tropic

T-tropic HIV strains cause syncytia: formation of giant cells as a T-tropic HIV strains cause syncytia: formation of giant cells as a result of fusion of cells via the gp120 protein on viral coats.result of fusion of cells via the gp120 protein on viral coats.

Infection of Human Cell Infection of Human Cell with HIVwith HIV

HIV gp120 surface protein HIV gp120 surface protein binds CD4 on target cellbinds CD4 on target cell

Transmembrane component, Transmembrane component, gp41, binds coreceptor CXCR4 gp41, binds coreceptor CXCR4 to enhance fusionto enhance fusion

Viral genome and other Viral genome and other proteins are able to enter the proteins are able to enter the cell via nucleocapsidcell via nucleocapsid

RT transcribes the ssRNA RT transcribes the ssRNA genomegenome

The next DNA strand is made, The next DNA strand is made, making a double stranded DNA making a double stranded DNA molecule called a provirusmolecule called a provirus

The dsDNA is transferred to The dsDNA is transferred to the nucleus to be added to the the nucleus to be added to the host genome via the viral host genome via the viral integrase protein at HIV LTR integrase protein at HIV LTR sitessites

Activation of ProvirusActivation of Provirus In a latent cell, the In a latent cell, the

integrated provirus must be integrated provirus must be activates by transcriptional activates by transcriptional factors to make genomic factors to make genomic ssRNA and mRNAsssRNA and mRNAs

Genomic RNA is exportedGenomic RNA is exported Host ribosomes transcribe Host ribosomes transcribe

viral mRNAs, and the viral mRNAs, and the proteins are either with the proteins are either with the genomic RNA or part of the genomic RNA or part of the membranemembrane

The membrane buds to The membrane buds to form a viral envelopeform a viral envelope

The mature virus is The mature virus is released outside the cellreleased outside the cell

These latent cells are These latent cells are dangerous because they dangerous because they can remain latent for long can remain latent for long periods of timeperiods of time

HIV Infected T-CellHIV Infected T-Cell

Overview of Overview of InfectionInfection

The viral load is kept at a steady The viral load is kept at a steady state; half life for infected cells is state; half life for infected cells is roughly 1.5 daysroughly 1.5 days

In addition to these lytic cells, In addition to these lytic cells, there are small numbers of latent there are small numbers of latent cells that can persist for long cells that can persist for long periods of timeperiods of time

Diagnosis for AIDS includes finding Diagnosis for AIDS includes finding the HIV virus in the patient, <200 the HIV virus in the patient, <200 TTHH cells/mm cells/mm33, impaired DTH, and , impaired DTH, and the occurrence of opportunistic the occurrence of opportunistic infectionsinfections

Infections that result from the Infections that result from the diminished immune system include diminished immune system include infections with infections with Candida albicansCandida albicans, , flu, tuberculosis, encephalopathy, flu, tuberculosis, encephalopathy, and other abnormalities of CNS and other abnormalities of CNS and PNS. and PNS.

Progression of HIV to Progression of HIV to AIDSAIDS

Testing for HIVTesting for HIV Enzyme-linked immunosorbent assay (ELISA).Enzyme-linked immunosorbent assay (ELISA). This This

screening test is usually the first test used to detect screening test is usually the first test used to detect infection with HIV. If antibodies to HIV are present infection with HIV. If antibodies to HIV are present (positive result), the test is usually repeated. (positive result), the test is usually repeated.

Western blot.Western blot. This test requires high technical skills. This test requires high technical skills. It is more difficult than the ELISA to perform and It is more difficult than the ELISA to perform and interpret accurately, but it is less likely to give a false-interpret accurately, but it is less likely to give a false-positive result because it can distinguish HIV positive result because it can distinguish HIV antibodies from other antibodies that may react to the antibodies from other antibodies that may react to the ELISA. A Western blot is usually done to confirm the ELISA. A Western blot is usually done to confirm the results of two positive ELISA tests. results of two positive ELISA tests.

