AIDSWEEKLY Plus, Monday, December 15, 1997.
Daniel J. DeNoon, Senior Editor
A gene therapy already in Phase II clinical trials is intended to stimulate the same kind of cellular immune responses seen in people who remain healthy despite long-term HIV infection.
The therapy calls for the genetic engineering of cytotoxic lymphocytes (CTLs) so that they express the universal T-cell receptor - the CD3 zeta chain - in combination with the CD4 receptor to which all strains of HIV bind.
New in vitro studies show that these universal-receptor (UR) T cells recognize and destroy HIV infected cells as well as naturally occurring HIV-1 specific CTL clones.
"Our data indicate that UR-T cells...are likely to function in the presence of small amounts of intact HIV-1 envelope on the cell surface," wrote Harvard researcher Otto O. Yang, Bruce D. Walker, and colleagues in the Proceedings of the National Academy of Sciences ("Lysis of HIV-1-Infected Cells and Inhibition of Viral Replication by Universal Receptor T Cells," PNAS, 1997;94:11478-83).
The UT T-cell approach is under development by Cell Genesys Inc., Foster City, California. A proof-of-principle clinical trial in identical twin infants showed the approach to be safe (see AIDS Weekly Plus, February 12, 1996); Phase II trials in this population are nearing completion and new Phase II trials are testing the strategy in combination with antiretroviral drugs.
Several laboratories are working to develop vaccines capable of stimulating natural anti-HIV CTL. But Yang et al. noted that these approaches have a number of limitations:
CTL antigens must be expressed and presented within cells for proper human leukocyte antigen (HLA) class I presentation.
* Individual HLA types limit the number of HIV epitopes a person can recognized. A vaccine for general use would therefore have to incorporate a large variety of CTL epitopes.
* Vaccines would have to incorporate epitopes from a wide range of clinical HIV-1 isolates.
* HIV is capable of generating viable CTL escape mutants.
To circumvent these limitations, Yang et al. engineered CTLs bearing a chimeric T-cell receptor comprised of the UR zeta domain combined with either the human CD4 molecule or the binding regions of an antibody specific for the HIV-1 gp41 transmembrane glycoprotein.
"Unlike native T-cell receptors, class I HLA is not required for recognition by UR," Yang et al. noted. "Furthermore, because binding of HIV-1 gp120 to CD4 is a necessary step in the life cycle of all strains of HIV-1, the CD4-zetaUR should be broadly cross-reactive against all isolates and less prone to escape by sequence variation."
In vitro studies showed that CD8(+) cells transduced with the chimeric UR receptors could lyse cells acutely infected with HIV-1 and inhibit replication of the virus.
Because help from CD4(+) T cells may be needed for efficient CTL activity, Yang et al. suggested that UR- transduced CD4 cells could be created and administered together with UR-transduced CTL.
"UR-transduced CD4(+) cells have been shown to produce high levels of cytokines such as interleukin 2, suggesting that coinfusion of UR-modified CD4(+) cells may enhance survival and activity in vivo of CD8(+) UR-T cells," they wrote.
In March 1997, Cell Genesys announced plans to expand clinical studies of its AIDS gene therapy. The studies include an evaluation of a new manufacturing process and a pilot study designed to enhance the detection of antiviral effects in patients receiving antiviral drug therapy.
"We believe that Cell Genesys' AIDS gene therapy may represent an important new treatment strategy for this disease," said Cell Genesys researcher Stephen A. Sherwin. "Since antiviral drugs inhibit replication of the virus, the infection can recur due to the persistence of HIV infected cells when these drugs are stopped. These HIV infected cells are being targeted for elimination by our gene therapy."
Preliminary data from a completed clinical study demonstrated no serious treatment-related safety problems and showed that the gene-modified cells could persist for at least six months. The HIV positive twins who received AIDS gene therapy also received antiviral drug therapy including protease inhibitors. While consistent antiviral activity in addition to the effects of combination drug therapy has not yet been observed, Phase II studies with a different design are planned to determine whether the treatment can allow patients to decrease the continuous requirement for combinations of three or more antiviral drugs.
In addition, a pilot study has been planned by Cell Genesys to evaluate whether the combination of AIDS gene therapy and antiviral drugs can delay the recurrence of HIV infection, which has been generally observed in patients who discontinue their antiviral drug therapy. It is hoped that the gene therapy can reduce the requirement for long-term treatment with combinations of antiretroviral drugs.
The Yang et al. study was supported by Public Health Service Grants F32 AI 09280-01, AI 28568, and AI 30914 from the National Institute of Allergy and Infectious Diseases.
The corresponding author for this study is Otto O. Yang, Infectious Disease Unit, Room 5234, Massachusetts General Hospital, 149 13th Street, Charlestown, Massachusetts 02129.
Published by Charles Henderson, Publisher. Editorial & Publishing Office: P.O. Box 5528, Atlanta, GA 30307-0528 / Telephone: (800) 633-4931; Subscription Office: P.O. Box 830409, Birmingham, AL 35283-0409 / FAX: (205) 995-1588 - by Daniel J. DeNoon, Senior Editor
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Published by Charles Henderson, Publisher. Editorial & Publishing Office: P.O. Box 5528, Atlanta, GA 30307-0528 / Telephone: (800) 633-4931; Subscription Office: P.O. Box 830409, Birmingham, AL 35283-0409 / FAX: (205) 995-1588 http://www.newsfile.com
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