1. Ch19 Disorders Associated with the Immune System: AIDS

2. Student Learning Outcomes
Explain the attachment of HIV to a host cell List two ways in which HIV avoids the host’s antibodies Describe the stages of HIV infection Describe the effects of HIV infection on the immune system Describe how HIV infection is diagnosed List the routes of HIV transmission Identify geographic patterns of HIV transmission List the current methods of preventing and treating HIV infection

3. Acquired Immunodeficiency Syndrome (AIDS)
Radio Lab - Patient Zero
Start at 16 mins
Origin and History
1981: In US, cluster of Pneumocystis pneumonia and Kaposi's sarcoma in young homosexual men discovered. The men showed loss of immune function.
1983: Discovery of virus causing loss of immune function.
1986: Scientists started to identify the virus with "HIV" abbreviation.
HIV is thought to have crossed the species barrier into humans in central Africa about 1908.
Patient who died in 1959 in Congo is the oldest known case.
Virus spread in Africa as result of urbanization. World-wide spread through modern transportation and unsafe sex.
Norwegian sailor who died in 1976 is the first known case in Western world.

4. Human Immunodeficiency Virus
Fig1.1e

5. HIV Infection – Review from Ch 13
Fig13.19

6. Pathogenesis: HIV cellular targets
Th cells
APCs
brain cell
intestinal epithelium

7. HIV Infection – AIDS is Final stage of HIV Infection
HIV: Retrovirus with ssRNA, RT, and envelope with gp120 spikes. Gp120 attach to CD4 on ________ cells, M, dendritic cells. Function of RT? Provirus latent or directs active virion synthesis HIV evades IS via latency, vacuoles, antigenic change
Fig 19.13

8. HIV Attachment, Fusion, and Entry
Fig 19.13

9. Latent vs. Active HIV Infection in CD4+ T Cells
Fig19.14b

10. Active HIV Infection in Macrophages
Fig19.15

11. The Stages of HIV Infection
Phase 1: Asymptomatic or chronic lymphadenopathy Phase 2: Symptomatic; early indications of immune failure Phase 3 is AIDS: Characterized by indicator conditions, such as: CMV, TB, Pneumocystis, toxoplasmosis, and Kaposi's sarcoma (see Table 19.5) Phases 1 and 2 are reported as AIDS if CD4+ T cells <200 cells/µl; Phase 3 always reported as AIDS Progression from HIV infection to AIDS:  10 y The life of an AIDS patient can be prolonged by the proper treatment of opportunistic infections People lacking CCR5 are resistant to HIV infection
CCR5, short for chemokine (C-C motif) receptor 5 is a protein which in humans is encoded by the CCR5 gene[1] which is located on chromosome 3 on the short (p) arm at position 21. CCR5 has also recently been designated CD195 (cluster of differentiation 195).
The CCR5 protein functions as a chemokine receptor. The natural chemokine ligands that bind to this receptor are RANTES, MIP-1α and MIP-1β. CCR5 is predominantly expressed on T cells, macrophages, dendritic cells and microglia. It is likely that CCR5 plays a role in inflammatory responses to infection, though its exact role in normal immune function is unclear. HIV uses CCR5 or another protein, CXCR4, as a co-receptor to enter its target cells. Several chemokine receptors can function as viral coreceptors, but CCR5 is likely the most physiologically important coreceptor during natural infection. A number of new experimental HIV drugs, called entry inhibitors, have been designed to interfere with the interaction between CCR5 and HIV, including PRO140 (), Vicriviroc (Schering Plough), Aplaviroc (GW ) (GlaxoSmithKline) and Maraviroc (UK ) (Pfizer). A potential problem of this approach is that, while CCR5 is the major co-receptor by which HIV infects cells, it is not the only such co-receptor. It is possible that under selective pressure HIV will evolve to use another co-receptor.

12. The Progression of HIV Infection
Foundation Fig19.16

13. Survival with HIV Infection
Exposed, but not infected
1 – 3% of Caucasians
No CCR5 gene
Survival with HIV Infection
Long-term nonprogressors
1 in 300
Measurable PVL, CD4 count slightly 
Highly effective CTLs
PVL = plasma viral load

14. Some Diseases Commonly Associated with AIDS
See Table 19.5
Pneumocystis jirovecii

15. Diagnostic Methods
Seroconversion takes up to 3 months Standard test: ELISA to detect___________ Confirm by Western blot Alternative: APTIMA HIV-1 RNA Qualitative Assay (combination of target amplification, hybridization and magnetic capture) Conventional PLV is determined by PCR or NA hybridization

16. To be conclusive (HIV-positive), a Western Blot must have 5 horizontal stripes.

17. Below is a photograph of a Western Blot tests
Below is a photograph of a Western Blot tests. This series of tests illustrates how an HIV test result can change during the window period from HIV-negative to HIV-positive. Each column is one Western Blot test. On the left side of the image there are two columns to be used as points of comparison. The column marked "PC" is an HIV-positive test result and the column marked "NC" is an HIV-negative test result. Column 3 to Column 10 are tests performed on a single person beginning with the day when the person was first exposed to HIV (Column 3, Day 0) to when the person had a full-blown HIV infection (Column 10, Day 30). An HIV infection is not the same as an AIDS diagnosis. This series records the process during which a person's immune system produces a response to an HIV infection. Each black or dark grey horizontal stripe is representative of the presence of a different antibody against a protein found in HIV. To be conclusive (HIV-positive), a Western Blot must have 5 horizontal stripes.

18. Transplacental infection of fetus Blood-contaminated needles
HIV Transmission
HIV survives 6 h outside a cell and > 1.5 d inside a cell
Infected body fluids transmit HIV via
Sexual contact
Breast milk
Transplacental infection of fetus
Blood-contaminated needles
Organ transplants
Artificial insemination
Blood transfusion
In developed countries, blood transfusions are not a likely source of infection anymore

19. AIDS Worldwide
Heterosexual intercourse (85%) Injected drug use (IDU) Women comprise 42% of infected
1.5 mio
Fig 19.17
10th ed.

20. AIDS Prevention Condoms and sterile needles!
Health care workers use Universal Precautions:
Wear gloves, gowns, masks, and goggles
Do not recap needles
Risk of infection from infected needle stick injury is 0.3%
Vaccine difficulties due to
Mutations
Geographical clades
Quick integration into DNA
Need to also stimulate CTLs
(Many failed vaccines last phase III trial in Thailand)

21. AIDS Chemotherapy The End
Treatment has much improved with HAART Highly Active Anti-Retroviral Therapy - cocktail)
Reverse transcriptase inhibitors (most are nucleoside /-tide analogs, e.g.: AZT)
Fusion inhibitors / Cell entry inhibitors
Protease inhibitors
Integrase inhibitors
HIV protease cleaves viral polypeptide into functional proteins
Protease inhibition  HIV cannot mature and noninfectious viruses are produced.
The End