Important note: Information in this article was accurate in January 1999. The state of the art may have changed since the publication date.AIDSWEEKLY Plus; Monday, January 11, 1999
Daniel J. DeNoon, Senior Editor
If so, these important immature cells could be the key to repairing immune systems ravaged by HIV disease.
Harvard researchers Hongmei Shen, David T. Scadden, and colleagues report studies confirming that hematopoietic stem cells express the CD4 receptor and CXCR4 or CCR5 coreceptors needed by HIV to infect human cells. Their extraordinarily good news is that despite expression of these receptors, the cells remain impervious to the virus.
"These data define the hematopoietic stem cell as a sanctuary cell which is resistant to HIV-1 infection by a mechanism independent of receptor and coreceptor expression that suggests a novel means of cellular protection from HIV-1," Shen et al. reported. "Whether this mechanism can be used to protect other cell types remains to be determined."
Shen et al. announced their findings in the Journal of Virology ("Intrinsic Human Immunodeficiency Virus Type 1 Resistance of Hematopoietic Stem Cells Despite Coreceptor Expression," J Virol, 1999; 73(1):728-37).
Even after successful, highly active antiretroviral therapy (HAART) the immune systems of people infected with HIV are slow to recover. And the situation is of course far worse for those whom HAART fails or is unavailable. One strategy for immune reconstitution for all of these patients is the genetic engineering a person's own stem cells to resist HIV infection. Such cells would then differentiate into various cell types, all of which would putatively resist infection.
But such strategies rely on a supply of uninfected stem cells, and upon the ability of lentiviral vectors to transduce these quiescent cells.
"Defining the issue of HIV-1 infection of stem cells may improve our understanding of stem-cell dysregulation in AIDS and has practical implications for stem-cell gene therapy for AIDS and the use of lentivirus vectors for the transfer of genes into stem cells," Shen et al. observed.
The researchers therefore examined stem cells at various stages of hematopoietic development for the presence of HIV-1 receptors, determined whether these receptors were functional, explored HIV-1 interactions with the receptors, and determined whether the virus could use the receptors to enter cells.
At least a subset of all cell types examined coexpressed CD4 with the CXCR4 or CCR5 coreceptors. With the single exception of true stem cells, HIV-1 could infect all other hematopoietic progenitors. Experiments with stem cells isolated from AIDS patients confirmed that these cells cannot be infected by HIV-1.
"The stem cell is therefore not a potential long-lived reservoir of virus and is an appropriate cell to consider for use in autologous gene therapy approaches to AIDS," Shen et al. concluded. "To the extent that this cell can be recovered from AIDS patients, it may be envisioned to be a virus-free cell type that may be transduced with anti-HIV constructs for possible immune reconstitution."
Shen et al. were able to transduce stem cells with such constructs only by using lentiviral vectors pseudotyped within vesicular stomatitis virus (VSV) G-protein envelopes.
Exactly how stem cells resist HIV-1 is an important issue, particularly if such resistance can be conferred on other cells.
"We hypothesize that the basis for resistance resides in either the need for an additional receptor complex component or an inhibitory alteration of the receptor complex that is present in all stem cells," Shen et al. suggested.
This work was supported by grands from DARPA and NIH.
The corresponding author for this study is David T. Scadden, AIDS Research Center, Massachusetts General Hospital, Bldg. 149, 13th St., Rm. 5212D, Boston, Massachusetts 02129. Phone: (617) 726-5615. Fax: (617) 726-4691. Email: <scadden.david@mgh.harvard.edu>.
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