Combining Cell and Gene Therapy in an Effort to Eradicate HIV

Abstract

More than 30 million people are infected with HIV, and HIV remains the fifth leading cause of disabilityadjusted life years worldwide. Antiretroviral therapy (ART) dramatically decreases mortality rate, but there are side effects, long-term toxicities, expenses, stigmas, and inconveniences associated with chronic treatment, and HIV-infected individuals on ART have an increased risk of malignancies, cardiovascular disease, neurologic disease, and shortened life expectancy. Therefore, a cure for HIV remains an important goal. Combining new cell and gene therapy technology is an exciting approach that appears promising in vitro. Animal testing and careful clinical trials will be needed to determine if these strategies are clinically useful.

Simian Immunodeficiency Virus (SIV)-Specific Chimeric Antigen Receptor-T Cells Engineered to Target B Cell Follicles and Suppress SIV Replication

“…As mentioned, we hypothesize that treatment with autologous CAR/CXCR5-transduced T cells can be a valuable component for achieving sustained remission of HIV. Future studies to evaluate the in vivo efficacy of CAR/CXCR5 immunotherapy must address multiple complexities under active study in the cancer field ( 56 , 83 , 84 ), plus others distinct for HIV ( 60 , 85 , 86 ). Robust proliferation and persistence of the adoptively transferred cells is especially critical for the long-term (life-long?)…”

Targeting reservoirs of HIV replication in lymphoid follicles with cellular therapies to cure HIV

“…CAR‐engineered NK cells are also being explored for the treatment of various hematological and nonhematological cancers . In addition to treating cancers, HIV‐targeting CAR‐T cells and CAR‐NK cells are also being explored as a treatment for HIV . The approach of hematopoietic stem cell transplant with CAR‐transduced stem cell precursors is also being pursued .…”

“…Many innovative and promising HIV functional cure strategies are currently being developed. These include broadly neutralizing antibodies, bi‐ and tri‐specific antibodies, BIKES, and TRIKES; inactivating HIV in latently infected cells; activating latently infected cells for clearance; creating T cells and macrophages that are resistant to infection; and cellular immunotherapies that target HIV‐replicating cells . Whilst detailed discussion of all of these and other exciting current HIV‐cure strategies are beyond the scope of this mini‐review, here I will focus on the three cell therapy approaches and discuss them in the context of targeting lymphoid follicle reservoirs of HIV replication.…”

HIV Receives a “One Two Knockout Punch”

“…However, there have been concerns about the potential for HIV to infect adoptively transferred T cells (particularly since some strategies used a CD4-zeta CAR). 9 The knockdown of CCR5 is a potential strategy to confer HIV resistance, especially since the sole documented patient cured of HIV was an HIV + individual with acute myeloid leukemia (AML) who received an allogeneic stem cell transplant from a healthy donor who was homozygous for the CCR5d32 mutation. This mutation prevents infection of CCR5 strains of HIV onto CD4 + T cells because these viruses rely on CCR5 as a co-receptor for entry.…”

“…11 Nevertheless, results from the HIV CAR T cell studies and studies utilizing zinc finger nuclease approaches to knock down CCR5 suggest that combining these two modifications to produce a T cell therapeutic that has potent anti-HIV activity and is resistant to HIV infection is highly desirable. 9 In this issue of Molecular Therapy, Hale et al 2 present a glimpse into how such a product might look. Using HDR, their work describes directed delivery of a second generation CAR based off broadly neutralizing antibodies specific for the HIV envelope glycoprotein into the CCR5 locus (see Figure 1).…”