In a small study of HIV-infected people, researchers supported in part by the National Institute of Allergy and Infectious Diseases (NIAID) have shown that a novel form of gene therapy can prolong, with no apparent side effects, the survival of critical immune system cells that are typically depleted during the course of HIV disease. Gary Nabel, M.D., Ph.D., of the University of Michigan, and his colleagues report their findings in the April 2, 1996 Proceedings of the National Academy of Sciences.
Dr. Nabel's paper is the first published report of a gene therapy study in which doctors have treated HIV-infected patients with their own CD4+ T cells that have been modified with an antiviral gene. The approach has the advantage of not requiring cells from donors who would need to be matched immunologically with the recipient.
This work is an example of NIAID's commitment to the development of innovative therapies for HIV-infected people," says Anthony S. Fauci, M.D., NIAID director.
This pilot study suggests that gene transfer can be used to prolong the survival of CD4+ T cells and may, ultimately, help to sustain the immune systems of HIV-infected people," says Dr. Nabel, also an investigator at the Howard Hughes Medical Institute. "Additional studies, now under way, will help to define the optimal methods of CD4+ T cell gene transfer and determine the clinical efficacy of this approach."
In the study, the researchers drew blood from three HIV-infected people, and separated out each patient's CD4+ T cells. These cells, sometimes called "T-helper" cells, are the main targets of HIV.
Into these cells, which were treated with two antiretroviral drugs to block HIV replication, the researchers inserted one of two altered HIV rev genes. Normally, rev produces a protein, Rev, that allows transport of certain HIV genetic material within the infected cell from the nucleus to the cytoplasm, a critical step in viral replication.
Into half the cells from each patient, the researchers inserted an altered rev gene that produces a defective protein, Rev M10, which suppresses HIV replication by competing with the function of normal Rev. The altered rev gene was developed in the late 1980s in the laboratory of NIAID grantee Bryan Cullen, Ph.D., of Duke University.
Into the other cells from each patient, the scientists inserted a "dummy" gene that produces a protein that does not compete with normal Rev, and therefore has no anti-HIV activity.
The researchers treated both sets of cells with interleukin-2 to expand them to large numbers, and then re-infused each patient with their own cells. The patients were monitored closely, and the researchers tracked the survival of both Rev M10-producing cells and the cells with the "dummy" rev gene. As had previously been shown in test tube experiments, the CD4+ T cells expressing Rev M10 persisted longer than the cells with the "dummy" gene.
"Our data suggest that genetically modified cells can be detected, and the cells expressing Rev M10 demonstrated a 4- to 5-fold selective survival advantage," the authors write.
None of the patients in the pilot trial experienced any adverse effects from the treatment. "These results indicate that this form of genetic treatment could be used safely in a larger number of HIV-infected patients," says Dr. Nabel.
Dr. Nabel is the principal investigator of a research team sponsored by the Strategic Programs for Innovative Research on AIDS Treatment (SPIRAT), an initiative of NIAID's Division of AIDS.
"This elegantly designed study circumvented the usual problem of person-to-person variation in clinical trials by essentially using each individual as both a positive and negative control," says Nava Sarver, Ph.D., chief of the Targeted Interventions Branch of NIAID's Division of AIDS, and the program officer for SPIRAT. "This approach already has been emulated by other gene therapy researchers beginning clinical trials."
"Dr. Nabel's work provides critical information as to the feasibility of gene transfer therapy for HIV infection, providing preliminary answers to several important questions," she adds. "For example, we now have evidence that this procedure is safe; that we can insert genes into cells from HIV-infected individuals without inducing HIV replication in cell culture; that we can trace these cells once we put them back into the body; and that delivery of anti-HIV genes using non-viral delivery vehicles (vectors) is feasible."
SPIRAT, launched in 1994, supports studies at the interface of basic and clinical research, leading to the implementation of pilot clinical studies to test novel therapeutic strategies to combat HIV disease. Examples include strategies to restore and maintain a functional immune system via immune cell or tissue restoration, and direct suppression of HIV replication through molecular or cellular mechanisms.
NIAID is a component of the National Institutes of Health. NIAID conducts and supports research to prevent, diagnose and treat illnesses such as AIDS and other sexually transmitted diseases, tuberculosis, asthma and allergies. NIH is an agency of the U.S. Public Health Service, U.S. Department of Health and Human Services.
Woffendin C, et al. Expression of a protective gene prolongs survival of T cells in human immunodeficiency virus-infected patients. Proc Natl Acad Sci USA 1996;93:2889-94.
Bridges SH, Sarver N. Gene therapy and immune restoration for HIV disease. Lancet 1995;345:427-32.