HIV-1-Specific Chimeric Antigen Receptors Based on Broadly Neutralizing Antibodies.

Despite remarkable advances in treating HIV infection with drugs that allow people to survive long term, these drugs do not cure infection and must be taken life-long. A true “cure,” replacing the need for ongoing treatment that is expensive, potentially toxic, and monitoring-intensive, remains elusive. An arm of the immune system, “cytotoxic T lymphocytes” (CTLs) survey the body for cells expressing abnormal proteins, and kill them. These killer cells therefore have important roles protecting against virus infections and cancers; viruses produce their proteins inside infected cells, and cancers involve altered proteins that cause dysregulated cell growth. Cells in the body transport small pieces of the proteins inside them to display on their surface to allow CTLs to scan for abnormal proteins. All CTLs have unique receptors (T cell receptors, TCRs) on their surfaces that determine what they target, and if a receptor binds an abnormal protein on another cell, the CTL kills that cell. Thus each CTL varies in its targeting, and only a few may target any given abnormal virus or cancer protein. CTL successfully control many viral infections, often completely removing the virus, such as in influenza, or keeping the infection under chronic control so that it is not life threatening, such as in herpes. For HIV infection, CTLs are not as effective; while they delay the onset of AIDS, they ultimately fail to prevent it. The reason for this failure is not clear, but important factors are that there may be too few healthy CTLs with receptors against HIV, and that the virus mutates to avoid TCR binding. Our work takes advantage of recently discovered “broadly neutralizing antibodies” (bnAbs) that bind the HIV surface, at areas where HIV has difficulty mutating to avoid being bound. We use genetic engineering to create artificial TCRs using bnABs, called chimeric antigen receptors (CARs). Genes for CARs can be put into CTLs isolated from a person, re-targeting them against HIV, potentially creating lots of CTLs against HIV that the virus doesn’t mutate to escape. When these CARS are put into CTLs from healthy HIV-uninfected volunteers, the CTLs become active against virus-infected cells, killing them. These are candidates for gene therapy against HIV to boost the CTL response to control infection without drug treatment. Recently, CAR gene therapy has shown remarkable promise in the treatment of some cancers, providing proof-of-concept for this approach. Ironically, HIV was the first disease for which CAR gene therapy was tried in the late 1990s, but it was abandoned because the early CAR used likely had inadequate efficacy. Our design of new CARs offers new hope for revisiting this approach as a treatment for HIV infection, with the goal boosting the CTL response to control the virus and obviate the need for chronic drug treatment.