AIDSWEEKLY Plus, Monday, December 15, 1997.
Daniel J. DeNoon, Senior Editor
Reconstitution of HIV-ravaged immune systems is possible with effective antiretroviral therapy, mouse studies suggest.
The studies provide in vivo evidence that people receiving highly active antiretroviral therapy (HAART) can regain most, but not all, lost immune function. They also suggest that stem-cell replacement, possibly incorporating anti-HIV gene therapies, could fully restore immune function.
"Hematopoietic microenvironments in HIV-1 infected individuals might remain functional to such an extent that immune reconstitution and stem cell gene therapeutic strategies for the treatment of AIDS may be feasible, provided that virus replication can be sufficiently inhibited," proposed Elizabeth S. Withers-Ward and colleagues of the University of California, Los Angeles ("Transient Renewal of Thymopoiesis in HIV Infected Human Thymic Implants Following Antiviral Therapy," Nature Medicine, 1997;3(10):1102-9).
The researchers noted that immune reconstitution of CD4 cells - whether endogenous or via exogenous stem-cell gene therapeutic strategies - requires the existence of functionally intact differentiation-inducing stromal elements. To explore whether such elements can survive HIV infection, they used severe combined immunodeficient (SCID) mice reconstituted with human fetal thymus and liver tissues.
These SCID-hu mice were infected with HIV-1 (strain NL4- 3). Six weeks after infection, drug-treated mice received combination antiretroviral therapy with zidovudine (AZT), didanosine (ddI), and the protease inhibitor A77003 (a less effective parent compound in the series that led to the development of ritonavir). A control group received no antiviral drugs; after seven weeks the female Thy/Liv implants of some of the animals in each group received male CD34(+) stem-cell reconstitution. Biopsies, consisting of approximately one-fourth of each Thy/Liv implant, were taken at six, nine to 11, and 13 weeks.
Before drug treatment, all of the implants in the HIV infected mice had severe depletions of CD4(+)/CD8(-) and CD4(+)/CD8(+) thymocytes. The treated animals subsequently exhibited renewal of these populations; CD4 cell renewal ranged from 32 to 65 percent of the total thymocyte population.
"Renewal of the CD4(+) population was seen regardless of whether exogenous CD34(+) cells were injected into the HIV depleted implants, indicating that endogenous precursor cells could be induced to differentiate," Withers-Ward et al. reported. "Y chromosomal sequences were detected in two mice that received exogenous CD34(+) cells, suggesting that exogenous CD34(+) cells could repopulate HIV infected, drug- treated implants. However, because of the small number of animals, we were unable to draw any quantitative conclusions about reconstitution efficiency with exogenous cells.
Unfortunately, reconstitution in this model was only temporary. While reconstitution was still significant 11 weeks after infection, by 13 weeks there was no difference between drug-treated and untreated animals. The authors noted that detectable viral replication occurred in some drug- treated animals and may have been responsible for the transience of reconstitution.
"It is possible that further optimization of antiviral therapy in this model may result in more marked and sustained reconstitution of thymopoiesis," they wrote, noting that a further experiment with other protease inhibitors showed an increased effect.
Withers-Ward et al. suggested that gene therapies could be combined with HAART to improve treatment of HIV disease.
"Progenitor cells isolated from HIV infected individuals may be appropriate for autologous immune reconstitution and gene transfer protocols," they wrote. "It is conceivable that the combined effect of a reduction in viral load by the administration of antiviral drugs and the protective effects of anti-HIV gene therapeutic reagents, followed by the subsequent renewal of the depleted CD4(+) population might reduce or delay the pathology associated with HIV infection, resulting in an effective therapeutic strategy."
This work was supported by NIH grants AI 36554, AI 36555, AI 36059, and HL 55205; by the Pediatric AIDS Foundation; and by a Tumor Immunology Institutional Training Grant (CA09120).
The corresponding author for this study is Jerome A. Zack, Division of Hematology-Oncology, Department of medicine, UCLA School of Medicine, 10833 LeConte Avenue, Los Angeles, California 90095.
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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