HIV and AIDS

Acquired Immunodeficiency Syndrome • Disease caused by an infectious agent: a retrovirus

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HIV and AIDS
History of an infectious agent In Los Angeles 1967-1978: only two cases of Pneumocystis carinii pneumonia • 1979 - 5 cases of Pneumocystis carinii pneumonia All Homosexual
Dot-like intracystic bodies of Pneumocystis carinii in lung
Cytologic preparation from a bronchoalveolar lavage – Giemsa stain

Pneumocystis jiroveci 2

HIV and AIDS
History of an infectious agent

Pneumocystis pneumonia
107 cases of Pneumocystis carinii pneumonia reported in the United States before the AIDS epidemic AIDS epidemic has resulted in 166,368 cases up to 1999

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HIV and AIDS

With dissemination to extrapulmonary sites, Pneumocystis carinii tends to produce foci with prominent calcification, as 4 seen in the kidney

HIV and AIDS
an infectious agent – Kaposi’s Sarcoma Early 1981 MMWR: 5 cases of Kaposi’s sarcoma Hitherto: rare (immunocompromization) Elderly - Non-aggressive 1981 - 26 cases of Kaposi’s sarcoma • Young • Male • San Francisco and New • All York Homosexuals
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HIV and AIDS
an infectious agent – Kaposi’s Sarcoma

Before 1981: 40 - 120 cases per year in United States 1981-1999: 46,684 definite cases in United States

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HIV and AIDS
Two rare diseases in the gay community linked to

IMMUNOSUPPRESSION OPPORTUNISTIC INFECTIONS
Also Lymphadenopathy (diffuse, undifferentiated non-Hodgkins lymphoma) 1977- 1980: No cases in the young male (20 - 39 years old) population of the San Francisco area March 1981 - January 1982: four cases within 10 months • Gay-Related Immune Deficiency • Acquired Immune Deficiency Syndrome (AIDS)
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HIV and AIDS
Little in common but: • Young • White • Male • Large towns • Homosexual community But not all gay men got the disease
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HIV and AIDS
Distinguishing characteristics

• Clusters of infected men • Apparent concentration within sexually interactive groups • High numbers of sex partners Suggests an infectious agent
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HIV and AIDS
More evidence for an infectious agent
Different ways of getting a similar syndrome • Blood transfusions • Intravenous drug use • Hemophilia (clotting factor) Female sex partners of AIDS-positive IV drug users and hemophiliacs
Not just in the Gay community Haitian origin
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HIV and AIDS
1983: The 4H Club
• Homosexuality among males • Hemophilia • Heroin use (drug use that may involve shared needles) • Haitian origin

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HIV and AIDS
Obvious agent: A virus……that is now in the blood supply Primary route of transmission: Sex AIDS is a sexually-transmitted viral disease

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HIV and AIDS The Cellular Picture
CD4+ T4 helper cells A fall in the CD4+ cells always precedes disease In advanced disease: the loss of another cell type CD8+ cytotoxic killer cells Suggests an infectious agent
A virus But initially difficult to grow Rapidly kills cells on which it grows
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ss of one cell type throughout the course of the dise

AIDS • AIDS is currently defined as the presence of Definition 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 14 us

AIDS Statistics
• Approximately 30,000,000 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 15

AIDS Statistics
• As of December 2006, 1,106,400 Americans have been reported with AIDS • At least half of them have died • 9,101 children under 15

About ONE MILLION persons in the United States are living with HIV infection
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HIV and AIDS

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HIV and AIDS

Prevalaence

AIDS Deaths

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HIV and AIDS

Black White Hispanic

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AIDS Statistics
• About 1 million new cases of AIDS per year

Sub-Saharan Africa

• At least 20 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

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Impact of AIDS on life expectancy in five African countries, 1970–2010

70 65 60 55

Botswana South Africa Swaziland Zambia Zimbabwe

Life expectancy at birth (years)

50 45 40 35 30 25 20 1970–1975 1980–1985 1990–1995 2000–2005 1975–1980 1985–1990 1995–2000 2005–2010

Source: United Nations Population Division (2004). World Population Prospects: The 2004 Revision, database.

