Novel strategies for Novel strategies for prevention and prevention and treatment of HIV treatment of HIV infectioninfection

Prasit Faipenkhong Pairoaj Vonghathaipaisarn

Rodjana Chunhabundit Zhang Jianjun

Prasit Faipenkhong Pairoaj Vonghathaipaisarn

Rodjana Chunhabundit Zhang Jianjun

2

OutlineOutline•Introduction

• -Interleukin 2

•Summary

•Gene therapy

•Vaccines

3

• Problems with currently available antiretroviral therapy

•only control not cure•viral resistance•drug-drug interactions•adverse effects

IntroductionIntroduction

4

•Promising strategies for treatment or prevention

•gene therapy

• -Interleukin 2

IntroductionIntroduction

•vaccines

-2Interleukin-2Interleukin

6

•cytokine•helper T cells (CD4+ T cells), cytotoxic T cells (Tc, CD8+ T cells), natural killer cells (NK cells)• induce proliferation and differentiation of CD4+ T cells and cytotoxic T cells induce B cell proliferation, stimulate macrophage activity, increase number and toxicity of NK cells

Interleukin-2 (IL-2)Interleukin-2 (IL-2)Interleukin-2 (IL-2)Interleukin-2 (IL-2)

7

Interleukin-2 (IL-2)Interleukin-2 (IL-2)Interleukin-2 (IL-2)Interleukin-2 (IL-2)

•production is decreased in HIV infected patients

8

•a human IL-2 derivative•absence of a N-terminal alanine, replacement of cysteine with serine at position 125, absence of glycosylation• possess immunological activities similar to -those observed in native IL 2

AldesleukinAldesleukinAldesleukinAldesleukin

9

AldesleukinAldesleukinAldesleukinAldesleukin

• has been approved by FDA for treating metastatic renal cell carcinoma and metastatic melanoma•p hase III clinical trials in HIV infected patients

10

Clinical aspect of aldesleukin Clinical aspect of aldesleukin• Immunological benefits in several clinical trials increase CD4 + cells without sustained increase in viral load

• Subcutaneous injection is similar to intravenous infusion improvement in immunological parameters

•Lower dosage (3 MIU/day) is still effective increase CD4+ counts

11

Clinical aspect of aldesleukin Clinical aspect of aldesleukin

•duration of intermittent therapy appears to be important

•Adversely affects virtually every organ system requiring aggressive supportive care

•Adversely affects virtually every organ system requiring aggressive supportive care

Flu-like symptoms

swelling, redness, or lumps

capillary leak syndrome (CLS)

Gene therapyGene therapy

13

Gene therapy in HIVGene therapy in HIV

Ribozymes: - inhibit viral replication 1 0 1 0 0 0 fold in

- T cells, and CD3 4 stem cell progeny (Phase ee

eeeeeeeeeeeee ee e eeeeeeeeeee against tat, rev, reverse transcriptase

Transdominant mutant cells transduced with vector carrying rev

M1 0 gene survived and expressed theeeee eee eeeeee eee e eeeeeee

VaccinesVaccines

15

•The need for HIV vaccine

high infection rate, high cost ofsymptomatic treatment and drug therapy

to stop the global HIV pandemic

VaccinesVaccines

•Types of HIV vaccine

eeeeeeeeeee ee eeeeee eeeeeeeee eeee eeeeeeeeee -vaccines,subunit vaccines, live vector based

vaccines, DNA vaccines

16

Subunit vaccines Subunit vaccines Subunit vaccines Subunit vaccines

•Components of a pathogenic organism•Components of a pathogenic organism

•Advantages: stable, safe, defined chemically and free from contaminate proteins and nucleic acids

•Advantages: stable, safe, defined chemically and free from contaminate proteins and nucleic acids

•Disadvantage: expensive, altered conformation of antigenic determinants

•Disadvantage: expensive, altered conformation of antigenic determinants

•gp120•gp120

99induce Ab in > % of the subjects phase III clinical trials

99induce Ab in > % of the subjects phase III clinical trials

17

Subunit vaccines Subunit vaccines Subunit vaccines Subunit vaccines

•gp160•gp160

broaden binding Ab response and boost cellular immune responses

induce strong T cell responses against a variety of HIV Ag

no evidence thatgp1 6 0 has efficacy as therapeutic vaccine in early stage HIV

infection

broaden binding Ab response and boost cellular immune responses

induce strong T cell responses against a variety of HIV Ag

no evidence thatgp1 6 0 has efficacy as therapeutic vaccine in early stage HIV

infection

18

Live vector-based vaccinesLive vector-based vaccinesLive vector-based vaccinesLive vector-based vaccines

•Live virus or bacteria vectors carrying HIV gene

•Live virus or bacteria vectors carrying HIV gene

• - -, / / , - -canarypox env,canarypox env/gag

phase I or I I

• - -Vaccinia env, vaccinia env/gag/pol, - -canarypox env,canarypox env/gag

phase I or I I • Sustained expression of large amount of eeeeeeeeeeee eee eeee eeeeeeeee, ,

• Sustained expression of large amount of HIVAg, neutralizing Ab, CTLs responses

19

DNA vaccinesDNA vaccinesDNA vaccinesDNA vaccines•Research Findings

chimpanzees immunized with plasmids carrying four HIV genes (env, rev, gag, pol)

can be protected againstHIV infection

chimpanzees immunized with plasmids carrying four HIV genes (env, rev, gag, pol)

can be protected againstHIV infection

rhesus monkey immunized with plasmids carrying only env gene can be protected

againstHIV infection

rhesus monkey immunized with plasmids carrying only env gene can be protected

againstHIV infection

•Human studies will be held in China at early 2001

•Human studies will be held in China at early 2001

20

SummarySummary• - interleukin 2 : phase III• gene therapy: phase I or II• vaccines: phase III