Solving Mystery of Rare Cancers Directly Caused by HIV

PITTSBURGH – Scientists have long known that HIV integrates a DNA copy of its genetic information into host cell genes that have the potential to cause cancer. When animals are infected with other retroviruses, those animals often develop cancer. But, perplexingly and fortunately, that doesn’t happen frequently in people infected with HIV, the retrovirus responsible for the AIDS pandemic.

A team led by scientists from the University of Pittsburgh School of Medicine and the National Cancer Institute (NCI) announced today in Science Advances that they’ve discovered why doctors aren’t seeing high rates of T cell lymphomas—a type of cancer of the immune system—in patients living with HIV.

“We seem to have explained some of the mystery of why HIV is rarely the direct cause of cancer,” said co-lead author John Mellors, M.D., chief of the Division of Infectious Diseases at Pitt and UPMC. “Our investigation showed that it requires a very unusual series of events involving changes in HIV and additional mutations in human genes in someone with HIV to develop lymphoma, a cancer of immune cells called lymphocytes.”

When HIV enters the body, it seeks out T cells and inserts a DNA copy of its genetic sequence—called the “provirus”—into the cell’s DNA. This instructs the T cells, which normally patrol the body in search of foreign pathogens, to produce HIV. 

Previous research by the NCI and Pitt teams showed that proviruses can be inserted into the T cell’s DNA in places that prompt the infected cells to divide and grow into large, noncancerous clones. It isn’t the goal of the virus to induce the growth of infected cells; it’s simply the result of where the provirus happened to be inserted in the T cell’s DNA. 

These prior discoveries gave rise to a paradox: If HIV can integrate into genes in T cells that can cause the cells to grow into large clones, then why doesn’t it also cause lymphomas? 

To answer this question, the team obtained tumor samples from 13 HIV patients with lymphomas and found that three of the samples had high levels of HIV proviruses. These samples were then studied further.

They then determined where the provirus had inserted into the T cell’s DNA. This analysis revealed that, when the HIV provirus inserts into a gene called STAT3 or STAT3 and another gene called LCK, it can prompt the cells with those proviruses to proliferate. If there are additional nonviral mutations in other human genes, this can result in T cell lymphomas. Both STAT3 and LCK are involved in regulating the growth of T cells.

“This is a complicated, multistep process that requires rare events—insertion into STAT3 or STAT3 and LCK genes in just the right spot,” said Mellors. “As a physician, I am reassured that these events are rare. Although we need to be aware that HIV has the potential to cause lymphomas, it’s such a rare occurrence that there is no need for heightened anxiety now. Clinicians should always screen their patients for cancer as part of routine health care, but people with HIV do not need to fear that they will inevitably develop lymphomas.”

Because people with HIV are living longer due to advances in medication and care, there is more time for them to accumulate mutations in host genes. When that is coupled with the effects of proviruses already inserted in oncogenes, the frequency of lymphomas in people living with HIV could increase over time, Mellors noted, although this has not been observed so far. The research team stressed the importance of additional studies to assess the role that HIV medications may play in preventing T cell lymphomas, particularly when started early in the course of HIV infection, coupled with continued surveillance for T cell lymphomas in people with HIV.

Shuang Guo, Ph.D., of Leidos Inc., is the co-lead author and Xiaolin Wu, Ph.D., of Leidos Inc., and Stephen H. Hughes, Ph.D., of NCI, are co-senior authors of this research. Additional authors are Asma Naqvi, Leah D. Brandt, Ph.D., Kevin W. Joseph, and Elias K. Halvas, Ph.D., all of Pitt; Ling Su, Zhonghe Sun, Dimiter Demirov, Ph.D., Donna Butcher, and Baktiar Karim, D.V.M., Ph.D., all of Leidos Inc., and Beth Scott, Aaron Hamilton, Ph.D., and Marintha Heil, Ph.D., all of Roche Molecular Diagnostics. 

This research was supported by the NCI Intramural Program and National Institutes of Health contracts 12XS547 and HHSN261200800001E.