A CD4 derivative prevents SHIV infection in monkeys!

CD4 caught my interest because not only is it essential in the immune system of the human body, but it is also an important component in the infection of HIV. Because of this, there has been recent research of how CD4 derivatives could be used in HIV treatment. This protein seems to be at the center of a lot, so I wanted to investigate it further.

Interactions of CD4 with MHC class II molecules, T cell receptors and p56Lck

Vignali, D.A., Doyle, C., Kinch, M.S., Shin, J. & Strominger, J.L. Interactions of CD4 with MHC class II molecules, T cell receptors and p56Lck. Phil. Trans.: Biol. Sciences 342, 13–24 (1993).

There have been many studies on many aspects of the CD4 protein, so a review article is a necessary starting point. First, it provides some necessary background info.

CD4 is a coreceptor located on T Cells. It is a coreceptor along with the TCR (T cell receptor). Together the TCR and CD4 recognize antigens presented by antigen-presenting cells. T Cells that have the CD4 coreceptor on their surface are called CD4 T Cells. These CD4 T cells bind specifically to MHC class II molecules which are located on antigen presenting cells. In contrast, a different coreceptor CD8 binds to MHC class I molecules.

These CD4 T cells are called “helper” T cells because once the antigen is recognized, the T cell is activated and sends out many cytokine proteins. There are many different kinds of cytokines that all facilitate different types of immune responses.

Image source: Vignali, D.A., Doyle, C., Kinch, M.S., Shin, J. & Strominger, J.L. Interactions of CD4 with MHC class II molecules, T cell receptors and p56Lck. Phil. Trans.: Biol. Sciences 342, 13–24 (1993).

This review paper from 1993 is old, but provides a good introduction to the basic function and actions of CD4. The review discusses three important interactions of CD4:

1) investigations showing that CD4 binds with MHC II on the surface of an APC 

2) how CD4 physically associates with the TCR, leading to T cell activation 

3) how phosphorylation regulates and affects interaction between CD4 and the protein tyrosine kinase p56lck, also located on the Tcell.

HIV: Cell binding and entry

Wilen C.B., Tilton J.C., Doms R.W. HIV: Cell binding and entry. Cold Spring Harb. Perspect. Med. 2012;2 doi: 10.1101/cshperspect.a006866

Image source: Wilen C.B., Tilton J.C., Doms R.W. HIV: Cell binding and entry. Cold Spring Harb. Perspect. Med.2012;2 doi: 10.1101/cshperspect.a006866

Next, a review article about HIV and its infection sheds light on the significance of CD4 in disease. The first step of the HIV replication cycle is to bind and enter into the host cell. CD4 serves as a host protein that HIV’s Env (envelope) protein binds to. After binding to CD4,  Env undergoes conformational changes that allow it to bind to the second cellular receptor CCR5. This then leads to membrane fusion, allowing infection of HIV. The review article also provides information on the history of discovery of CD4 and HIV binding as well as info into how CD4 signalling from p56lck effects effective HIV infection.

AAV-expressed eCD$-Ig provides durable protetion from multiple SHIV challenges.

Gardner, M. R., Kattenhorn, L. M., Kondur, H. R., von Schaewen, M., Dorfman, T., Chiang, J. J., … Farzan, M. (2015). AAV-expressed eCD4-Ig provides durable protection from multiple SHIV challenges. Nature, 519(7541), 87–91. doi:10.1038/nature14264

Image source: https://www.flickr.com/photos/jimnicholson/6005070459/

This Nature article is what attracted me to CD4 in the first place: Monkeys who are immune to SHIV. Too good to be true? Let's see.

This is a very recent primary research article from March 2015. In the study, the Farzan research group’s goal is to attempt to create an entry inhibitor of HIV that is more efficient than current bNAbs (broadly neutralizing antibodies) which require high concentration for protection. The Farzan group created an artificial antibody by taking CD4 and attaching a small piece of the second cellular receptor, CCR5. This new construct was named e-CD4Ig. The idea is that HIV will bind to this eCD4Ig instead of a CD4 on a T cell, thus preventing infection.

The Farzan group saw that eCD4Ig outperformed other HIV antibodies in cell culture studies. E-CD4Ig  then was introduced in rhesus macaques, a species of monkey, by inserting it in the harmless AAV virus which was given to the macaques. The macaques were given increasing doses of SHIV (SHIV stands for Simian-Human Immunodeficiency Virus) for 34 weeks, but none of the e-CD4Ig macaques were infected, while non e-CD4Ig macaques were. In the words of the article, “Our datasuggest that AAV-delivered eCD4-Ig can function like an effective HIV-1 vaccine.”