stem cell based gen therapy

Stem-Cell-Based Gene

Therapy for HIV

Infection VIPIN MOHAN

2011-09-112

College of Agriculture

Vellayani, TVM

HIV lifecycle

Engineering HIV Resistant Cells

• The first targets are cellular genes necessary for viral replication.

• Second strategy directly targets HIV gene expression itself.

• Lastly, one that introduces genes that interfere with HIV replication, such as

host restriction factors and fusion inhibitors.

Targeting Expression of Cellular Genes that Are

Essential for Viral Replication

• CCR5 gene

• Berlin patient- bone marrow transplantation

• Maraviroc – inhibitor of CCR5 / HIV interaction.

• Genetherapy modifies peripheral blood T cells or HSCS can be used to

mimic the CCR5 Δ32 / Δ32 condition

• Block expression by distrupt it’s genome sequence by zinc finger proteins.

Targeting HIV Gene Expression

• HIV genes are essential for viral replication.

• Tat and Rev are regulatory proteins of HIV.

• Tat- Hammerehead ribozymes.

• Rev-dominant mutans or trans dominant.

• Targeting cellular factors such as CCR5 by RNAi are more effective than

targeting gene expression.

Introduction of Genes that Interfere with HIV

Replication

• Alternative strategy of HSC modification for HIV genes.

• Exogeneous factors inhibit key steps of HIV infection.

• Gp41-derived protein and C46 – structurally similar to inhibitor enfuvirtide.

• TRIM5-alpha, APOBEC (3F, 3G & letherin)-prevent HIV infection.

Combination Therapy to Prevent Viral Escape

• Virus have high genetic variability.

• Lentivirus are used as vector.

• Eg: In AIDS related lymphoma both retroviral vector and CD3+

hematopoetic stem cells are used.

• This modification persist atleast 24 months.

Engineering anti-HIV Immunity

• Immunity plays important role in controlling HIV infection.

• HIV doesn’t posses immunogenicity.

• Host doesn’t have ability to adequate response against HIV.

• Therapeutic vaccines are developed for HIV specific CD4 & CD8 T cell response.

• Molecularly cloned TCR or CAR receptors.

• Modified HSCS with SL9 TCR in humanized mice were able to suppress viral

replication.