AIDS and Other Immunodeficiencies

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AIDS and Other Immunodeficiencies

• By Luz Arboleda, Sameer Jain, and
• Ranoo Patel.

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Overview

• Immunodeficiency
• Primary Immunodeficiency
• Secondary Immunodeficiency
• AIDS
• i. Discovery of AIDS
• ii. Origin of AIDS Virus
• iii. Epidemiology Statistics
• iv. HIV-1
• v. Transmission of HIV-1
• vi. Treatment of HIV/AIDS

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Introduction

• The immune system is subject to failure of some
  or all of its parts.
• If the system is not able to protect the host
  from disease-causing agents or from malignant
  cells, an immunodeficiency results.
• There are two types of immunodeficiency Primary
  and secondary or acquired.

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• Primary immunodeficiency results from a genetic
  or developmental defect of the immune system.
  The condition is present at birth, though it may
  not manifest itself until later in life.
• Secondary (acquired) immunodeficiency is the loss
  of immune function that results from exposure to
  various agents. The most common example is AIDS
  or acquired immunodeficiency syndrome, which
  results from infection with the HIV-1. or human
  immunodeficiency virus 1.

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Primary Immunodeficiencies

• Primary Immunodeficiencies may affect either
  adaptive (T or B cells) or innate (macrophages or
  complement) immune functions, which enables us to
  categorize them according to the type of
  developmental stage of the cells involved.
• So, lymphoid cell disorders may affect T cells, B
  cells, or, in combined immunodeficiencies, both B
  and T cells. Myeloid cell disorders affect
  phagocytic function.

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Cellular Development in the Immune System
Figure 19-1
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Defects in the lymphoid lineage

• May involve B cells, T cells, or both of these
• Lineages. B-cell immunodeficiency disorders
• cause recurrent bacterial infections. T-cell
• deficiency though, can affect both humoral and
• cell-mediated responses.
• SCID Severe Combined Immunodeficiency
• WAS Wiskott - Aldrich syndrome
• Interferon-Gamma-Receptor Defect
• X-Linked Agammaglobulinemia
• X-Linked Hyper-IgM Syndrome
• CVI Common Variable Immunodeficiency
• Ataxia Telangiectasia
• Immune Disorders Involving the Thymus

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Interaction Between T and B Cells

• Defects in cell interaction and signaling can
  lead to severe immunodeficiency.
• A number of primary immunodeficiencies are rooted
  in defects in these interactions. SCID is an
  example.

Figure 19-3
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Defects in the myeloid lineage

• Defects affect the innate immune functions. Most
• of them result in impaired phagocytic processes
• that are manifested by recurrent microbial
  infection
• of greater or lesser severity.
• Reduction in Neutrophil Count
• CGD Chronic Granulomatous Disease
• Chediak-Higashi Syndrome
• LAD Leukocyte Adhesion Deficiency
• Defects in the Complement Lineage
• Many complement deficiencies are associated with
• increased susceptibility to bacterial infections
• and/or immune-complex diseases.

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Treatment of Immunodeficiency

• Although there are no cures for immunodeficiency
  disorders, there are various treatment
  possibilities. In addition to complete isolation
  from exposure to any microbial agent, treatment
  options for the immunodeficiencies include
• 1) Replacement of a missing protein
• 2) Replacement of a missing cell type or lineage
  
• 3) Replacement of a missing or defective gene

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Secondary Immunodeficiencies

• Loss of immune function that results from
  exposure to various agents.
• Acquired Hypogammaglobulinemia
• Recurrent infection that manifests itself in
  young adults. There are usually very low levels
  of total immunoglobulin, though T-cell numbers
  and function may be normal. It is treated with
  gammaglobulin therapy.
• Agent-Induced Immunodeficiency
• Results from exposure to any of a number of
  chemical and biological agents that induce an
  immunodeficient state.
• AIDS Acquired Immunodeficiency Syndrome

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Discovery of AIDS

• AIDS was first reported in the United States in
  1981 in Los Angeles, New York, and San Francisco.
• The first patients displayed unusual infections
  by opportunistic agents, such as Pneumocystis
  carinii, which causes PCP or P. carinii
  pneumonia, as well as other rare opportunistic
  infections.
• Opportunistic agents are microorganisms that
  healthy individuals can harbor with no ill
  consequences but that cause disease in those with
  impaired immune function.
• They also displayed Kaposis sarcomaan extremely
  rare skin tumor.

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Origin of AIDS Virus

• Within a few years after recognition of AIDS, the
  causative agent was discovered to be a
  retrovirus.
• Only one other human retrovirus has been
  described before HIV, the human T-lymphotropic
  virus I or HTLV-I.
• There is also another human virus known as HIV-2,
  which is less pathogenic than HIV-1. It infects
  nonhuman primates that are not infected by HIV-1.
  
