Human Immunodeficiency virus (HIV) today has been wrecking the lives of the people today. Categorized as one of the top world killers in the world, scientists have worked hard to find the cure. For those who are patiently waiting for a cure, many participate in CARTs or combination antiretroviral therapy which uses the combination of different antiretroviral drugs to stop HANDS or HIV associative neurocognitive disorders. Patients participating in this therapy were found to experience increase damage to brain. It was concluded the therapy is not an effective way to combat HANDS. Mihyun and her team exposed hippocampi of rats to gp120 for different lengths of time, than inhibited suspected proteins of the pathway such as CXC4R and then viewed the results with Open Lab software and calcium imaging.
Gp120, a surface protein that functions to bind to T-cells, is a toxin that enhances NMDA activation, but how, no one knows how. Studies found by disrupting the trafficking of NMDA resulted in disorders such as Alzheimer's. Evidence suggested that gp120 assembles NMDA receptors into clumps or modified microdomains. This occurred by increasing the size and stability of lipid rafts which are involved in receptor trafficking. Mihyun and her team used this theory as a baseline to discover the mechanism.
The team was successful in finding a mechanism. First gp120 enhanced the transport of NMDA receptors into the membrane by signaling phosphorylation of the C terminal which regulated transportation of NMDA. Exposure of gp120 to the hippocampi was found to increase the levels of phosphorylation, specifically phosphorylation of serine 897 and serine 896. Finally inhibition of PKA or PKC resulted in halting gp120 activity. PKA and PKC were thus concluded as the kinases activated by gp120 to phosphorylate the C terminal.
Then gp120 stabilized NMDA receptor microdomains by increasing the size of lipid rafts. Ceramide, a substance used by lipid rafts, was believed to be involved in increasing the size and stability of lipid rafts. Ceramide is synthesized by hydrolysis of sphingomyelin, a type of lipid. By blocking hydrolytic pathways in the hippocampi, the lipid rafts were observed not to be increase in size. In particular the enzyme nSMase2 which hydrolyzes sphingmyelin, was found to be the one responsible for increasing lipid raft sizes. Mihyuan took this further and inhibited key factor from a separate pathway that also increased lipid rafts. CXCR4, a protein that HIV uses, was found to increase lipid rafts with the use secondary messengers called IP3 and PKC.
Finally Mihyun and team found that by stabilizing the lipid rafts, NMDAR receptors were prevented from dispersing from the microdomains. Gp120 were first exposed to hippocampi then exposed to Beta cyclodextrin, a drug that is used to disrupt lipid rafts.
Mihyun and her team had made a great contribution which will has brought us one step closer to finding a cure. Though it may seem like only a baby step, at least we are one step closer.
Bae, Mihyun, et al. "The Human Immunodeficiency Virus Coat Protein gp120 Promotes Forward Trafficking and Surface Clustering of NMDA Receptors in Membrane Microdomains." The Journal of Neuroscience 31.47 (2011): 17074-17090