Faculty Stories

Vaccine and Infectious Disease Division

Faculty Stories

Scientists working together inside a Vaccine and Infectious Disease Division (VIDD) lab

Curing HIV with Hans-Peter Kiem

Dr. Hans-Peter Kiem

Hans-Peter Kiem remembers a time, not too long ago, when the thought of an HIV cure was unheard of.

Photo by Fred Hutch News Service

We have achieved major success in the HIV epidemic with antiretroviral therapy (ART). ART successfully suppresses viral replication, keeping viral levels low and in most cases undetectable, thus blocking the progression to AIDS. It does not, however, eliminate the virus from the body. Quiescent, latent HIV reservoirs remain “sleeping” in those on ART and if treatment is disrupted or removed, viral loads rapidly rebound. Thus, in order to prevent lifelong ART for HIV+ individuals, an HIV vaccine or cure is needed.

Gene therapy shows great promise as a method for curing HIV. The goal is to replace normal blood and immune cells with cells that are resistant to HIV infection. Dr. Hans-Peter Kiem, member of VIDD and CRD, studies ways to cure HIV through genetically modified stem cell transplantation. The overall interest in his lab is: can we make blood cells resistant to HIV? It has been shown that deleting or downregulating receptors like CCR5 (the receptor HIV uses to enter cells) or expressing a protein to block fusion of HIV attachment can make cells resistant or less susceptible to HIV. Some researchers are interested in doing this in T cells, because those cells are the main targets of HIV infection.

“But my lab has been interested in stem cells because those cells make all the other cells, like dendritic cells and macrophages, which can get infected in addition to T cells,” Kiem said.

“A perfect storm for the field”

A huge gain for the HIV field came in 2009 with the announcement that Timothy Ray Brown was cured of HIV after receiving hematopoietic cell transplantation for leukemia with donor cells carrying a mutation in CCR5. Brown discontinued ART right at his transplant and never went back on, and now 10 years later HIV is undetectable. Thus, Δ32 CCR5 cell transplantation offered a novel method for using gene therapy to cure HIV. Not long after publication of Brown’s case, the NIH/NIAID announced the Martin Delaney Collaboratory programs, in honor of the recently deceased AIDS activist and educator Martin Delaney, to fund HIV cure research.

“It is really mindboggling how two people enabled such a change for the entire HIV field,” said Kiem, referring to Brown and Delaney.

People didn’t talk about cure before that. But Brown’s cure and the Delaney grants created ‘a perfect storm’ for Kiem’s research. His group was doing hematopoietic stem cell (HSC) transplants and VIDD Member Keith Jerome was developing gene editing technology for disrupting HIV. Kiem and Jerome were awarded one of three Martin Delaney Collaboratory grants in 2011. The goal of their program, defeatHIV, is to take the allogeneic donor out of the equation by engineering an individual’s own autologous stem cells to be HIV resistant. 

The Kiem lab’s goal is to study the HIV reservoir after transplantation and establish an HIV resistant immune system in patients. Kiem’s lab uses a nonhuman primate (NHP) model for studying the effect of stem cell transplantation on HIV infection and progression. Pigtailed macaques have been widely used as a model for stem cell transplantation, gene therapy as well as SIV. However, their use for studying SHIV and/or HIV has been less well characterized. Kiem’s lab developed an infection model in these NHP using a SHIV strain that enters host cells via CCR5. Infection results in establishment of a latent reservoir of HIV and treating NHP post-infection with ART results in viral suppression, closely mimicking what happens during human HIV infection. The macaques also underwent a depletion in CD4 T cells soon after infection, with a restoration of these cells after ART initiation.

An important question for these studies was whether the conditioning regimen, i.e., the chemotherapy and radiation therapy given to patients to treat any residual cancer and facilitate engraftment, would also decrease or eliminate the viral reservoir. Thus, in their NHP model they used a total body irradiation (TBI) based conditioning regimen that enables engraftment of HSCs and eliminates cancer cells. Because TBI also kills lymphocytes, this regimen should reduce the population of HIV infected or susceptible cells. Animals were infected with SHIV and then treated with ART for 6 months and then underwent an autologous transplant with unmodified HSCs and myeloablative TBI or continued on ART. After seven more months, ART treatment was stopped and, surprisingly, they found higher viral rebound in animals that underwent transplantation. The conditioning regimen led to an increase in T-cell exhaustion and loss of SHIV-specific immune responses, thus impairing the ability of the immune system to respond to replicating virus thus resulting in the increased viral rebound.

CCR5 disruption

Stem cells were isolated from animals, genetically modified ex vivo for CCR5 disruption, expanded, and then reinfused back into the monkey. Sequencing of peripheral blood from animals showed CCR5 disruption in lymphoid and myeloid cell lineages. Each colored bar is one animal.

Adapted from Petersen CW et al. Blood. 2016 May 19;127(20):2416-26.

These studies have important implications for the design of studies in patients since they show that the highly toxic TBI regimen was not important in terms of clearing infected cells and decreasing or eliminating the viral reservoir. Thus less toxic and non-genotoxic conditioning regimens could be used in the future to transplant gene-modified, HIV-resistant hematopoietic stem cells.

With the NHP SHIV infection and transplantation model established, Kiem then wanted to transplant genetically modified, HIV resistant cells. CD34+ cells were isolated from the animals and then modified ex vivo to disrupt the CCR5 gene. When ex vivo modified cells were reinfused back into the animal, Kiem found CCR5 disruption in CD4 T cells, CD8 T cells and monocytes (see Figure). Therefore, they successfully disrupted CCR5 in the precursor stem cells, which contributed to the lymphoid and myeloid lineage in the NHP. They have also found that the presence of HIV or SHIV resistant CD4 T cells allowed for the generation of a more effective immune response.

 “That is really what facilitated (in the animals) recovery from the infection and also the slow decline in the viral load seen in some animals,” said Kiem. “The animals now develop an immune response that is much more potent than it could have been before.”

As part of defeatHIV, Kiem’s lab is continuing to develop CCR5 gene editing of stem cells and T cells as a curative therapy for HIV. His lab also works on hematopoietic stem cell transplantation and gene therapy for cancer and genetic diseases, such as glioblastoma and Fanconi anemia and hemoglobinopathies. Kiem has several close collaborations with other VIDD investigators, including Jerome, Josh Schiffer, Larry Corey and Stephen De Rosa. He received his MD and PhD from the University of Ulm in Germany, and came to Fred Hutch 25 years ago to be at the center of stem cell transplantation science and medicine.

In addition to being a member of VIDD and CRD, he holds the Endowed Chair for Cell and Gene Therapy at Fred Hutch, and is Director of the Stem Cell and Gene Therapy Program, Professor of Medicine/Oncology and Pathology (Adjunct) at UW, and Associate Head of the Heme Malignancy Program of the UW/Fred Hutch Cancer Consortium. He was also the inaugural recipient of the José Carreras / E. Donnall Thomas Endowed Chair for Cancer Research from 2009-2014. 
 

Hans-Peter Kiem faculty profile

Kiem Lab website

 

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