HIV plays a direct role in causing blood cell cancers in rare instances, says a new study of HIV and tumor DNA.
Scientists have long known that HIV contributes to several cancers by weakening the immune system’s ability to fend off cancer-causing infections like Kaposi sarcoma–associated herpesvirus and Epstein-Barr virus. However, this latest study, published in Science Advances this week, is the first to demonstrate HIV as a cause.
“Instead of being [just] what I guess I would call a cancer-facilitating virus, allowing cancers to grow, it’s a bona fide, in-its-own-right cancer virus,” said Steve Hughes, Ph.D., a senior author on the study who leads the Center for Cancer Research’s Retroviral Replication Laboratory and Host-Virus Interaction Branch at NCI at Frederick.
The scientists, a team spanning NCI at Frederick, Frederick National Laboratory (FNL), the University of Pittsburgh, and Roche Molecular Diagnostics, identified HIV’s role in rare cases of T-cell lymphoma. The virus integrates its own DNA into STAT3 and LCK, two cancer-driving genes in the person’s cells, triggering necessary steps on the cells’ path to becoming tumors.
“It’s not a very efficient oncogenic virus, unlike other retroviruses, like HTLV-1 or any of the herpesviruses or papillomaviruses, but we’ve found compelling evidence that it’s contributing to lymphoma depending on where it inserts itself in the human genome,” said lead author John Mellors, M.D., distinguished professor of medicine and chief of the Division of Infectious Diseases at Pitt.
“The good news is that lymphomas caused directly by HIV-1 are very rare,” he added.
The findings raise awareness that HIV can contribute to cancer, and they allow the scientific and medical communities to be vigilant for its role in these tumors.
The ‘Aha’ Moment
HIV survives by infecting white blood cells called “T cells” and hijacking their innate genetic machinery to make more of itself. That process requires HIV to insert its own genetic sequence, the “provirus,” into the cells’ DNA. There are countless places for an HIV provirus to land, including genes that lead to rapid cell division, one of the main characteristics of tumor cells.
In past studies, members of the team showed that HIV proviruses can be inserted into genes in a way that leads to the infected cells’ growth and survival. The cells were noncancerous but grew into large clones, as if the provirus had activated the genes. The team wondered whether the insertions could be part of the chain of events leading to tumor formation.
The current study was the search for the answer.
Mellors scoured tumor repositories across the U.S. and managed to acquire 13 samples from lymphoma patients with HIV. His team at Pitt collaborated with Roche to analyze the tumor cells for the presence of high levels of HIV. Three had high levels of viral DNA. Mellors describes it as an “aha moment”—a possible indicator that HIV was directly involved in the cancer.
“Then we asked, ‘Where is the HIV [provirus] in those lymphoma cells?’”
‘We Watched It Shoot the Target’
Shuang “Amber” Guo, Ph.D., in FNL’s Genomics Technology Laboratory, analyzed the integration sites, the places where the provirus had inserted into the tumor cells’ DNA. Every tumor had provirus in STAT3, and STAT3 was clearly activated. Surprisingly, STAT3 wasn’t one of the genes the team had found in the previous studies of expanding noncancerous infected cells, but it was another clue: active STAT3 is known to drive T-cell lymphomas in people without HIV.
“When Amber … ran the first analysis and got the same integration site, STAT3, a thousand times out of 8,000 total [genetic] sequences, we knew we were there,” Hughes said, calling it a “magic moment.”
But provirus generally can’t disrupt the genome and associated cellular processes enough to activate STAT3 on its own. STAT3 activation depends on interactions from proteins made by other genes.
Further analyses revealed its conspirator: proviruses also landed in LCK in two of the samples. Activated LCK produces a protein that can activate STAT3.
A provirus had inserted into LCK in just the right way to activate the invaded gene and allow it to make a functional protein. Hughes says the true kicker was when two tumors from the same patient had provirus in exactly the same place in STAT3, indicating they descended from the same infected parent cell, but had a provirus in two different spots in LCK. It confirmed that LCK activation happened independently from STAT3 and that activated LCK was necessary for STAT3 activation.
For the final test, the team checked whether the tumors had sufficient protein from LCK to account for the high levels of activated STAT3. They did.
“The likelihood that that’s a coincidence is nil,” Mellors said. “There are millions of sites in the human genome where HIV can integrate, and we found the proviruses in the same two oncogenes.”
The two genes were working together to contribute to the tumor formation.
“It’s not just a smoking gun; [we] watched it shoot the target,” Hughes said.
‘The Story Just Unfolded in Front of Our Eyes’
Xiaolin Wu, Ph.D., a senior author and the head of FNL’s Genomics Technology Laboratory, calls the study “the most exciting project that [our laboratory] has worked on” because of the opportunity to use its arsenal of genomic technologies to make a substantial impact. His laboratory performed the genetic analyses that identified how HIV helps drive the tumors. Several of the samples were of suboptimal quality, but a technology they invented made it possible to analyze the DNA.
“I just feel so gratified,” Wu said. “The story just unfolded in front of our eyes.”
Baktiar Karim, D.V.M., Ph.D., a lead pathologist in FNL’s Molecular Histopathology Laboratory, the group that performed the histopathology stains and analysis that detected the LCK protein, also feels the importance of the work.
“It is an honor to find new discoveries to identify driver pathways of HIV-associated lymphoma and therapeutic targets,” he said.
A Call for Vigilance
While the results come in a small sample size, the samples represent all that were available for analysis in the U.S.
“It just speaks to the rarity of the events that we described,” Mellors said. “What HIV is doing is providing hits, and in the vast majority [of people]—the overwhelming majority—the hits provided by HIV aren’t sufficient to cause cancer. These three outlier cases, the hits contributed in a big way.”
The early generations of people who acquired HIV as young adults are now becoming senior citizens, a population traditionally more likely to develop cancer. It’s unclear whether the frequency of these T-cell lymphomas will increase as a result, but the team believes physicians will need to have an answer for a cause if it does. Both the scientific and medical communities now have new targets to study in these cancers in people living with HIV.
“It’s not good that it happened, but … it’s good we know it,” Hughes said.
Samuel Lopez is a technical editor in Scientific Publications, Graphics & Media (SPGM), where he writes for NCI at Frederick and Frederick National Laboratory’s news outlets; manages the day-to-day operations of the Poster newsletter; informally serves as an institutional historian; and edits scientific manuscripts, corporate documentation, and a slew of other written media. SPGM is the facilities’ creative services department and hub for editing, illustration, graphic design, formatting, and multimedia training and support.