Indirect fluorescent antibody (IFA).Indirect fluorescent antibody (IFA). This test also This test also detects antibodies made to fight an HIV infection. Like detects antibodies made to fight an HIV infection. Like a Western blot test, it is used to confirm the results of a Western blot test, it is used to confirm the results of an ELISA. an ELISA.

Polymerase Chain ReactionPolymerase Chain Reaction (PCR). (PCR). This test detects This test detects the RNA of HIV, rather than detecting antibodies to the RNA of HIV, rather than detecting antibodies to HIV. Therefore, PCR can reveal an HIV infection before HIV. Therefore, PCR can reveal an HIV infection before antibodies can be detected. PCR can also accurately antibodies can be detected. PCR can also accurately determine whether a baby born to an infected mother determine whether a baby born to an infected mother has HIV. has HIV.

Immunological problems Immunological problems associated with HIV associated with HIV

infectioninfection

Other Immune Evasions Other Immune Evasions Mechanisms of HIVMechanisms of HIV

TTCC cells are able to generate a response for years cells are able to generate a response for years until finally they are no longer effective against until finally they are no longer effective against HIVHIV The HIV peptides that act as epitopes to the MHC I The HIV peptides that act as epitopes to the MHC I

molecules mutate at a high rate and the Tmolecules mutate at a high rate and the TCC cells are not cells are not able to keep upable to keep up

Some HLA haplotypes are more susceptible to HIV Some HLA haplotypes are more susceptible to HIV attack than othersattack than others

HIV gene products have functions in addition to HIV gene products have functions in addition to viral replication functions; some are able to down viral replication functions; some are able to down regulate host cell MHC-I expression so fewer regulate host cell MHC-I expression so fewer peptides are presented to the defense mechanismspeptides are presented to the defense mechanisms Tat represses transcription of MHC-ITat represses transcription of MHC-I Vpu keeps MHC-I molecules from leaving the Vpu keeps MHC-I molecules from leaving the

endoplasmic reticulumendoplasmic reticulum Nef selectively internalizes some MHC-I molecules from Nef selectively internalizes some MHC-I molecules from

the plasma membrane, so that the cells have fewer MHC the plasma membrane, so that the cells have fewer MHC molecules in total. It leaves the MHC-I molecules that molecules in total. It leaves the MHC-I molecules that will help prevent lysis by NK cells.will help prevent lysis by NK cells.

3 Points In HIV Cell Cycle Where Replication Can be Stopped3 Points In HIV Cell Cycle Where Replication Can be Stopped Nucleoside Reverse Transcriptase Inhibitors (NRTIs)Nucleoside Reverse Transcriptase Inhibitors (NRTIs) Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) Protease InhibitorsProtease Inhibitors All 3 of these treatments are usually prescribed at once. Known as All 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 HAART, the combination of all 3 fights the ability of the virus to rapidly mutate.mutate.

Reverse Transcriptase Reverse Transcriptase InhibitorsInhibitors

Reverse Transcriptase Inhibitors interfere Reverse Transcriptase Inhibitors interfere with the reverse transcriptase (RT) enzyme with the reverse transcriptase (RT) enzyme that HIV needs to make copies of itself. There that HIV needs to make copies of itself. There are 2 types of inhibitors each working are 2 types of inhibitors each working differently. differently.

Type 1: Type 1: NRTI’sNRTI’s – nucleoside drugs provide – nucleoside drugs provide faulty DNA building blocks, stopping the DNA chain faulty DNA building blocks, stopping the DNA chain the virus uses to make copies of itself. the virus uses to make copies of itself.

