Engineered Human Cells: STOP HIV

Problem & Idea

Basic principle
Current disease treatment is based on interfering with HIV replicating system and reducing symptoms that are consequence of immune deficiency. There are also rare efforts to completely eliminate HIV virus from the human cells after the infection, by cutting out the DNA with designer enzyme. But no long term solution exists.
We decided to join the fight against plague of 21st by introducing some new elements to human cells, which would hopefully provide human being with immunity against virus HIV. To achieve this purpose we have used evolutionary old model of multi cellular organisms – sacrificing small amount of cells to the benefit of whole organism.

By combining genes from different organisms we have constructed completely new signaling pathway that triggers apoptosis and is induced immediately after HIV infection or even in later phases of disease. Because viruses need live cells to multiply, this new pathway drastically reduces number of potential host cells in organism and therefore ensure immunity to the whole human being.

Project ideas
In the beginning of summer we have discussed following project ideas:

  • Dimerization of two human transmembrane receptors involved in HIV infection (CD4 and CCR5 or CXCR4) as induction signal for apoptosis. That would include constructing and introducing a novel signaling pathway to the mammalian cells.
  • Specific catalytic activity of HIV protease as induction signal for apoptosis.
  • Modifying existing signal pathways in mammalian cells in the way that cells would be able to recognize some parts of the virus and react with apoptosis. That would include engineering of novel interconnections between signaling pathways.
  • Using HIV specific LTR promoter to control expression of death efector protein.

Selected project
We have not decided to realize last two ideas, because modifying existing signaling pathways can lead to unwanted side effects and because the LTR promoter which is induced by the HIV proteins (Tat or Rev) is not completely silent in absence of this inducer.

Basic principle

Main principle

On the contrary first two ideas have some perspective characteristics. Dimerization of CD4 and CCR5 or CXCR4 is the initial step in the HIV infection cycle. If this event is a signal for apoptosis, there is definitely not enough time for virus to multiply or even assemble, before cell dies. Another advantage of this idea is its resistance to virus mutations. It is well known, that HIV virus is very mutable. But whatever the mutation is virus still needs CD4 and CCR5 or CXCR4 receptor to enter the cell. Dimerization of these two receptors is unavoidable step in infection and as already mentioned our signaling pathway connects it to apoptosis pathway.

Second idea is about constructing propeptide, which becomes active after specific cleavage with HIV protease. Active form of protein than induce apoptotic pathway. Likewise first second idea is resistant to virus mutations. HIV protease is important element of virus and is responsible for its maturation. Protease cleaves long inactive propeptide forms of Gag, Pro, Pol and Env proteins and activates them. If HIV virus mutates in protease it should also mutate in series of other proteins and that is more unlikely. So series of synchronous mutations should occur in virus to avoid inducing our pathway which leads to apoptosis in presence of specific HIV protease.

We have decided to join both ideas and develop system that recognizes HIV virus and launch alarm at two different stages of virus cycle. Protease triggering in this system as some kind of second wall defense. In next section we describe project in details.

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