• Viruses related to HIV-1 have been found in
  nonhuman privatessuch as SIV Simian
  immunodeficiency virus. Other animal
  retroviruses are the feline and bovine
  immunodeficiency viruses and the mouse leukemia
  virus. These dont yield information pertinent
  to HIV-1. Only the studies made on chimpanzees
  when infected with HIV-1 can be useful but they
  rarely develop AIDS.
• Why isnt there a suitable host to study HIV-1?
• a) Lack of cell-surface receptors required for
  entry of virus into host.
• b) Dependence of HIV on host-cell factors for
  early events in the
• replication process, such as
  transcription and splicing of viral messages.

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Epidemiology Statistics

• Since its discovery in 1981, AIDS has increased
  to epidemic proportions.
• According to the National Centers for Disease
  Control and Prevention (CDC), 42 million people
  are estimated to be living with HIV/AIDS. Of
  these, 38.6 million are adults, 19.2 million are
  women, and 3.2 million are children under 15.
• An estimated 5 million people acquired the human
  immunodeficiency virus (HIV) in 2002, including 2
  million women and 800,000 children under 15.

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Epidemiology Statistics

• During 2002, AIDS caused the deaths of an
  estimated 3.1 million people, including 1.2
  million women and 610,000 children under 15.
• Women are becoming increasingly affected by HIV.
  Approximately 50, or 19.2 million, of the 38.6
  million adults living with HIV or AIDS worldwide
  are women. Compared to accounting for only 6 of
  the total cases in 1985.
• The UN predicts that by 2010, more than 25
  million children will have lost at least one
  parent to AIDS.

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Global Estimates of HIV/AIDS
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HIV-1 Virus

• The virus that causes AIDS
• It is a retrovirus with two copies of single
  stranded RNA genome
• It uses reverse transcriptase to transform its
  ss-RNA genome into a ds-DNA for integration into
  its host genome
• It has marker proteins (gp120) in the protein
  coat that allow it to recognize specific cells in
  the human body
• The protein coat also contains MHC-I and MHC-II
  molecules

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HIV genome

• gag gene codes for nucleocapsid proteins
• env gene codes for envelope glycoproteins, i.e.
  gp41 (transmembrane protein) and gp120 (surface
  protein)
• pol gene codes for enzymes such as reverse
  transcriptase, protease and integrase
• Other genes code for various activators and
  accessory proteins

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Complete Activation of HIV

• While CD4 is recognized by the virus, it is not
  sufficient for viral attack it needs a
  costimulatory signal.
• T cells coreceptor is CXCR4, which also acts as
  a receptor for the chemokine SDF-1 there is
  competitive inhibition between chemokine and HIV
  for binding the HIV strain is called T-tropic
• Monocytes coreceptor is CCR5, which is a
  receptor for chemokines, which also act as
  competitive inhibitors to HIV the HIV strain is
  called M-tropic
• T-tropic HIV strains cause syncytia formation of
  giant cells as a result of fusion of cells via
  the gp120 protein on viral coats.

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Infection of Human Cell with HIV

• HIV gp120 surface protein binds CD4 on target
  cell
• Transmembrane component, gp41, binds coreceptor
  CXCR4 to enhance fusion
• Viral genome and other proteins are able to enter
  the cell via nucleocapsid
• RT transcribes the ssRNA genome
• The next DNA strand is made, making a double
  stranded DNA molecule called a provirus
• The dsDNA is transferred to the nucleus to be
  added to the host genome via the viral integrase
  protein at HIV LTR sites

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Activation of Provirus

• In a latent cell, the integrated provirus must be
  activates by transcriptional factors to make
  genomic ssRNA and mRNAs
• Genomic RNA is exported
• Host ribosomes transcribe viral mRNAs, and the
  proteins are either with the genomic RNA or part
  of the membrane
• The membrane buds to form a viral envelope
• The mature virus is released outside the cell
• These latent cells are dangerous because they can
  remain latent for long periods of time

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HIV Infected T-Cell
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Overview of Infection

• The viral load is kept at a steady state half
  life for infected cells is roughly 1.5 days
• In addition to these lytic cells, there are small
  numbers of latent cells that can persist for long
  periods of time
• Diagnosis for AIDS includes finding the HIV virus
  in the patient, lt200 TH cells/mm3, impaired DTH,
  and the occurrence of opportunistic infections
• Infections that result from the diminished immune
  system include infections with Candida albicans,
  flu, tuberculosis, encephalopathy, and other
  abnormalities of CNS and PNS.