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4.1

HIV prevalence (%) in adults in Africa, 2005

Zimbabwe

Botswana Lesotho Swaziland
2.5

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Several countries in sub-Saharan Africa report infection rates of over 25%, especially urban areas

• Zimbabwe: 33.7% of adult population infected • 90% of truck drivers in Zimbabwe are infected • In Zambia, 1 in 5 urban girls is HIVpositive by the age of 20
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Human Immunodeficiency Virus

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HIV and AIDS The Virus
The virus only grows on T4 cells that are proliferating in response to an immune stimulus -- Therefore difficult to grow in culture Reverse transcriptase in activated T4 cells in blood of patients with AIDS • Robert Gallo : HTLV-3 • Luc Montagnier and Françoise Barré-Sinoussi: LAV

uman Immunodeficiency Virus (HIV)

Human immunodeficiency viral particles are seen at medium magnification in this electron micrograph (CDC) 25

HIV and AIDS
The cellular and immunological picture - The course of the disease

virus

antibody
CD4 cells

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HIV and AIDS
The cellular and immunological picture - The course of the disease

CD8 cells

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HIV and AIDS
The cellular and immunological picture The course of the disease
• High virus titer 1. Acute Infection • 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 the body if sexually transmitted Macrophages bring HIV into
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HIV and AIDS
2. A strong immune response
Virus almost disappears from circulation • Good cytoxic 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 •

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HIV and AIDS
3. A latent state Latency of virus and of symptoms • Virus persists in extravascular tissues • Lymph node dendritic cells • Resting CD4+ memory cells (last a very long time - a very stable population of cells) carry

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HIV and AIDS
• 10 billion HIV particles per day • Virus half life 5.7 hours • 100-10 million virions per ml blood (set point) • Small minority of T4 cells are infected • Virus found in lymph nodes
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HIV and AIDS

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 by it • 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
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HIV and 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
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5. Advanced disease - AIDS

HIV and AIDS

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

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HIV and AIDS

Viral load predicts survival time

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HIV and AIDS

CD4 cell count is not a good predictor of progression to disease

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HIV and AIDS

Cofactors
Not all cases of Kaposi’s are associated with HIV Not all HIV infected persons suffer from Kaposi’s 20% of homosexual HIV+ males get Kaposi’s Kaposi’s sarcoma associated herpes virus Few IVHuman herpes virus-8 drug users or hemophiliacs get 37

HIV and AIDS
Three Views of AIDS Gallo: Infection by HIV is sufficient to cause AIDS Montagnier: HIV may be harmless in the absence of other co-factors Duesberg / Mullis: HIV is too silent to be the etiologic agent of AIDS. It is a much maligned by-stander So far it seems that >50% of HIV-infected persons have progressed to AIDS There is NO strong evidence there is any other 38 infectious agent involved than HIV

HIV - The Virus
Retrovirus

Membrane: host derived
Three genes GAG – POL – ENV Three polyproteins

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HIV - The Virus
Retrovirus

Two glycoproteins: gp160 gp41 sugars ENV gene

gp120 and

gp41 is fusogen that spans the membrane
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vaccine problem

HIV - The Virus
Retrovirus
Group-Specific Antigens

17: inner surface - myristoylated p24: nucleocapsid

9: nucleocapsid associated with RNA

GAG gene
Polyprotein
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HIV - The Virus
Enzymes

Retrovirus

• Polymerase (reverse transcriptase – RNA dependent DNA polymerase) • Integrase • Protease (cuts polyproteins)

• POL gene
Polyprotein
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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
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HIV - The Virus

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HIV - The Virus
Life History
A retrovirus
• Latency • Specific destruction of CD4+ cells

