Professor Luis Lamberti Pinto da Silva and PhD candidate Yunan Janurio at the University of So Paulo’s Ribeiro Preto Medical School (FMRP-USP) in Brazil said, “Researchers have succeeded in obtaining the three-dimensional structure between Nef-CD4 and AP-2, showing the contact surfaces and making possible other studies designed to yield a molecule that occupies this space so as to prevent the effects of the protein from advancing. This ‘photograph’ can serve as the basis for the development of other anti-HIV therapies.”
The two authors of the study stated, ” Notably, the study by Kwon et al. provides the structural basis for the cooperative assembly of the AP-2-Nef-CD4 tripartite complex and shows that Nef directly bridges CD4 and AP-2. The study also reveals a structural relationship between Nef-mediated downregulation of CD4 and Nef’s antagonism of major histocompatibility complex I (MHC-I).”
Silva has stated that Nef is important to the advancing effects of HIV as AIDS progresses. Additionally, this protein is continuously produced by the virus in the patients undergoing treatment and also in those patients whose viral load (amount of virus present in an infected person’s blood) is low. “This has been linked to co-morbidities of the infection. Nef is important, and no drugs exist to target it.”
Nef is known as a multifunctional protein which allows the virus to replicate by modifying the cells. Scientists have not yet found a way to block this Nef protein.
Currently there are several classes of drugs to treat HIV (antiretroviral drugs) available. Commonly used antiretrovirals are nucleoside and nucleotide reverse transcriptase inhibitor, protease inhibitor, integrase inhibitor and entry inhibitors.
These drugs inhibit various stages of virus multiplication, can reduce viral load and even stop the development of the disease. But due to the development of resistance against these drugs and their side effects, there is a need to find different drugs to fight this virus.
According to the United Nations Program on HIV and AIDS (UNAIDS), there are 38 million people having HIV which also includes 1.8 million children of the age 14 and below. Out of this only 67% have access to antiretroviral therapy.
According to the study the mechanism by which the Nef acts is that it binds to AP-1G2 on the human cell membrane and sends the CD4 cells to the lysosomes (breakdowns protein and other molecules). CD4 is used as the receptor by HIV to gain entry into the cell. If CD4 is not removed from the surface of the cell, the entry of the virus into the cell is blocked. Hence Nef protein removes it from the surface of the cell which leads to infection.
Silva said that, ” We pointed to the common point between these two pathways. In order to send CD4 and MHC-I to lysosomes, Nef hijacks a third cell protein common to both pathways. These findings can help other groups show exactly how Nef interacts with the third protein to identify a novel target, just as was done with AP-2.”
Silva and his group are currently working on another study to identify the different targets of the Nef protein. He said, ” Several ingredients are available. Now someone has to come along to bring it all together and obtain this molecule capable of inhibiting Nef”