Genetically Altered Cells More Effective Against HIV

Cytotoxic T-lymphocyte (CTL) response is a critical defense mechanism against human immunodeficiency virus (HIV), the precurser to acquired immune deficiency syndrome (AIDS) . Researchers at the Albert Einstein College of Medicine at Yeshiva University have recently genetically engineered CTLs in order to make them more efficient in recognizing HIV, and the results were favorable.

CTLs are immune cells that are able to “recognize cells infected with HIV and kill them before they become HIV-producing factories.” This ability hinders HIV significantly for an initial period of time, and depending on each individual host, can hold off the development of AIDS for months or multiple years. Unfortunately, because HIV is capable of mutating very quickly in the body, “the virus typically evades and ultimately overpowers the immune system, leading to an increase in viral load that, in the absence of drug therapy, results in AIDS.”

By analyzing the CTLs of HIV infected individuals who were able to hold off the development of AIDS (these people are referred to as “elite controllers”), researchers genetically engineered normal CTLs to behave in the efficient way that CTLs of elite controllers behaved. Specifically, the T-cell receptors of CTLs were genetically altered in order to better detect the peptides that show up on HIV infected cells.

In addition to better recognition of HIV infected cells, the CTLs of elite controllers are thought to bind more tightly to the infected cells in order to destroy them. The genetic modifications made by the researchers also were intended to demonstrate this tighter bonding.

Tests were done on both animals and “naive” human blood (not infected with HIV) confined to test tubes. Results showed that the genetically modified CTLs, whose T-cell receptors had been altered to behave more like those of elite controllers, were far more effective in killing HIV infected cells than normal CTLs. “We demonstrated that these genetically reprogrammed CTLs have very strong activity in terms of killing HIV-infected cells in both test tubes and an animal model,” says Dr. Harris Goldstein, senior author of the study.

The benefits of this study could be profound, and could lead to a new way of treating HIV, a disease in which there is no known cure. The fatal form of the disease, AIDS, is present in more than 33 million people worldwide, and claims the lives of over 2 million people each year (over 300 thousand being children). The most problematic region for the disease is sub-Saharan Africa, though approximately 450 thousand individuals are living with the disease in America.

Further research needs to be done in genetically altering T-cell receptors, as the research in this study only used genes from a single CTL T-cell receptor. “To make this strategy even more effective, we’re now in the process of isolating a “cocktail” of CTL receptor genes that are specific for many different HIV peptides—an approach analogous to today’s combination drug therapy for treating HIV infection,” says Dr. Goldstein. While not at the stage of implementation, this new approach appears to be on a very positive track.

Source: Defeat Diabetes Foundation: Joseph, Aviva. Zheng, Jian Hua. Goldstein, Harris. et al. Journal of Virology. “Lentiviral Vectors Encoding Human Immunodeficiency Virus Type 1 (HIV-1)-Specific T-Cell Receptor Genes Efficiently Convert Peripheral Blood CD8 T Lymphocytes into Cytotoxic T Lymphocytes with Potent In Vitro and In Vivo HIV-1-Specific Inhibitory Activity.” March 2008. Gardner, Karen. Journal of Virology press release. March 2008.