AIDSWEEKLY Plus, Monday, 28 July 1997
Daniel J. DeNoon, Senior Editor
A year of highly active antiretroviral therapy (HAART) partially reverses - but does not fully restore - the delicate balance of the immune system.
T cells normally maintain stable levels, expanding when needed to fight disease and contracting to original levels (by elimination of cells no longer needed) when the threat has passed: a phenomenon known as T-cell homeostasis. But HIV infection results in chronic activation of CD4(+) T cells and severe perturbation of homeostatic mechanisms.
Now that HAART has shown that HIV levels can be reduced exponentially, the major question for AIDS therapy is whether T-cell homeostasis will be restored if the virus is kept in check. A new study by Brigitte Autran and colleagues at Pitie-Salpetriere Hospital, Paris, France, provides a qualified hint of good news.
"Decreasing the HIV load can reverse HIV driven activation and CD4(+) T-cell defects in advanced HIV infected patients," Autran et al. concluded from intensive study of T-cell subsets in AIDS patients receiving HAART.
They reported their findings in the journal Science ("Positive Effects of Combined Antiretroviral Therapy on CD4(+) T-Cell Homeostasis and Function in Advanced HIV Disease," Science, 1997;277:112-6).
Autran et al. studied two groups of patients: eight previously untreated adults with advanced HIV disease (mean CD4 count 164 +/-86 cells/(micro)L) who received triple combination therapy with the protease inhibitor ritonavir, zidovudine (AZT), and dideoxycytosine (ddC); and six previously untreated adults with similar CD4 counts receiving a similar HAART regimen.
T-cell reconstitution followed the same three-phase pattern in all patients: a large initial increase in CD4(+) and CD8(+) cells, due to redistribution of memory cells; a reduction in T-cell activation in proportion to decreasing viral activity with improved CD4(+) T-cell reactivity to recall antigens; and a gradual increase in naive CD4(+) cells with a decrease in CD8(+) cells.
These observations led Autran et al. to suggest that HIV activity is itself the driving force behind the chronic T-cell activation seen in HIV disease. This activation, they suggested, causes the defective antigen-specific CD4(+) T-cell activation and proliferation at the heart of the perturbation of T-cell homeostasis and CD4(+) T-cell loss.
"This impairment of the mature CD4(+) cell repopulation process was, in part, reversible under effective antiviral treatment, although the balance between CD4(+) and CD8(+) subsets was not yet normalized with CD8(+) counts still higher than normal and CD4(+) counts remaining below normal thresholds," they wrote. "Earlier or stronger therapeutic interventions should reasonably achieve better reversibility."
In an accompanying article ("Recovering from the Ravages of HIV," Science, 1997;277:33), Autran told Science writer Jon Cohen that she believes the pattern of CD4(+) T-cell reconstitution during HAART to resemble that seen in recipients of bone-marrow transplants. These patients gradually reestablish relatively normal T-cell levels and function.
"I'm quite optimistic that if we could diminish the level of viral replication enough, we could approach that situation," Autran told Cohen.
But Donald Mosier of The Scripps Research Institute, La Jolla, California, told Cohen that he is far less optimistic about the ability of HAART to permit continued T-cell reconstitution.
"I'd frankly be surprised if you could continue to do this year after year," he told Cohen.
Support for the Autran et al. study was provided by SIDACTION and the Agence Nationale de Recherches sur le SIDA.
The corresponding author for this study is Brigitte Autran, Laboratoire d'Immunologie Cellulaire, URA CNRS 625, Hopital Pitie-Salpetriere, 47-83 Boulevard de l'Hopital, Paris, France. Email: autran@psl.ap-hop-paris.fr.
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