• How does the virus 45

HIV - Life History
• Fusion at ambient pH • No need for entry into lysosomes • Syncytia Profound significance for AIDS progression: Spread from cell to cell Profound significance for therapy: Humoral antibody will 46 not stop spread – need

HIV - Life History
Entry into the cell T4 (CD4+) cells are major target Human HeLa Cell Human HeLa Cell transfected with CD4 antigen

NOT INFECTED

INFECTED

But NOT the whole answer since this does not happen if CD4 is transfected into a MOUSE cell

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HIV - Life History
Why do CD4-transfected human cells become infected but CD4-transfected mouse cells do not?
Human cells must possess a co-factor for infection that mouse cells do not

Co-Receptors CD8+ Cells MIP-1 alpha MIP-1 beta RANTES

Chemokines Block HIV infection of macrophages
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HIV - Life History

HIV

CD4 CD4 CCR5

CCR 5

chemokin e
CD4

Mutant CCR5

macrophage Chemokine receptors are necessary co-receptors along with CD4 antigen
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HIV and AIDS
Some people do not get AIDS

Long term survivors Exposed uninfected persons
The chemokine receptor story

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HIV and AIDS
Co-receptors and HIV infection
• CCR5 is a chemokine receptor • Cells with homozygous mutant CCR5 molecules are not infected by HIV 1 in 100 Caucasians No Africans • Persons with heterozygous mutant CCR5 molecules progress to AIDS more slowly
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HIV and AIDS Co-receptors
• 25% of long term survivors are CCR5 or CCR2 mutants (deletions) • The same CCR5 mutation (called “delta 32”) is thought to be the mutation that rendered some people immune to the plague in the middle • Many other chemokine receptors ages
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HIV and AIDS

Long term non-progressers
• People who have been infected with HIV for more than seven years that have stable CD4+ cell counts above 600 per cu mm with no symptoms and no chemotherapy • Many have produced a very good immune response to the virus
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HIV and AIDS
• Nairobi prostitutes
Client infection rate more than 25%

• Rare HLA antigens
• Associations between resistance to infection and their class I and class II MHC (HLA) haplotypes
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HIV - Life History

HIV is a retrovirus

t carries with it:
HIV genes
GAG POL ENV

• Reverse transcriptase

• Integrase

• Protease

• tRNA primer HIV has no oncogene but could still be oncogenic

vaccine problem

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HIV - Life History

Latency – Cellular – The problem of memory T4 cell cel

y activated T4 cells can replicate virus

st infected T4 cells are rapidly lyzed but are replaced

me T4 cells revert to resting state as memory cells which are long-liv

mory T4 cells cannot replicate the virus unless they become activate

Clinical Latency
HIV infection is not manifested as disease for years
56 During apparent clinical latency, virus is being replicated

apoptosis etc

Dynamics of CD4 T cells in an HIV infection ChronicallyCell death
Return to resting state

infected memory T cells with provirus

Uninfecte d

Infectio n

activat ed
T cell

Long lived!
Uninfecte d unactivat ed

Reactivati on

Cell death immune destruction

Long lived!
Adapted from Saag and Kilby Nat Med 5: 609, 1999

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Long term latent HIV
Immune response

T4 resting memory cell

T4 activated

It may be impossible to cure the patient of HIV Even if combination therapy stops HIV replication HIV production
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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 Of great importance to therapeutic strategy
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Virus destroys the cell as a result of budding

But few cells are infected: Early stage of infection 1:10,000 Late 1:40

1. PUNCTURED MEMBRANE

Why do all T4 cells disappear? 60

Why do all T4 cells disappear? 2
Infected CD4 cell Gp120 positive

But syncytia not common Most T4 cells are not HIV+ Could “sweep up” uninfected cells

Cells Fuse

Killing of CD4 cells 2. Syncytium Formation

Uninfected CD4 cell Gp120 negative

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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

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

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Why do all T4 cells disappear?
Induction of apoptosis

CD8 cell
HIV
(no CD4 antigen)

gp120 chemokine

Macrophage

?

