AIDSWEEKLY Plus, Monday, 4 August 1997
Daniel J. DeNoon, Senior Editor
HIV is unable to replicate in CD4(+) T cells made to express interleukin 16 (IL-16).
While exogenous IL-16 inhibits HIV replication by 70 to 90 percent, constitutive expression of 1,000-fold smaller amounts of the cytokine by genetically engineered CD4(+) cells inhibited viral replication by as much as 99 percent.
"In the long term, gene therapy might be used to introduce IL-16 cDNA (perhaps with other anti-HIV genes) into CD4(+) stem cells from HIV infected patients, before these stem cells give rise to CD4(+) HIV susceptible cells, and render them resistant to HIV infection," suggested Paul Zhou and colleagues of the National Institutes of Health, Bethesda, Maryland.
Zhou et al. reported their findings in the journal Nature Medicine ("Human CD4(+) Cells Transfected with IL-16 cDNA Are Resistant to HIV-1 Infection: Inhibition of mRNA Expression," Nature Med, 1997;3(6):659-664).
IL-16 is produced by CD8(+) T lymphocytes. Nanomolar concentrations of the cytokine, initially dubbed lymphocyte chemoattractant factor, induces chemotaxis of other cells including CD4(+) T cells. Perhaps more importantly for antiviral purposes, it also induces expression of IL-2 receptors and apparently corrects some of the functional defects seen in HIV infected cells (see AIDS Weekly Plus, July 28, 1997).
Zhou et al. noted that the cDNA for IL-16 has been cloned and found to encode a 130-amino-acid protein that appears to be the functional, C-terminal domain of the chemokine (Bazan et al., Nature, 1996;381:29-30 and Bannert et al., Nature, 1996;381:30).
In 1995, Michael Bair, Reinhard Kurth, and colleagues at the Paul Ehrlich Institute, Lungen, Germany, reported that IL- 16 produced in bacteria could suppress HIV-1 replication in CD8(+) depleted PBMCs (Bair et al., Nature, 1995;378:563). This discovery led Zhou et al. to explore whether functional IL-16 could be expressed in CD4(+) T cells.
"Since CD4(+) cells are a prime target for HIV replication and IL-16 renders these cells resistant to HIV infection, the genetic engineering of CD4(+) cells to express IL-16 protein constitutively represents a new approach for rendering cells resistant to HIV infection," they wrote.
To achieve this, the researchers transfected CD4(+) Jurkat T cells with human IL-16 cDNA (a 390 base-pair open reading frame encoding the active 130 amino-acids of IL-16) under the control of a heterologous promoter/enhancer sequence and the 5' and 3' untranslated sequences of the mammalian vector.
The transfected cells stably secreted IL-16 with no changes in their growth rate or expression of CD4(+) receptors.
"We estimate that the concentration of IL-16 in the culture supernatant of the transfectants was between 1 and 10 ng/ml and HIV was inhibited by 90 to 99 percent," Zhou et al. reported.
At least some of the anti-HIV activity appeared to occur within the transfected cells. Examination of proviral DNA and RNA transcripts within the transfected cells showed that IL-16 did not block either virus entry or reverse transcription but interfered with the transcription of early HIV regulatory genes, possibly by down-regulating the viral long-terminal- repeat (LTR) promoter.
"These results suggest that the inhibition of HIV replication by IL-16 is at the level of RNA expression and, most likely, at early regulatory-gene transcription," Zhou et al. wrote. "The mechanism by which this occurs is still not known."
In an accompanying commentary article ("Fighting HIV-1 with IL-16," Nature Med, 1997;3(6):605-6), Baier and Kurth suggested that IL-16 exerts its anti-HIV effects by cross- linking CD4 molecules, possibly by their CDR-3-like regions. This begins a signalling cascade resulting in inhibition of HIV promoter activity.
"In addition to IL-16's ability to crosslink CD4 resulting in delivery of a negative regulatory signal into the cell, this interleukin has been shown to suppress both mixed lymphocyte reactions and activation of CD4(+) T cells via the T-cell receptor/CD3 complex," they wrote. "It appears that IL-16, which was originally classified as a T-cell growth factor, should be more accurately defined as a suppressor of CD4(+) T-cell activation."
Baier and Kurth assert that it is essential to elucidate the "enormously complex" role of cytokines in the lymph-node microenvironment.
"As cytokine-mediated regulation of virus expression appears to be widespread in many virus infections, a clearer understanding of this regulation may allow the development of intervention strategies, such as that suggested by Zhou and colleagues, for HIV and for other viruses that are notoriously resistant to drug therapy."
The corresponding author for the Zhou et al. study is Paul Zhou, Branch of Oral Infection and Immunity, National Institute of Dental Research, National Institutes of Health, Bethesda, Maryland 20892. - by Daniel J. DeNoon, Senior Editor
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