HIV-infected T cells help transport the virus throughout the body

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 it infects," says Thorsten Mempel, MD, PhD, of the MGH Center for Immunology and Inflammatory Diseases, who led the study. "Infected T 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 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 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 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 ," 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 pathogenesis."

Related Stories

Exhausted B cells fail to fight HIV

Jul 14, 2008

HIV tires out the cells that produce virus-fighting proteins known as antibodies, according to a human study that will be published online July 14 in the Journal of Experimental Medicine.

AIDS resistance secret may be in blood

Feb 12, 2007

U.S. scientists say the absence of a specific marker in the blood and tissues of certain monkeys might be part of the key to understanding AIDS resistance.

New memory for HIV patients

Mar 26, 2012

The hallmark loss of helper CD4+ T cells during human immunodeficiency virus (HIV) infection may be a red herring for therapeutics, according to a study published on March 26th in the Journal of Experimental Medicine.

Exhausted B cells hamper immune response to HIV

Jul 14, 2008

Recent studies have shown that HIV causes a vigorous and prolonged immune response that eventually leads to the exhaustion of key immune system cells--CD4+ and CD8+ T-cells--that target HIV. These tired cells become less ...

Recommended for you

Structured education program beneficial for anaphylaxis

Nov 21, 2014

(HealthDay)—A structured education intervention improves knowledge and emergency management for patients at risk for anaphylaxis and their caregivers, according to a study published online Nov. 19 in Allergy.

Every step you take: STING pathway key to tumor immunity

Nov 20, 2014

A recently discovered protein complex known as STING plays a crucial role in detecting the presence of tumor cells and promoting an aggressive anti-tumor response by the body's innate immune system, according to two separate ...

User comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.