Researchers at Johns Hopkins Medicine have reported a potential step toward an HIV cure, based on observations in a patient undergoing chemotherapy for metastatic lung cancer who was also living with HIV. Their findings were published in the Journal of Clinical Investigation.
The study focused on the impact of chemotherapy drugs paclitaxel and carboplatin on CD4+ T cells infected with HIV. In people living with HIV, these cells often contain dormant proviruses—strands of HIV DNA integrated into their genome—which can reactivate and produce new virus particles if antiretroviral therapy is interrupted. The persistence of these clonally expanded, infected T cells has been a major barrier to eradicating the virus from the body.
“CD4+ T cells with dormant HIV proviruses make it difficult to eradicate the virus from the body, because the potential is always there for a renewed HIV infection,” said Joel Blankson, M.D., Ph.D., professor of medicine at Johns Hopkins University School of Medicine and co-senior author of the study. “It’s vitally important for us to learn why there were significantly fewer clonally expanded, infected CD4+ T cells in the patient who received chemotherapy. If we can understand the mechanism by which that happened, perhaps it can be translated into a means of curing HIV.”
Blankson explained that their experiments showed that when infected CD4+ T cell clones from this patient were treated with paclitaxel and carboplatin—or an antiproliferative drug called mycophenolate mofetil—the proliferation of these clones was halted. Untreated infected clones continued to multiply.
“We treated the stimulated T cells with paclitaxel and carboplatin in one experimental group, and an antiproliferative drug, mycophenolate mofetil, in another experimental group while leaving the stimulated clones in the control group untreated,” said Blankson. “The untreated infected clones continued to proliferate, but the treated infected ones did not. This was a significant finding, because it suggests a means by which infected cells could be selectively eliminated.”
Francesco Simonetti, M.B.Ch.B., Ph.D., assistant professor at Johns Hopkins University School of Medicine and co-senior author on the study, added: “We suspect the reason that the infected T cell clones we studied were so susceptible to chemotherapy and the antiproliferative drug is because they rely on frequent proliferation to persist in the body. Showing this happens in other people living with HIV will provide evidence that this suspicion is correct, and in turn, direct future research toward HIV cure strategies.”
“A key advantage of such an approach is that it can eliminate infected T cells without having to deal with other mechanisms that enable HIV to persist in the body,” Simonetti noted.
The research team included Tyler Beckley (lead author), Filippo Dragoni, Isha Gurumurthy, Kellie Smith and Joel Sop from Johns Hopkins University School of Medicine.
Funding for this study came from multiple federal sources including grants from several offices within the National Institutes of Health (NIH). Additional support came from institutional programs at Johns Hopkins University as well as foundations dedicated to AIDS research and cancer immunotherapy.
Simonetti disclosed payments received from Gilead Sciences for participation at scientific meetings. Smith holds inventorship rights related to technologies described in this paper and receives support from AbbVie and Bristol-Myers Squibb; Smith also owns equity in Clasp Therapeutics.
