VANCOUVER, B.C. _ The delicate balance of cell host factorsillustrate quite dramatically how the replication of the AIDS virus istightly controlled, said Anthony Fauci, chief of the National Instituteof Allergy and Infectious Diseases (NIAID) Laboratory ofImmunoregulation.
Speaking to a standing room only audience Wednesday at the XIInternational Conference On AIDS, he said the interplay betweenpositive and negative host factors may be the reason why thereplication of HIV is kept at a low level for years in people infectedwith the virus. Disrupting the delicate balance, however, can result ina dramatic increase in HIV replication, heralding the onset of theserious manifestations of the disease.
At the molecular level, the interactions involve cytokines, some ofwhich boost HIV replication and some of which are suppressive.
"The data underscore the importance of the body's own defensemechanisms to the HIV disease process, provide new insights into thepathogenic mechanisms of HIV, and suggest potential new targets fortherapies," Fauci said.
Presenting the latest data from his lab, naturally occurringsuppressive cytokines such as interleukin-4 (IL-4), interleukin-10(IL-10) and transforming growth factor beta (TGF-beta) can blockthe inductive cytokines in cell culture, thereby stopping HIVreplication. IL-10 appears to interfere with HIV replication byblocking the activity of inductive cytokines normally involved ininflammatory responses, such as tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6).
Using this data, the researchers then studied the immune cells ofnormal volunteers who were given either a placebo injection or aninjection of IL-10. Following placebo injections, the cells of thenormal volunteers were easily infected with HIV in vitro. The cellsalso produced large amounts of TNF-alpha. However, the cells drawnfrom volunteers given IL-10 were able to resist infection by HIV forup to 48 hours.
"The experiments clearly demonstrate that HIV replication isregulated by a delicate balance among the body's own cytokines, andthat by altering this balance, you can dramatically influence thereplication of the virus in vitro and potentially even in the body,"Fauci said.
Fauci told the delegates that the next step in the research process willbe to design a trial which will examine the effects of IL-10administered to HIV-infected people.
In addition to the work on IL-10, Fauci reported on what is provingto be a very hot topic in AIDS research: the so-called "suppressorphenomenon" associated with CD8+ T cells. Part of the CD8suppressor phenomenon seems to be due to the secretion by theCD8+ T cells of beta-chemokines, signaling molecules that normallyrecruit inflammatory cells to the site of an infection.
Three of these molecules _ RANTES, MIP-1 alpha and MIP-1 beta_ have been shown by Robert Gallo and his group at the MedicalBiotechnology Center, University of Maryland, in Baltimore, to bepotent suppressors of HIV-1. Their mode of action seems to bethrough interference with the receptor sites normally required for theentry of macrophage-tropic strains of HIV into their target cells.
Although it was initially thought that the effects of these threechemokines fully explained the CD8 suppressor phenomenon, Fauciand his colleagues have shown that not all non-cytolytic suppressionof HIV by CD8+ T cells can be explained by the three factors alone.The investigators were able to demonstrate that even when RANTES,MIP-1 alpha and MIP-1 beta were blocked with antibodies, HIVremained suppressed in HIV-infected cells cultured with CD8+ Tcells. n
-- Peter Winter Special To BioWorld Today
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