1. HIV and AIDS Acquired Immunodeficiency Syndrome
Disease caused by an infectious agent:
a retrovirus

2. HIV and AIDS History of an infectious agent
In Los Angeles : only two cases of Pneumocystis carinii pneumonia
cases of Pneumocystis carinii pneumonia
All Homosexual
Dot-like intracystic bodies of Pneumocystis carinii in lung
Cytologic preparation from a bronchoalveolar lavage – Giemsa stain

3. HIV and AIDS
With dissemination to extrapulmonary sites, Pneumocystis carinii tends to produce foci with prominent calcification, as seen in the kidney

4. HIV and AIDS an infectious agent – Kaposi’s Sarcoma
Early 1981: 5 cases of Kaposi’s sarcoma
Hitherto: rare (immunocompromization)
Elderly - Non-aggressive
cases of Kaposi’s sarcoma
Young
Male
San Francisco and New York

5. AIDS Definition
AIDS is currently defined as the presence of one of 25 conditions indicative of severe immunosuppression OR
HIV infection in an individual with a CD4+ cell count of <200 cells per cubic mm of blood
AIDS is therefore the end point of an infection that is continuous, progressive and pathogenic
With the prevalence of HIV in the developing world, HIV and its complications will be with us for generations

6. AIDS Statistics
Approximately 44,000,000 people in the world are HIV-infected
Approximately 14,000 new HIV infections occur daily around the world
Over 90% of these are in developing countries
1000 are in children less than 15 years of age.
Of adult infections, 48% are in women and 15% in individuals years

7. Global summary of the AIDS epidemic
Number of people living with HIV in 2008
Total 33.4 million [31.1 million–35.8 million]
Adults 31.3 million [29.2 million–33.7 million]
Women 15.7 million [14.2 million–17.2 million]
Children under 15 years 2.1 million [1.2 million–2.9 million]

8. Global summary of the AIDS epidemic
People newly infected with HIV in 2008
Total 2.7 million [2.4 million–3.0 million]
Adults 2.3 million [2.0 million–2.5 million]
Children under 15 years [ – ]

9. Global summary of the AIDS epidemic
AIDS-related deaths in 2008
Total 2.0 million [1.7 million–2.4 million]
Adults 1.7 million [1.4 million–2.1 million]
Children under 15 years [ – ]

10. HIV and AIDS

11. AIDS Statistics Sub-Saharan Africa
About 1 million new cases of AIDS per year
30 million people with HIV infection
AIDS is responsible for a decrease in life expectancy and increase in child mortality. Child mortality rates in East Africa will double by 2010 and adult life expectancy has declined in that region
Several countries in sub-Saharan Africa report infection rates of 20-25%, especially urban areas
Zimbabwe: 33.7% of adult population infected
In Zambia, 1 in 5 urban girls is HIV-positive by the age of 20

12. SUB-SAHARAN AFRICA
Number of people living with HIV 2008: 22.4 million 2001: 19.7
Number of new HIV infections 2008: 1.9 million 2001: 2.3 million
Number of children newly infected 2008: :
Number of AIDS-related deaths 2008: 1.4 million 2001: 1.4

13. Important Properties
The virus only grows on T4 cells that are proliferating in response to an immune stimulus -- Therefore difficult to grow in culture
Human immunodeficiency viral particles are seen at medium magnification in this electron micrograph (CDC)

14. TAT – REV – NEF – VIF – VPR – VPU
HIV - The Virus
Retrovirus
Three genes
GAG – POL – ENV
Three polyproteins
Six regulatory genes
TAT – REV – NEF – VIF – VPR – VPU

15. HIV - The Virus Retrovirus ENV gene
Two glycoproteins: gp gp120 and gp41
gp41 is fusogen that spans the membrane
ENV gene

16. HIV - The Virus Retrovirus GAG gene Group-Specific Antigens
p17: inner surface - myristoylated
p24: nucleocapsid
p9: nucleocapsid associated with RNA
GAG gene
Polyprotein

17. HIV - The Virus Retrovirus POL gene Enzymes
Polymerase (reverse transcriptase – RNA dependent DNA polymerase)
Integrase
Protease (cuts polyproteins)
POL gene
Polyprotein

18. The Genome of HIV Three structural genes LTRs
Extra open reading frames are clue to latency
These ORFs code for small proteins - antibodies in AIDS patients

19. Viruses similar to HIV
HIV-2: was isolated from AIDS patients in West Africa 1986
Simian immunodeficiency virus (SIV): was isolated from monkeys with an AIDS-like illness
Human T-cell lymphotropic virus (HTLV-4): infect T cells, no kill, no disease

20. Summary of Replicative cycle
Typical retrovirus cycle
Entry: (gp120, binding ; gp41, fusion)
- Chemokine receptors (CXCR4, CCR5)
- Mutation in these receptors (infection??)
Uncoating, Treanscription of viral RNA genome „RNA-dependent DNA polymerase“
Transcription of viral mRNA from proviral DNA by host cell RNA polymerase
Translation to several large polyproteins
Released by budding from the cell membrane

21. T4 (CD4+) cells are major target
HIV - Life History
Entry into the cell
T4 (CD4+) cells are major target
Human HeLa Cell transfected with CD4 antigen
Human HeLa Cell
Human HeLa cells are not infected by HIV because they do not have CD4 antigen. When CD4 gene was transfected into the HeLa cells, they became able to bind HIV and were infected.
NOT INFECTED
INFECTED

22. Chemokine receptors are necessary co-receptors along with CD4 antigen
HIV - Life History
HIV
chemokine
Mutant CCR5
CD4
CCR5
CD4
CCR5
CD4
macrophage
Chemokine receptors are necessary co-receptors along with CD4 antigen

23. Transmission & Epidemiology
Sexual contact
Blood transfusion
From infected mother to neonate
or via breast feeding
Infection occurs by transfer of either HIV-infected cells or free HIV
2/3 of AIDS victims living in Africa, Asia, & Latin america
AIDS is the 4th leading cause of death worldwide

24. Pathogenesis & Immunity

25. The cellular and immunological picture - The course of the disease
This time course of HIV infection applies to persons not receiving chemotherapy.