CXCR4 chemokine receptor

G protein signal

?

Binding to CXCR4 results in expression of TNFalpha receptor II

Binding to CXCR4 results in expression of TNF-alpha on the cell surface

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Why do all T4 cells disappear?
Induction of apoptosis

CD8 cell
CXCR4

Macrophage

Death

CD8 T cell apoptotic bodies

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HIV

Macrophages may be infected by two routes
gp12 0 CD 4

HIV gp120 binds to macrophage CD4 antigen Virus is opsonized by anti gp120 antibodies which bind to macrophage Fc receptors - an enhancing antibody

Fc receptor Antigp120

vaccine problem
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HIV

Macrophages - The Trojan Horse
Early HIV isolated during infection are macrophage tropic (have a macrophage chemokine co-receptor (CCR5)) Virus probably infects patient via macrophages in semen etc Infection by HIV leads to altered cytokine production “slim disease” Macrophages form a Visna in outside the blood Slim disease very like reservoirsheep - also infects macrophages Carry virus into different organs (brain) Non-proliferating mature macrophages sustain HIV 67 production for a long time without being killed by

Population Polymorphism
HIV is a retrovirus
Retroviruses use host cell RNA polymerase II to replicate their genome Pol II has a high error rate 1:2,000-10,000 HIV genome 9749 nucleotides
Therefore EVERY new virus has at least one mutation! Every possible single mutation arises daily 1% of all possible double mutations arise daily The HIV that infects a patient is very different from that seen by vaccine

problem 68

Population Polymorphism
• Initial infecting virus is

macrophage-tropic (has CCR5 as co-receptor) • These are non-syncytiuminducing strains (Note: most vaccines have been made against syncytiuminducing T4 cell tropic strains) • As virus mutates, it changes 69

Population Polymorphism
Early in infection:
• Macrophage-tropic • Non-syncytium-inducing • Slowly replicating

Late in infection •T4 cell tropic vaccine problem
• Syncytium-inducing • High titer virus
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Population Polymorphism
• The most variable protein is gp120 • Amino acid sequence within a single patient varies by 1-6% • Up to 30% in population

vaccine problem

• Glycosylation masks conserved sites

vaccine problem
Co-infection may result in recombination

vaccine problem

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Population Polymorphism
• Variation in reverse transcriptase leads to resistance to nucleoside analogs

drug problem

• Variation in protease leads to resistance to protease inhibitors

drug problem

Polymorphism due to high mutation rate as a result of lack of proof-reading in reverse transcriptase and RNA pol II Sub-populations arise with altered cell
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Other cells infected by HIV CD4•

Epithelial cells of bowel and vagina • Endothelial cells of brain

• Brains cells : Astroglia, oligodendroglia

73 Galactocerebroside

Anti-HIV Strategies

Education

Sexually transmitted Not highly infectious

• Chemotherapy
Mutation selection but Suppress replication No capacity for mutation74 Resistance

Anti-HIV Strategies
Highly Active AntiRetroviral Therapy
HAART: Two nucleoside analog RT inhibitors and 1 protease inhibitor
75 Or: Two nucleoside analog RT inhibitors and 1 non nucleoside

Does HIV Cause AIDS?
Single common factor between: • Gay San Franciscans • New York I.V. drug users • African heterosexuals • Hemophiliacs • Spouses of hemophiliacs and drug users
76 • Children of hemophiliacs and drug users

Does HIV Cause AIDS?
• HIV precedes AIDS in every population in which AIDS occurs • Infection by cloned virus
SIV HIV

Simian AIDS

Human AIDS

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Education led to leveling off of rate of increase in AIDS

Remember!

• 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 78 infected people of virus, the problem of

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