Secondary immunodeficiency

• Secondary immunodeficiencies


  Acquired failure of immunological function resulting from an infection or use of immunosuppressive drugs
• Secondary immunodeficiencies


  • Malnutrition = cell mediated immunity
  • Viral infections = immunosuppressive
  • Therapeutic agents = x-rays, cytotoxic drugs
  • B lymphoproliferative disorders = chronic lymphocytic leukaemia, myeloma
• Secondary immunodeficiencies are far more prevalent than primary immunodeficiency
• Acquired Immunodeficiency Syndrome (AIDS)


  Caused by infection with Human Immunodeficiency Virus (HIV), isolated in 1983
• HIV 1 originated from chimpanzees, HIV 2 originated from sooty mangabey
• HIV uses CD4 as its cellular receptor and cannot bind in chimpanzees, therefore cannot become infected
• AIDS


  • Massive reduction in circulating CD4+ T cells
  • Severe recurrent infections = pneumocystis carinii
  • High incidence of aggressive forms of cancers = Kaposi sarcoma
• HIV 1


  Main cause of AIDS in most countries, without treatment kills almost everyone it infects
• HIV 2


  Endemic to West Africa and spread throughout Asia, less virulent and causes slower progression to AIDS
• HIV recruits 273 human proteins for its own benefit to prevent the immune system from terminating HIV infections
• Gp120 and gp41


  Virally encoded glycoproteins that form the viral spike
• Infection by HIV


  1. Sexually via mucosal surfaces spread throughout the lymphatic system

  2. Blood products = infection through blood/semen containing HIV 1/2

  3. Maternally = Infected to mother to her infant

  4. Viral gp120 binds to CD4 on helper T cells, macrophages, dendritic cell, and microglia

  5. Dendritic cells populate mucosa & project dendrites through epithelial cells

  6. Binding to CD4 initiates fusion of gp41 (virus) to chemokine receptors CCR5 & CXR4 (host)
• Rapid progression of HIV infection due to continual microbial attack
• Life cycle of HIV in human cells

  1. Gp120 envelope protein binds to CD4, enabling gp120 to bind a co-receptor

  2. Binding releases gp41, causing fusion of the viral envelope with plasma membrane and release viral core into the cytoplasm

  3. RNA genome released & reverse transcribed into ds cDNA

  4. DNA migrates to the nucleus with viral integrase and becomes integrated into the cell genome as a provirus

  5. Activation of the T cell causes low level transcription of the provirus into mRNA, directing the synthesis of the early protein Tat & Rev

  6. Protein changes the pattern of provirus transcription to produce mRNA encoding the protein of the virion and RNA molecules corresponding to HIV genome

  7. Envelope proteins travel to plasma membrane, whereas viral proteins and viral genomic RNA assemble into nucleocapsids

  8. New virus particles bud from cell, acquiring their lipid envelope and envelope glycoproteins
• Progression of HIV 1 infections to AIDS

  1. Infected with HIV, virus produces an infection that resists the immune response

  2. Initial acute infection is controlled, disease not apparent, virus remains and replicates

  3. Severe immunodeficiency, death
• Progression of HIV 1 infection


  1. Viruses in initial inoculum enter human cells & use these cells biosynthetic machinery to make more copies of themselves

  2. Newly viruses burst out of each cell and go to infect other cells

  3. In early stages, the virus multiplies relatively unchecked while innate system gives its best shot, and the adaptive system is mobilized

  4. After a week the adaptive system is being mobilized and virus specific B cells, helper T cells and CTLs are activated, proliferate & start to work

  5. During early acute phase, rise in number of viruses in the body as the virus multiplies in infected cells

  6. Followed by a decrease in the viral load as virus-specific CTLs go to work

  7. The end phase of the acute phase, memory B & T cells are produced to protect against infection by the same virus

  8. HIV 1 leads to chronic phase, lasts for 10/more years, struggle between the immune system and AIDS virus and the virus always wins

  9. During chronic phase, viral loads decrease to low levels compared to those that reached the height of the acute phase

  10. HIV virus wins the battle, as the chronic phase progresses the total number of Th cells slowly decreases, because these cells are killed because of viral infection

  11. Not enough Th cells left to provide the help by virus-specific CTLs, number of CTLs decline & viral load increases as there few CTLs left to cope with newly infected cells

  12. Immune defences are overwhelmed, profound state of immunosuppression leaves the patient open to unchecked infections by pathogens that normally would not be problem for a person with intact immune system
• Deficiency of CCR5


  Mutations of CCR5 co receptor confer resistance to infection, 10% Europeans are heterozygous, 1% Europeans are homozygous and cannot be infected
• An HIV individual developed acute myeloid leukaemia, received an allogenic bone marrow transplant, was found to be homozygous for CCR5-Δ32, and was cured of both leukaemia and HIV infection
• How HIV 1 defeats the immune system and resists antiviral drugs

  • Forms latent infection, can't be detected by CTLs
  • Reverse transcriptase is highly prone, producing mutations, allowing HIV 1 to be 1 step ahead of CTLs/Abs directed against it
  • Specifically targets helper T cells, macrophages & dendritic cells
  • Uses immune cells to spread infection
• Anti-retroviral drugs


  Rapidly clear virus from the blood and increase CD4 T cells
• HIV causes immunodeficiency and death
• Laboratory diagnosis of HIV

  • Reversal of CD4:CD8
  • Quantitative PCR of HIV RNA measures viral load
  • Delayed hypersensitivity skin response
• Treatment of HIV


  • Antiretroviral agents
  • Immunization
  • Chemoprophylaxis
  • Aggressive treatment of infections
  • Aggressive treatment of malignancies
  • Triple therapy HAART
• Issues with HIV 1 vaccines

  • Production of memory cytotoxic T cells requires infection of antigen presenting cells, so non-infectious vaccines made from a dead virus/single viral protein can be used to produce a vaccine that will elicit protective antibodies
  • Designing a vaccine that produces memory killer T cell is more difficult
  • AIDS vaccines must have no risk of causing disease
  • Possible that a carrier virus vaccine/DNA vaccine might produce a robust killer T cell memory, yet be safe for general use