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HIV Vaccine Research

Created by Ramil SapinoroLaboratory of Dr. Stephen Dewhurst

University of Rochester Medical Center

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History of HIV

1930

HIV-1arises

1959

Earliestsero-positive

1981

AIDSemerges

1983

HIV-1identified

1986

HIV-2identified

1997

Advent ofHAART

HIV

2006

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HIV: Virion (Virus Particle)

gp120

gp41

viral e nvelopeglycoproteins

lipidmembrane of

envelope

(host derived)

matrix (p17)

viral core(p24)

reversetranscriptase

viral RNA (ss)(2 copies)

HIV Virion Structure

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HIV Lifecycle

T Cell

CD4

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Course of HIV infection

0 3 6 9 12 1 2 3 4 5 6 7 8 9 10 11 12

Weeks Years

Primary InfectionSeeding of lymphoid organs

Dissemination

0

250

500

750

1000

CD4count(cells/

l)

Clinical Latenc y

Virus

RNA

(copies/ml)

AIDS(Opportunistic

Infections)

Modified from Sabin et al. JAIDS 23:172 , 2000.

~0.1 log per yearrise in HIV load

10

10

10

10

10

6

5

4

3

2

Course of HIV Infection

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Worldwide HIV -1 infections, Dec. 2002

N. America

1.0 millionSubtypes: B

Latin America, Caribbe an1.9 million

Subtypes:B, C

Africa30.0 million

Subtypes:C, A, D, E, B

W. Europe0.6 million

Subtypes: B

Sth, SE Asia6.0 million

Subtypes: C, E, B

Global Total (approx)Total: 42 million

http//ww w.unaids.org/hivaidsinfo/documents.html

Omitted

subt ypes F-J (rare); groups N, O

E. Asia, Pacific1.2 million

Subtypes:C & ?

E. Eur/Cen Asia1.2 million

Subtypes:B & ?

Global HIV infections, Dec 2005

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HIV Treatment: Anti-virals

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X

Reverse TranscriptionInhibitors

Protease Blockers

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What Might a Successful Vaccine

Do? Antibodies

Bind virus; neutralize or stop virus from

infecting cells; eliminate virus Cytotoxic T lymphocytes (CTL)

Recognize cells infected with virus and killthose cells

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Challenges in HIV Vaccine

Research

Viral Genetic Diversity: HIV is not

just one specific virus.

Immune Protection:We dont know

what immune responses areneeded, or how strong they need to

be.

Neutralizing Antibody: Difficult to

generate broadly neutralizing

antibodies.

Vaccine Testing: Slow process, very

expensive

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but on the Brightside

Precedent from other systems:

Success against other viral

infections

Precedent from animal studies:Long-term control of infection in

vaccinated monkeys

Immune control of HIV-1: Infected

individuals control infection

Vaccine Trials: In progress

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Antigen Presenting Cells*First-line Defense*Involved in capturing antigen*Display foreign antigens to

activate T Cells

T Cells*Involved in the killing of

virus-infected cells*Adaptive Immunity

B Cells*Involved in making

antibodies*Adaptive Immunity

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MHC

Viral Antigen

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APC

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T

APC

BT

.

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HIV Vaccine Approaches

Protein subunit

Synthetic peptide

Naked DNA

Inactivated Virus

Live-attenuatedVirus

Live-vectored Vaccine

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Status of HIV Vaccine

Development Over 60 Phase I/II trials of 30 candidate

vaccines

United States, Thailand, South Africa,Brazil

One Phase III trial

VaxGen gp120 protein subunit vaccine

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Vaccine Vector Platform

Vaccine Approach: Engineer, characterizeand optimize a viral vector system that can beused to deliver HIV antigen(s) to antigenpresenting cells (APCs) and that could alsoimprove immune responses to induce long-term immunological memory

Viral Vectors HSV-based Amplicon Vector

Recombinant Adenovirus Type 5 Vector

Bacteriophage Lambda Vector

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In vivoexpression of a luciferase reporter gene delivered byAmplicon vectors

K. Santos

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PercentPositiveCells

21 days post-infection 171 days post-infection

Inoculation of Amplicon particles expressing HIV-1 gp120results in a durable cellular immune response

P. Hocknell

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Inoculation of Amplicon particles expressing HIV-1 gp120results in the production of gp120-specific cytotoxic T cells

Percent

Killing

P. Hocknell

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Inoculation of Amplicon particles expressing HIV-1 gp120results in the production of gp120-specific antibody

EndpointAntib

odyTiter

P. Hocknell

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Adenovirus Biology

Non-enveloped, DNA virus

Primary cell surface receptor:

Coxsackie and Adenovirus Receptor(CAR) Expressed on many cells

types

Fiber knob

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T B

APC

Heart

Muscle

Lungs

Liver

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APC

T

BT

.

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Target Receptor

APC

APC-targeted Ad

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APC-targeted Ad

APC

Target Receptor

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T

APC

BT

.

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APC-targeted Adenovirus expressing areporter gene enhances transduction of

APCsAd-GFP only APC-targeted Ad-GFPAPC only

R. Sapinoro

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Thirty-six years ago, President

Kennedy gave us a goal of

reaching the moon, and we achieved

it - ahead of time

Let us today set a new national goal

for science in the age of biology.

Today, let us commit ourselves todeveloping an AIDS vaccine within

the next decade

- President Bill Clinton, 1997

Vaccine development remains the #1

priority of AIDS research. It is the best

hope for protection against HIV infection.