Type 2: Type 2: NNRTI’sNNRTI’s- non-nucleoside RT - non-nucleoside RT inhibitors bind RT so the virus cannot carry out its inhibitors bind RT so the virus cannot carry out its copying functioncopying function

Examples Include: AZT, 3TC, Combivir, NevirapineExamples Include: AZT, 3TC, Combivir, Nevirapine

Protease InhibitorsProtease Inhibitors Protease InhibitorsProtease Inhibitors (PI), discovered in (PI), discovered in

1995, block the protease enzyme. When 1995, block the protease enzyme. When protease is blocked, HIV makes copies of protease is blocked, HIV makes copies of itself that can’t infect new cells. itself that can’t infect new cells.

PI Side EffectsPI Side Effects: PI’s can cause high : PI’s can cause high blood sugar and consequently diabetes. blood sugar and consequently diabetes. Another main concern is lipodystrophy, Another main concern is lipodystrophy, where your body absorbs fats and where your body absorbs fats and nutrients in an irregular manner. Latent nutrients in an irregular manner. Latent HIV can hide out in these fat cells. HIV can hide out in these fat cells.

Death rateDeath rate

Death rates per 100,000 population from leading causes of death among persons 25–44 years old, United States, 1987–2000

What does the future hold?What does the future hold?

Scientists are working on more potent Scientists are working on more potent protease inhibitors, less toxic RT inhibitors, protease inhibitors, less toxic RT inhibitors, as well as 2 new classes of drugs: as well as 2 new classes of drugs:

**Fusion Inhibitors-Fusion Inhibitors- Drugs which Drugs which act to block HIV before it enters the human act to block HIV before it enters the human immune cell. This class of drugs works to stop immune cell. This class of drugs works to stop HIV replication at an earlier stage. HIV replication at an earlier stage.

**Integrase Inhibitors- Integrase Inhibitors- Aim to block Aim to block the integration of the virus’s DNA into the cell’s the integration of the virus’s DNA into the cell’s chromosome. 2 different integrase inhibitors are chromosome. 2 different integrase inhibitors are currently in human trials. currently in human trials.

Can HIV be Vaccinated Can HIV be Vaccinated Against?Against?

ChallengesChallenges --HIV thrives in the presence ofHIV thrives in the presence of circulating antibodies directed circulating antibodies directed

against it. against it.

- HIV integrates itself into the host - HIV integrates itself into the host genome and may stay dormant for years. All genome and may stay dormant for years. All retroviruses prove difficult to removeretroviruses prove difficult to remove

-HIV mutates and can show up to -HIV mutates and can show up to

101099 viruses per day, while the common cold with 100 viruses per day, while the common cold with 100 subtypes has proven to difficult to make a vaccine forsubtypes has proven to difficult to make a vaccine for

Summary of HIV Summary of HIV transmissiontransmission

HIV is a retrovirus with a single stranded RNA HIV is a retrovirus with a single stranded RNA genome; it is the virus that causes AIDSgenome; it is the virus that causes AIDS

There are two major strains of HIV that infect There are two major strains of HIV that infect T cells or monocytesT cells or monocytes

The gp120 interacts with CD4 on the host cell, The gp120 interacts with CD4 on the host cell, but there are coreceptors that are necessary but there are coreceptors that are necessary for attackfor attack

The viral load of the plasma is a good indicator The viral load of the plasma is a good indicator of the disease courseof the disease course

Many secondary diseases can afflict the Many secondary diseases can afflict the patient from the lowered immunity that results patient from the lowered immunity that results from AIDSfrom AIDS

HIV/AIDS Therapy HIV/AIDS Therapy SummarySummary

3 primary methods to battle HIV/AIDS3 primary methods to battle HIV/AIDS - NRTI’s, NNRTI’s, PI’s - NRTI’s, NNRTI’s, PI’s

All 3 combine to form HAART which has All 3 combine to form HAART which has proven to be much more effective against proven to be much more effective against HIV’s mutations. HIV’s mutations.

New drugs which eliminate side effects or New drugs which eliminate side effects or target different steps in the replication target different steps in the replication process are under testing.process are under testing.

For now a vaccine still seems to be a pipe For now a vaccine still seems to be a pipe dreamdream