A new study has discovered one more way the human immunodeficiency virus (HIV) exploits the immune system. Not only does HIV infect and destroy CD4-positive helper T cells – which normally direct and support the infection-fighting activities of other immune cells – the virus also appears to use those cells to travel through the body and infect other CD4 T cells. The study from Massachusetts General Hospital (MGH) investigators, which will appear in the journal Nature and has received advance online release, is the first to visualize the behavior of HIV-infected human T cells within a lymph node of a live animal, using a recently developed "humanized" mouse model of HIV infection.
"We have found that HIV disseminates in the body of an infected individual by 'hitching a ride' on the T cells it infects," says Thorsten Mempel, MD, PhD, of the MGH Center for Immunology and Inflammatory Diseases, who led the study. "Infected T cells continue doing what they usually do, migrating within and between tissues such as lymph nodes, and in doing so they carry HIV to remote locations that free virus could not reach as easily. There are drugs that can manipulate the migration of T cells that potentially could be used to help control the spread of virus within a patient."
When HIV is introduced into blood or tissues, the virus binds to CD4 molecules on the surface of helper T cells, injecting its contents into cells and setting off a process that leads to the assembly and release of new virus particles. It has long been assumed that these free virus travel by diffusion through tissue fluids to encounter new cells that can be infected. But recent studies have suggested that HIV can also pass directly from cell to cell when structures called virological synapses form during long-lasting interactions between T cells. Since CD4 T cells usually migrate quickly and form only transient contacts with other cells, the current study was designed to examine whether HIV alters the migration of infected T cells, allowing the kind of persistent contact that facilitates the spread of infection.
The team's experiments used the humanized BLT mouse model, which has what is essentially a human immune system and is the only non-primate that can be infected with HIV. After first confirming that human T cells enter and normally migrate within the animals' lymph nodes – known to be important sites of HIV replication – the researchers injected the animals with HIV engineered to express green fluorescent protein (GFP), allowing them to track the movement of infected cells within living animals using a method called intravital microscopy. They first observed that, within two days, infected T cells continued to migrate and were uniformly distributed within lymph nodes but remained in nodes closest to the site of injection.
While the HIV-infected cells actively moved within lymph nodes, they did not move as quickly as comparable but uninfected T cells. In addition, 10 to 20 percent of the HIV-infected T cells formed abnormally long and thin extensions that appeared to trail behind moving cells, often exhibiting branches. The researchers hypothesized that the HIV envelope protein, which is expressed on the surface of infected T cells before they release new virus particles, might cause infected cells to form tethering contacts with uninfected cells, producing these extensions. A series of experiments verified that the elongated shape of some infected cells requires the presence of the envelope protein and that many of the elongated cells contained multiple nuclei, suggesting they had been formed by the fusion of several cells.
To test the role of T cell migration in HIV infection, the researchers injected another group of BLT mice with HIV and at the same time treated them with an agent that prevents T cells from leaving lymph nodes. Two months later, levels of HIV in the bloodstream and in lymph nodes distant from the site of injection were much lower than in untreated HIV-infected animals, supporting the importance of T cell migration to carry virus throughout the body. Treatment with the migration-suppressing agent, however, did not reduce viral levels in animals with already established HIV infection.
"While our observation of tethering interactions between infected and uninfected CD4-expressing cells suggest that HIV may be transmitted between T cells by direct contact, we will have to clearly show this in future studies and explore how important it is relative to the transmission by free virus," explains Mempel, an assistant professor of Medicine at Harvard Medical School. He adds that the availability of the BLT mouse was instrumental in their ability to carry out this study. "This approach provides a new vantage point to investigate previously unexplored aspects of HIV pathogenesis."
Lead author of the Nature paper is Thomas Murooka, PhD, of the MGH Center for Immunology and Inflammatory Diseases (CIID). Additional co-authors are Maud Deruaz, PhD, Francesco Marangoni, PhD, Vladimir Vrbanac, DVM, Edward Seung, PhD, Andrew Tager, MD, and Andrew Luster, MD, PhD, MGH CIID; and Ulrich von Andrian, Harvard Medical School. The study was supported by grants from the National Institutes of Health and the Ragon Institute of MGH, MIT and Harvard.
Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $750 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, transplantation biology and photomedicine. In July 2012, MGH moved into the number one spot on the 2012-13 U.S. News & World Report list of "America's Best Hospitals."
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