Tripartite motif 5α in news

Greetings

HIV is one of the most well studied virus in terms of global health. As I have repeated multiple times in this blog, it still haunts the best brains and no absolute cure or preventive measure is available. Except for a handful of cases, where people have demonstrated complete cure, or seem to be never infected. But just to say that as humans never evolved defence strategies against retrovirus is not true. Indeed our cells have restriction factors for multiple steps but virus has its own counter strategy. Indeed HIV has evolutionary advantage in terms of its speed of evolving which we don't have.

The restriction factors so far described include- Cyclophilin A, APOBEC3, TRIM-5α, SAMHD1, Mx-2 and BST-2 (read my previous post here). Of all these TRIM-5α has a special interest. That is because, HIV doesn't produce any factor to counteract its effects yet seems to be not effected by it. In other words Human TRIM-5α seems to be ineffective against HIV. And second, the monkey version of it is too good in defending from HIV. What is the difference?

Fig 1:Structure of the C3HC4 RING

finger domain. Source

    TRIM 5α (Tripartite motif 5α) or RING finger protein 88, was first identified in monkeys. It was demonstrated that expression of RhMTRIM5 ( Rhesus monkey TRIM 5 ) in human cells, which are normally permissive to HIV-1, restricts HIV-1. In human cells the action of TRIM 5α is very bleak. It is known that the TRIM interacts with capsid of the HIV in cytoplasm. TRIM5 spontaneously forms a hexameric protein lattice, which is greatly enhanced in the presence of the capsid lattice structure.

RING stands for "Really Interesting New Gene". Many different proteins are known to have structure referred as RING domains which belongs to a super family of zinc finger proteins. They basically contain a Cys3HisCys4 amino acid motif which binds two zinc cations. Their major function is in ubiquitination pathways. The probable role is to bind capsids and subsequently process the capsid to ubiquitination. There is some proof that the capsid is an essential element in importing the PIC (Pre integration complex). That explains how TRIM5 is supposed to be useful. 

   But just as I mentioned, TRIM5α seems to be not efficient enough. The question as to what is the reason for inefficiency is explained in the latest paper in nature. Based on a series of experiments the researchers concluded that the huTRIM5α (Human TRIM5α), was much less stable than the orthologue monkey version. By introducing mutations in B30.2/SPRY  domain (as little as 5 mutation), the stability was increased with better restriction activity.

    But that begs a question. Evolutionarily why did we change the sequence into a less stable factor? I don't have a clear explanation for this question. I have been told that TRIM restricts MLV (Murine Leukemia Virus), with a similar kind of capsid attack approach. It is my belief that probably TRIM5 is an important restriction factor for other retrovirus and HIV being a more recent phenomenon there is a lag.

    This study has set a small opening to look into pharmacological designs to improve the stability of TRIM5α. But that also requires us to understand the mechanism of action and the chemistry of interaction. Oh yes, you would say that we have a new perspective to look at.

     

Perron MJ, Stremlau M, Lee M, Javanbakht H, Song B, & Sodroski J (2007). The human TRIM5alpha restriction factor mediates accelerated uncoating of the N-tropic murine leukemia virus capsid. Journal of virology, 81 (5), 2138-48 PMID: 17135314

Richardson, M., Guo, L., Xin, F., Yang, X., & Riley, J. (2014). Stabilized Human TRIM5α Protects Human T Cells From HIV-1 Infection Molecular Therapy, 22 (6), 1084-1095 DOI: 10.1038/mt.2014.52