Advances in HIV/AIDS research, drug development, and clinical practice since the 1980s have made it possible for people living with HIV to live long, productive lives and to keep the virus under control at undetectable levels and noncommunicable as long as treatment is maintained. However, a cure – which completely rids the body of the virus – has only been documented in a few patients who underwent complex and high-risk bone marrow transplants for life-threatening blood cancers such as leukemia or lymphoma.
In an article published today at Journal of Clinical Investigation (JCI), researchers at Johns Hopkins Medicine report that they may have taken an early step toward a more practical HIV treatment. The researchers—in a largely federally funded study—focused on a patient undergoing cancer treatment and also living with HIV who, after chemotherapy, had a significant decrease in the number of CD4+ T immune cells that contained an HIV provirus—a key factor in HIV’s ability to persist in the body.
In a person living with HIV, proviruses—clones of HIV DNA—usually integrate into the T cell genome and become a permanent part of the cell’s genetic makeup. This integration allows the product to be transmitted to the daughter T cells when the parent cell divides – a process known as clonal expansion of HIV-infected T cells.
Over time, clonal expansion leads to an increase in the frequency of infected cells in a patient. Proviruses in daughter T cells can remain dormant or become active and start producing new HIV particles, especially if antiretroviral therapy is stopped.
CD4+ T cells (also known as helper T cells) are immune cells that recognize antigens, foreign invaders of the body such as bacteria and viruses. stimulate the production of antibodies by another type of immune cell, the B cell. and help a third type of immune cell, the CD8+ T cell (also known as a killer T cell), target and clear antigens from the body.
“CD4+ T cells with dormant HIV proviruses make it difficult to clear the virus from the body because there is always the potential for a renewed HIV infection,” says study co-leader Joel Blankson, MD, Ph.D., professor of medicine at Johns Hopkins University School of Medicine. “It is vital for us to know 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 this happened, perhaps it can be translated into a means of treating HIV.”
Blankson says the patient in the JCI study received two chemotherapy drugs for metastatic lung cancer: paclitaxel and carboplatin. “We suspect that the HIV-infected CD4+ T cells may have been too sensitive to these drugs and failed to proliferate in the patient,” says Blankson. “Our experiment was designed to find out if this actually happened.”
In the JCI study, researchers studied an HIV-infected clone of CD4+ T cells from the patient, a cell with an active, replication-competent (capable of infecting other T cells) product integrated into its genome. They stimulated the clones with T cell cognate peptide, a part of the HIV protein that activates the infected T cell and allows it 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,” says Blankson. “Untreated infected clones continued to proliferate, but treated infected ones did not. This was an important finding because it suggested a means by which infected cells could be selectively eliminated.”
As this effect was only seen in T cell clones from one patient, Blankson says his team plans to examine the HIV-clearing ability of CD4+ T cells from other people living with HIV.
“We suspect that the reason the infected T cell clones we studied were so sensitive to chemotherapy and the antiproliferative drug is because they rely on frequent proliferation to persist in the body,” says study co-senior author Francesco Simonetti, MBCh.B, Ph.D., assistant professor of Medicine at Johns Hopkins University School of Medicine. “Showing that this happens in other people living with HIV will provide evidence that this suspicion is correct and, in turn, will direct future research into HIV treatment strategies.”
“A key advantage of such an approach is that it can eliminate infected T cells without having to address other mechanisms that allow HIV to persist in the body,” says Simonetti.
Along with Blankson, members of the research team from Johns Hopkins University School of Medicine are Tyler Beckley, lead study author Filippo Dragoni, Isha Gurumurthy, Kellie Smith and Joel Sop.
Federal funding for the study includes support from the Director of the Office of the National Institutes of Health (NIH), grant DP5OD031834 from the National Institute of Dental and Craniofacial Research at NIH, grant UM1AI164566 from the National Institute of Allergy and Infectious Diseases at NIH, and NIH grant R0422414
Non-federal support for the study includes grants from the Johns Hopkins University Center for AIDS Research, the Vivien Thomas Scholars Initiative, the Bloomberg~Kimmel Institute for Cancer Immunotherapy, the Mark Foundation for Cancer Research, and the Cancer Research Institute.
Simonetti has received payments from Gilead Sciences for participation in scientific meetings. Smith is an inventor of a subset of technologies related to the FEST assay described in the paper, receives research support from AbbVie and Bristol-Myers Squibb, and owns founder’s equity in Clasp Therapeutics.
