HIV Vaccine Research

Created by Ramil Sapinoro Laboratory of Dr. Stephen Dewhurst University of Rochester Medical Center

History of HIV
HIV-1 arises
1930 1959

AIDS emerges
1981 1983

HIV-2 identified
1986 1997 2006

Earliest sero-positive

HIV-1 identified

Advent of HAART

HIV

HIV Virion Structure HIV: Virion (Virus Particle)

gp120 gp41 viral e nvelope glycoproteins

viral RNA (ss ) (2 copie s)

lipid membrane of enve lope (h ost derive d)

re vers e transcriptas e

viral core (p24)

matrix (p17)

CD4

T Cell

HIV Lifecycle

Course of HIV Infection Course of HIVinfection

Primary Infection Seeding of lymphoid organs Dissemination AIDS (Opportunistic Infec tions ) 10 6 Clinical Latenc y 10 10 ~0.1 log per year rise in HIV load 10
5 4 3

Virus RNA (copies/ml)

CD4 count (cells/l)

1000 750 500 250 0

10 2

6
Weeks

12

10

11

12

Years
Mod ified from Sa bin et al. JAIDS 23:172 , 20 00.

Worldwide HIV -1 infections, Dec 2005 Global HIV infections,Dec. 2002

http//ww w .unaids.org/hivaidsinfo/documents.html E. Eur/Cen Asia 1.2 million Subtypes: B & ? Sth, SEAsia 6.0 million Subtypes: C, E, B E. Asia, Pacific 1.2 million Subtypes: C & ? Global Total (approx) Total: 42 million

N. Ame rica 1.0 million Subtypes: B

W. Europe 0.6 million Subtypes: B

Africa 30.0 million Subtypes: C, A, D, E, B Latin Ame rica, Caribbe an 1.9 million Subtypes: B, C
Omitt ed subt ypes F-J (rare); groups N, O

HIV Treatment: Anti-virals

Reverse Transcription Inhibitors

Protease Blockers

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 kill those cells

Challenges in HIV Vaccine Research

Viral Genetic Diversity: HIV is not just one specific virus. Immune Protection: We dont know what immune responses are needed, or how strong they need to be. Neutralizing Antibody: Difficult to generate broadly neutralizing antibodies. Vaccine Testing: Slow process, very expensive

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

T Cells *Involved in the killing of virus-infected cells *Adaptive Immunity

B Cells *Involved in making antibodies *Adaptive Immunity

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

Viral Antigen

MHC

APC

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T APC

HIV Vaccine Approaches

Protein subunit

Synthetic peptide
Naked DNA Inactivated Virus Live-attenuated Virus

Live-vectored Vaccine

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

Vaccine Vector Platform

Vaccine Approach: Engineer, characterize and optimize a viral vector system that can be used to deliver HIV antigen(s) to antigen presenting cells (APCs) and that could also improve immune responses to induce longterm immunological memory Viral Vectors
HSV-based Amplicon Vector Recombinant Adenovirus Type 5 Vector Bacteriophage Lambda Vector

In vivo expression of a luciferase reporter gene delivered by Amplicon vectors

K. Santos

Inoculation of Amplicon particles expressing HIV-1 gp120 results in a durable cellular immune response

Percent Positive Cells

21 days post-infection

171 days post-infection

P. Hocknell

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

Percent Killing

P. Hocknell

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

Endpoint Antibody Titer

P. Hocknell

Adenovirus Biology
Non-enveloped, DNA virus Primary cell surface receptor: Coxsackie and Adenovirus Receptor (CAR)
Expressed on many cells types

Fiber knob

APC

Lungs Heart

T
Muscle

B
Liver

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T APC

APC-targeted Ad

Target Receptor

APC

APC-targeted Ad Target Receptor

APC

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T APC

APC-targeted Adenovirus expressing a reporter gene enhances transduction of APCs

APC only Ad-GFP only

APC-targeted Ad-GFP

R. Sapinoro

Thirty-six years ago, President Kennedygave 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 to developing 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.