Solving mystery of rare cancers directly caused by HIV

Date:
October 13, 2021
Source:
University of Pittsburgh
Summary:
For nearly a decade, scientists have known that HIV integrates
itself into genes in cells that have the potential to cause
cancer. And when this happens in animals with other retroviruses,
those animals often develop cancer. But, perplexingly and
fortunately, that isn't regularly happening in people living with
HIV. A new study reveals why doctors aren't seeing high rates of
T cell lymphomas -- or cancers of the immune system -- in patients
with HIV.



FULL STORY ==========================================================================
For nearly a decade, scientists have known that HIV integrates itself
into genes in cells that have the potential to cause cancer. And when
this happens in animals with other retroviruses, those animals often
develop cancer. But, perplexingly and fortunately, that isn't regularly happening in people living with HIV.


==========================================================================
A team led by University of Pittsburgh School of Medicine and National
Cancer Institute (NCI) scientists announce today in Science Advances
that they've discovered why doctors aren't seeing high rates of T cell lymphomas -- or cancers 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.,
who holds the Endowed Chair for Global Elimination of HIV and AIDS at
Pitt. "Our investigation showed that it requires a very unusual series
of events involving changes in both HIV and additional mutations in
human genes for someone with HIV to develop lymphoma. 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." When HIV enters the body, it seeks out T cells and inserts
its genetic sequence -- called the "provirus" -- into the cell's DNA. This effectively hijacks the T cells, which normally patrol the body in search
of foreign pathogens, instead instructing them to produce more HIV.

Previous research by the NCI and Pitt teams discovered that the provirus
can insert itself into the T cells' genetic code in a place that
prompts these infected cells to grow into large, noncancerous clones
of themselves and, in some instances, these clones can carry complete, infectious proviruses. Such clones are called "repliclones" because they
carry a replication-competent provirus. It isn't necessarily the goal of
the virus to induce the growth of repliclones; it's just the result of
where the provirus happened to insert itself in the T cell's genetic code.

These prior discoveries gave rise to a paradox: If HIV can integrate
into T cell oncogenes (genes involved in normal cell division that,
when mutated, result in cancerous cell growth), then shouldn't it also
cause lymphoma? To answer this question, the team obtained samples from
13 HIV patients with lymphoma and picked out three that had high levels
of HIV proviruses, indicating that the virus might be implicated in the
cancer formation.

They then examined those samples to learn where the provirus had inserted
into the T cell DNA. This painstaking analysis revealed that when the
HIV provirus inserts into a gene called STAT3 or STAT3 and another gene
called LCK, it can prompt cells with those proviruses to activate cell proliferation. With additional nonviral mutations in other human genes,
this can result in T cell lymphomas.

"This is a complicated, multistep process that requires rare events -
- insertion into STAT3or STAT3 and LCK genes in just the right spot
-- to even begin," said Mellors, who also is chief of the Division of Infectious Diseases at UPMC. "As a physician, I am reassured that these
events are rare. Although we need to be aware of the potential for HIV
to cause lymphomas, it's such a rare occurrence that there is no need
for heightened anxiety, yet." Because people with HIV are living longer
due to advances in medication and care, there are more years in which
mutations could accumulate in host genes.

When that is coupled with the effects of proviruses already inserted
in oncogenes, the frequency of lymphoma could increase over time,
Mellors noted.

So far, this has not been observed. Nevertheless, the research team
stressed the importance of additional studies to assess the role that
HIV medications may play in preventing T cell lymphomas, coupled with
continued surveillance for T cell lymphomas in people with HIV.

Shuang Guo, Ph.D., and Stephen H. Hughes, Ph.D., both of NCI, are co-lead
and senior authors of this research, respectively. 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, Baktiar Karim, D.V.M., Ph.D., and Xiaolin Wu, Ph.D.,
all of NCI; and Beth Scott, Aaron Hamilton, Ph.D., and Marintha Heil,
Ph.D., all of Roche Molecular Diagnostics.

This research was supported by National Institutes of Health contracts
12XS547 and HHSN261200800001E.

========================================================================== Story Source: Materials provided by University_of_Pittsburgh. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. John W. Mellors, Shuang Guo, Asma Naqvi, Leah D. Brandt, Ling
Su, Zhonghe
Sun, Kevin W. Joseph, Dimiter Demirov, Elias K. Halvas, Donna
Butcher, Beth Scott, Aaron Hamilton, Marintha Heil, Baktiar Karim,
Xiaolin Wu, Stephen H. Hughes. Insertional activation of STAT3 and
LCK by HIV- 1 proviruses in T cell lymphomas. Science Advances,
2021; 7 (42) DOI: 10.1126/sciadv.abi8795 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/10/211013152106.htm

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