26. The cellular and immunological picture - The course of the disease

27. 10 billion HIV particles per day Virus half life 5.7 hours
million virions per ml blood (set point)
Small minority of T4 cells are infected
Virus found in lymph nodes

28. Inexorable decline of CD4+ T4 cells
Why do all of the T4 cells disappear?
At early stages of infection only 1 in 10,000 cells is infected Late 1 in 40

29. Virus destroys the cell as a result of budding
But few cells are infected:
Early stage of infection 1:10,000
Late 1:40
Why do all T4 cells disappear?
1. PUNCTURED MEMBRANE

30. Why do all T4 cells disappear?
But syncytia not common
Most T4 cells are not HIV+
Could “sweep up” uninfected cells
Infected CD4 cell
Gp120 positive
Cells Fuse
Uninfected CD4 cell
Gp120 negative
Killing of CD4 cells 2. Syncytium Formation

31. Killing of CD4 cells 3. Cytotoxic T cell-mediated lysis
Why do all T4 cells disappear?
Cytotoxic T cell
Killing of CD4 cells 3. Cytotoxic T cell-mediated lysis
BUT: Most cells are not infected

32. Killing of CD4+ cells 4. Binding of free Gp120 to CD4 antigen makes uninfected T4 cell look like an infected cell Complement-mediated lysis
Could account for the loss of uninfected T4 cells

33. Clinical Findings Erly, acute stage Middle, latent stage
Late, immunodeficiency stage

34. Macrophages bring HIV into the body if sexually transmitted
High virus titer
Mild symptoms
Fall in CD4+ cells but recovers
Rise in CD8+ cells but recovers
A high virus titer (up to 10 million viruses per ml blood)
Macrophages infected
Macrophages bring HIV into the body if sexually transmitted
The cellular and immunological picture
The course of the disease
1. Acute Infection
HIV is now NOT replicating in resting T4 cells and most are resting in the peripheral circulation. At this time most replication is in lymph nodes in macrophages and dendritic cells.
Symptoms are ‘flu or mononucleosis-like.There is a cellular immune response within weeks. Antiviral antibodies and cytotoxic T cells rise to high levels and persist for years. They are very effective at keeping the virus in the circulation at low levels. The CD8 cells rises transiently while CD4 cells fall but5 again recover (almost at least). The loss of these CD4 cells may result from DIRECT INFECTION of T cells in the circulation.
Although antibodies lower HIV in blood, infection persists in the lymph nodes and in macrophages

35. 2. A strong immune response
Virus almost disappears from circulation
Good cytotoxic T cell response
Soluble antibodies appear later against both surface and internal proteins
Most virus at this stage comes from recently activated (dividing) and infected CD4+ cells
CD4+ cell production compensates for loss due to lysis of cells by virus production and destruction of infected cells by CTLs
2. A strong immune response

36. 3. A latent state Latency of virus and of symptoms
Virus persists in extra-vascular tissues
Lymph node dendritic cells
Resting CD4+ memory cells (last a very long time - a very stable population of cells) carry provirus
Persistent infection with no or minor symptoms: Night sweats, generalized lymphadenopathy, diarrhea
Virus persists as provirus in resting memory T cells. Reactivation of cells occurs contributing to overall viral load but this does not at this stage significantly affect CD4 cell number.
Nevertheless, CD4 cells drop in number throughout infection

37. 4. The beginning of disease
Massive loss of CD4+ cells
CD4+ cells are the targets of the virus
Cells that proliferate to respond to the virus are killed
Dendritic cells present antigen and virus to CD4 cells
Epitope variation allows more and more HIV to escape from immune response just as response wanes
Apoptosis of CD4+ cells
HIV patients with high T4 cell counts do not develop AIDS
4. The beginning of disease

38. 5. Advanced disease - AIDS
CD8+ cells destroy more CD4+ cells
CD4 cell loss means virus and infected cells no longer controlled
As CD4+ cells fall below 200 per cu mm virus titer rises rapidly and remaining immune response collapses
CD8+ cell number collapses
Opportunistic infections
Death in ~2 years without intervention
5. Advanced disease - AIDS
Also neuroplogical manifestations, lymphoid neoplasms
Opportunistic infects occur when CD4 cells drop below 300 cells per cu mm
Mechanism of this loss is still uncertain

39. HIV and AIDS Good correlation between number of HIV particles
measured by PCR and
progression to disease

40. HIV and AIDS
Viral load predicts
survival time

41. progression to disease
HIV and AIDS
CD4 cell count is not a
good predictor of
progression to disease

42. Laboratory Diagnosis ELISA Western Blot Analysis (gp41, p24)
OraQuick (rapid screening immunoassay)
PCR (very sensitive and specific method)

43. Anti-HIV Strategies Highly Active Anti- Retroviral Therapy
HAART: Two nucleoside analog RT inhibitors and 1 protease inhibitor
Now also: Two nucleoside analog RT inhibitors and 1 non nucleoside

44. HAART has greatly slowed death rate
Remember!
Education led to leveling off of rate of increase in AIDS
HAART has greatly slowed death rate
The fact that fewer people are dying per year from the infection means that the number of HIV-infected people in the population is rising!!!
Unless education continues to be successful and unless we can cure infected people of virus, the problem of virus spread, and will continue to be, with us