New Research Reveals How Protein Protects Cells From HIV Infection

A novel discovery by researchers at NYU Langone Medical Center and colleagues reveals a mechanism by which the immune system tries to halt the spread of HIV. Harnessing this mechanism may open up new paths for therapeutic research aimed at slowing the virus’ progression to AIDS. The study appears online ahead of print today in Nature Immunology.

“A lot of research on viruses, especially HIV, is aimed at trying to understand what the body’s mechanisms of resistance are and then to understand how the virus has gotten around these mechanisms,” said co-lead investigator Nathaniel R. Landau, PhD, a professor of microbiology at the Joan and Joel Smilow Research Center at NYU School of Medicine.

The research focused on a protein called SAMHD1. Recent studies have found that immune cells, called dendritic cells, containing the protein are resistant to infection by HIV. Since the discovery, scientists have sought to understand how SAMHD1 works to protect these cells, with hopes that science might find a way to synthetically apply that protection to other cells.

Dr. Landau and his team are now able to provide an answer:

When a virus, like HIV, infects a cell, it hijacks the cell’s molecular material to replicate. That molecular material is in the form of deoxynucleotide triphosphates (dNTPs), which are the building blocks for DNA. Once the virus replicates, the resulting DNA molecule contains all the genes of the virus and instructs the cell to make more virus.

Researchers wanted to understand how cells containing the SAMHD1 protein are protected from such hijacking. They found that SAMHD1 protects the cell from viruses by destroying the pool of dNTPs, leaving the virus without any building blocks to make its genetic information – a process researchers call nucleotide pool depletion. “SAMHD1 essentially starves the virus,” Dr. Landau said. “The virus enters the cell and then nothing happens. It has nothing to build and replicate with, so no DNA is made.”

Since the reporting of the first cases of AIDS in 1981, and the discovery of its etiologic agent, human immunodeficiency virus type 1 (HIV-1), in 1983, there has been substantial scientific progress in the development of both effective antiretroviral therapy and the understanding of virus–host cellular interactions. Nonetheless, the correlates of effective immunity to HIV remain elusive, and the paucity of knowledge has hindered development of effective vaccines. One approach to understanding the immune response to HIV and why it fails in most people lies in examining those few hosts who appear to be resistant either to acquisition of the virus or to its devastation once acquired.

Two phenomena have indicated that natural resistance to HIV-1 infection, while rare, does exist. First, there are individuals who have been exposed to HIV, in some cases repeatedly and over long periods of time, who have remained HIV-uninfected. Such "exposed-uninfecteds" have been reported among commercial sex workers, individuals having unprotected sex with seropositive partners, infants born to HIV-infected mothers, health workers with accidental occupational exposure intravenous drug users using contaminated needles, and hemophiliacs exposed to HIV-infected blood. Second, there are individuals who have become infected with HIV but whose disease has not progressed or has progressed very slowly compared to the average experience. Criteria defining these "long-term non-progressors" have varied among reports but usually include survival with HIV infection for ?7 years with consistently low levels of HIV-1 RNA and little or no loss of the primary target of HIV, CD4+ T-cells. Long-term non-progressors have been identified among various groups, including homosexual men, women, injection drug users and children.