Novel strategies for prevention and treatment of HIV infection Prasit Faipenkhong Pairoaj Vonghathaipaisarn Rodjana Chunhabundit Zhang Jianjun

2 Outline 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 Introduction

4 Promising strategies for treatment or prevention gene therapy Interleukin-2 Introduction vaccines

Interleukin-2

6 cytokine helper T cells (CD4+ T cells), cytotoxic T cells (T c, 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)

7 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 Aldesleukin

9 Aldesleukin has been approved by FDA for treating metastatic renal cell carcinoma and metastatic melanoma phase III clinical trials in HIV infected patients

10 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 duration of intermittent therapy appears to be important Adversely affects virtually every organ system requiring aggressive supportive care Flu-like symptoms swelling, redness, or lumps capillary leak syndrome (CLS)

Gene therapy

13 Gene therapy in HIV Ribozymes: inhibit viral replication fold in T-cells, and CD34 stem cell progeny (Phase I) Intracellular immunizations: against tat, rev, reverse transcriptase Transdominant mutant cells transduced with vector carrying rev M10 gene survived and expressed the gene for longer time periods

Vaccines

15 The need for HIV vaccine high infection rate, high cost of symptomatic treatment and drug therapy to stop the global HIV pandemic Vaccines Types of HIV vaccine inactivated or killed vaccines, live attenuated vaccines,subunit vaccines, live vector-based vaccines, DNA vaccines

16 Subunit vaccines Components of a pathogenic organism Advantages: stable, safe, defined chemically and free from contaminate proteins and nucleic acids Disadvantage: expensive, altered conformation of antigenic determinants gp120 induce Ab in > 99 % of the subjects phase III clinical trials

17 Subunit vaccines gp160 broaden binding Ab response and boost cellular immune responses induce strong T cell responses against a variety of HIV Ag no evidence that gp160 has efficacy as therapeutic vaccine in early stage HIV infection

18 Live vector-based vaccines Live virus or bacteria vectors carrying HIV gene Vaccinia-env, vaccinia-env/gag/pol, canarypox-env,canarypox-env/gag phase I or II Sustained expression of large amount of HIV Ag, neutralizing Ab, CTLs responses

19 DNA vaccines Research Findings chimpanzees immunized with plasmids carrying four HIV genes (env, rev, gag, pol) can be protected against HIV infection rhesus monkey immunized with plasmids carrying only env gene can be protected against HIV infection Human studies will be held in China at early 2001

20 Summary interleukin-2: phase III gene therapy: phase I or II vaccines: phase III