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Progression of HIV to AIDS
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Testing for HIV

• Enzyme-linked immunosorbent assay (ELISA). This
  screening test is usually the first test used to
  detect infection with HIV. If antibodies to HIV
  are present (positive result), the test is
  usually repeated.
• Western blot. This test requires high technical
  skills. It is more difficult than the ELISA to
  perform and interpret accurately, but it is less
  likely to give a false-positive result because it
  can distinguish HIV antibodies from other
  antibodies that may react to the ELISA. A Western
  blot is usually done to confirm the results of
  two positive ELISA tests.
• Indirect fluorescent antibody (IFA). This test
  also detects antibodies made to fight an HIV
  infection. Like a Western blot test, it is used
  to confirm the results of an ELISA.
• Polymerase Chain Reaction (PCR). This test
  detects the RNA of HIV, rather than detecting
  antibodies to HIV. Therefore, PCR can reveal an
  HIV infection before antibodies can be detected.
  PCR can also accurately determine whether a baby
  born to an infected mother has HIV.

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Immunological problems associated with HIV
infection
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Other Immune Evasions Mechanisms of HIV

• TC cells are able to generate a response for
  years until finally they are no longer effective
  against HIV
• The HIV peptides that act as epitopes to the MHC
  I molecules mutate at a high rate and the TC
  cells are not able to keep up
• Some HLA haplotypes are more susceptible to HIV
  attack than others
• HIV gene products have functions in addition to
  viral replication functions some are able to
  down regulate host cell MHC-I expression so fewer
  peptides are presented to the defense mechanisms
• Tat represses transcription of MHC-I
• Vpu keeps MHC-I molecules from leaving the
  endoplasmic reticulum
• Nef selectively internalizes some MHC-I molecules
  from the plasma membrane, so that the cells have
  fewer MHC molecules in total. It leaves the
  MHC-I molecules that will help prevent lysis by
  NK cells.

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• 3 Points In HIV Cell Cycle Where Replication Can
  be Stopped
• Nucleoside Reverse Transcriptase Inhibitors
  (NRTIs)
• Non-Nucleoside Reverse Transcriptase Inhibitors
  (NNRTIs)
• Protease Inhibitors
• 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 mutate.

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Reverse Transcriptase Inhibitors

• Reverse Transcriptase Inhibitors interfere with
  the reverse transcriptase (RT) enzyme that HIV
  needs to make copies of itself. There are 2 types
  of inhibitors each working differently.
• Type 1 NRTIs nucleoside drugs provide
  faulty DNA building blocks, stopping the DNA
  chain the virus uses to make copies of itself.
• Type 2 NNRTIs- non-nucleoside RT inhibitors
  bind RT so the virus cannot carry out its copying
  function
• Examples Include AZT, 3TC, Combivir, Nevirapine

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Protease Inhibitors

• Protease Inhibitors (PI), discovered in 1995,
  block the protease enzyme. When protease is
  blocked, HIV makes copies of itself that cant
  infect new cells.
• PI Side Effects PIs can cause high blood sugar
  and consequently diabetes. Another main concern
  is lipodystrophy, where your body absorbs fats
  and nutrients in an irregular manner. Latent HIV
  can hide out in these fat cells.

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Death 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?

• Scientists are working on more potent protease
  inhibitors, less toxic RT inhibitors, as well as
  2 new classes of drugs
• Fusion Inhibitors- Drugs
  which act to block HIV before it enters the human
  immune cell. This class of drugs works to stop
  HIV replication at an earlier stage.
• Integrase Inhibitors- Aim to block the
  integration of the viruss DNA into the cells
  chromosome. 2 different integrase inhibitors are
  currently in human trials.

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• Can HIV be
  Vaccinated Against?
• Challenges
• -HIV thrives in
  the presence of
• circulating
  antibodies directed
• against it.
  
• - HIV
  integrates itself into the host genome and may
  stay dormant for years. All retroviruses prove
  difficult to remove
• -HIV mutates
  and can show up to 109 viruses per day, while the
  common cold with 100 subtypes has proven to
  difficult to make a vaccine for

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Summary of HIV transmission

• HIV is a retrovirus with a single stranded RNA
  genome it is the virus that causes AIDS
• There are two major strains of HIV that infect T
  cells or monocytes
• The gp120 interacts with CD4 on the host cell,
  but there are coreceptors that are necessary for
  attack
• The viral load of the plasma is a good indicator
  of the disease course
• Many secondary diseases can afflict the patient
  from the lowered immunity that results from AIDS

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HIV/AIDS Therapy Summary

• 3 primary methods to battle HIV/AIDS
• - NRTIs, NNRTIs, PIs
• All 3 combine to form HAART which has proven
  to be much more effective against HIVs
  mutations.
• New drugs which eliminate side effects or target
  different steps in the replication process are
  under testing.
• For now a vaccine still seems to be a pipe dream