AIDSWEEKLY Plus, Monday, 4 August 1997
Daniel J. DeNoon, Senior Editor
HIV infection self-perpetuates by forcing quiescent T cells to become activated, infectable cells.
A paradox of HIV disease is that productive infection requires replacements for the two billion susceptible T cells that are eliminated daily. The virus can complete its life cycle only in activated cells, but the vast majority of T cells are quiescent.
Chiang J. Li of Dana-Farber Cancer Institute, Boston, Massachusetts and colleagues hypothesized that the HIV genome encodes a priming factor that activates T cells to provide new hosts for the virus. A series of experiments validated this hypothesis, pointing to the HIV-1 Tat protein as the culprit.
"Tat protein, which is secreted by infected cells, activated quiescent T cells in vitro and in vivo," they reported. "These Tat-activated uninfected cells became highly permissive for productive HIV-1 infection."
Li et al. reported their findings in the Proceedings of the National Academy of Sciences ("Tat Protein Induces Self- Perpetuating Permissivity for Productive HIV-1 Infection," PNAS, 1997;94(15):81160-20).
Interestingly, Tat activation of primary T cells involved integrin receptors.
Integrins are a family of cytokines that provide costimulatory signals to T cells during induction of responses to antigenic challenge. (beta)[1] integrins can rescue various cell types from undergoing apoptosis. However, most AIDS patients - particularly those with more advanced disease - have impaired integrin-mediated costimulation of T-cell- receptor (TCR)-induced T-cell proliferation and protection from abnormal cell death, apparently due to impairment of TCR/integrin-stimulated secretion of interferon gamma (IFN-g) (Ng et al., J Immunol, 1997;158(6):2984-9).
Specific regions of the HIV Tat protein engage integrin receptors and mediate migration of endothelial and Kaposi's sarcoma (KS) cells. NIH researcher Barbara Ensoli has suggested that integrins provide major target for anti-KS drugs (Ensoli, 3rd Conf Retroviruses Opportun Infect., see AIDS Weekly Plus, April 21, 1997). Indeed, snake venom disintegrin can inhibit the adhesion of KS cells to extracellular matrix proteins (Fry et al., Amer Assoc Cancer Res, 1996; see AIDS Weekly Plus, May 27, 1996).
A novel compound GT4Y-78BQ-N (GT4Y, Billings Pharmaceutical Co., Chicago, Illinois) inhibits HIV transmission by preventing chemokine-receptor-mediated upregulation of integrin (see AIDS Weekly Plus, July 28, 1997).
Li et al. found that monoclonal antibodies (MAbs) against the (alpha)[3] and (alpha)[5] integrin receptors blocked Tat- induced T-cell activation, while MAbs against the (beta)[5] integrin receptor had no effect.
While Tat was able to render quiescent T cells susceptible to HIV infection, it was not by itself induce T-cell proliferation. Studies showed that Tat moved cells from the G[0] to the late G[1] stage of the cell cycle.
"These results suggest that HIV-1 has evolved a self- perpetuating mechanism to actively generate cells permissive for productive and cytopathic infection," Li et al. concluded. "This mechanism provides a reliable way for HIV-1 to compensate for the rapid destruction of activated permissive lymphocytes during the highly cytopathic infection."
The finding is of more than academic interest.
"Our results suggest potential therapeutic strategies for HIV-1 infection by inhibiting extracellular Tat with neutralizing antibody or drugs, or interfering with Tat- induced aberrant cell-activation events," Li et al. wrote. "Tat protein may serve as a target for potential AIDS vaccine development."
This work was supported by National Institutes of Health Grant AI-35576.
The corresponding author for this study is Chiang J. Li, Division of Cell Growth and Regulation, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115. Email: cjli@mbcrr.harvard.edu. - by Daniel J. DeNoon, Senior Editor
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