Stem-cell based gene therapy aims to genetically modify cells to resist HIV infection through three main strategies: 1) targeting cellular genes essential for viral replication like CCR5, 2) directly targeting HIV gene expression, and 3) introducing genes that interfere with HIV replication. Combination therapy employing multiple genetic modifications may help prevent viral escape. Engineering immunity against HIV through therapeutic vaccines or modified T-cells and stem cells shows promise in controlling infection.

1. Stem-Cell-Based Gene
Therapy for HIV
Infection VIPIN MOHAN
2011-09-112
College of Agriculture
Vellayani, TVM

2. HIV lifecycle

5. 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.

7. 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.

8. 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.

9. 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.

10. 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.

11. 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.