AIDSWEEKLY Plus, Monday, December 15, 1997.
Daniel J. DeNoon, Senior Editor
HIV apparently hijacks the immune system's signalling system and uses it to its own ends.
The culprit is the viral Vpr protein. Studies by University of Pennsylvania researchers Velpandi Ayyavoo, David B. Weiner, and colleagues show that the protein acts like a glucocorticoid (GC) hormone to inhibit immune responses, to induce the programmed cell death (apoptosis) of T cells, and to preserve antigen-stimulated T cells as long-lived "factories" for production of new virus.
"These data suggest that Vpr may have a role in immune suppression and CD4 cell depletion in HIV infected patients," Ayyavoo et al. wrote in the journal Nature Medicine ("HIV-1 Vpr Suppresses Immune Activation and Apoptosis through Regulation of Nuclear Factor kB," Nature Med, 1997;3(10):1117- 23).
The HIV protein known as viral protein R (Vpr) is the 96- amino acid, 15-kDa product of the HIV vpr gene. This gene and its sister HIV regulatory genes vif, vpu, and nef are often referred to as auxiliary genes because they are not essential for HIV replication in established cell lines and because their activities are poorly understood. But unlike the other auxiliary genes products, Vpr is carried by HIV virions.
It was once thought that Vpr was an accessory gene product with no important function. But recent studies have changed that perception.
Perhaps the most dramatic of these studies is the finding that a woman infected with a vpr-defective HIV-1 mutant - and the child to whom she passed the infection - have remained disease free and asymptomatic for 13 years of follow-up (Wang et al., Virology, 1996;223:224-32).
Other studies have shown that extracellular Vpr makes cells more permissive to HIV replication - even cells that normally permit only low-level production of the virus (Levy et al. J Virol, 1995;69(2):1243-52). More recently, it was shown that Vpr permits HIV to infect promyelocytic cell lines via interactions with a GC receptor.
Because GCs have extensive immunosuppressive and apoptosis-influencing effects, Ayyavoo and colleagues explored the ability of Vpr to mimic GC activity. They found that:
* Vpr specifically blocks T-cell proliferation. This effect can be inhibited by the antisteroid compound RU486.
* Like GCs, Vpr suppresses production of the cytokines TNF- (alpha), IL-2, IL-4, IL-10, and IL-12 but not IL-7. The most dramatic inhibition was with IL-2 and IL-12. "Vpr's inhibitory effect on cytokine production could compromise the host immune response, particularly in cells that are not infected with HIV-1," Ayyavoo et al. suggested.
* Like GCs, Vpr inhibits cellular NFkB (a transcription factor crucial for cytokine regulation) by inducing transcription of the IkB (inhibitor of NFkB) gene.
* Like GCs, Vpr induces apoptosis of T cells. Again this effect was inhibited by RU486. But Vpr blocks apoptosis of antigen-stimulated T cells. "Infected cells that undergo antigen-specific activation could be spared as targets for apoptosis, thus functioning as efficient, long-lived, and productive viral factories," Ayyavoo et al. wrote.
The researchers suggested that further studies will be needed to determine precisely how the Vpr activities they identified relate to clinical HIV infection. They predicted that such studies will not only help clarify HIV pathogenesis, but will also yield insights into general immune function.
This study was supported in part by grants from the National Institutes of Health and by the Pediatrics AIDS Foundation.
The corresponding author for this study is David B. Weiner, Department of Pathology and Laboratory Medicine, 505 Steller-Chance Laboratories, 422 Curie Boulevard, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
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