AIDSWEEKLY Plus; Monday, June 29, 1998
Daniel J. DeNoon, Senior Editor
If so, it is more bad news for people with HIV infection. The finding means that antiretroviral drugs themselves - even when highly active - are unlikely to reverse the damage done by the virus.
Even though HIV directly infects very few early hematopoietic progenitor cells, animal studies show that a dramatic decline in these cells precedes the loss of T cells.
"The significance of this finding for treatment in humans is that durable suppression of viral replication may not be sufficient to restore hematolymphoid microenvironments that have been damaged by HIV-1 infection," wrote Morgan Jenkins, Joseph M. McCune, and colleagues at the University of California, San Francisco's Gladstone Institute of Virology and Immunology.
"Contributions of HIV-1 induced hematopoietic deficiency to the pathology of HIV-1 infection underscore the importance of augmenting combination antiviral regimens with therapies designed to restore or to improve hematopoietic function."
Jenkins et al. reported their findings in the journal Blood ("Human Immunodeficiency Virus-1 Infection Interrupts Thymopoiesis and Multilineage Hematopoiesis In Vivo," Blood, 1998;91(8):2672-8).
The researchers studies the dynamics of HIV infection in the SCID/hu Thy/Liv model, i.e., in immunodeficient mice whose immune systems were reconstituted by transplant of human thymus and liver tissues.
They found that a loss of early progenitor cells preceded the loss of CD4(+)CD8(+) and CD4(+)CD8(-) thymocytes. This happened even though very few HIV proviral genomes could be detected in the progenitor cells.
Earlier studies in the SCID/hu Thy/Liv model suggested that HIV affected a more mature population of intrathymic precursor cells. These findings led to a widely accepted model of HIV pathogenesis in which T-cell depletion was the direct result of HIV killing of thymic T cells and their offspring.
"Our findings prompt a reappraisal of this model and suggest that destruction of less mature hematopoietic progenitor cells may be as important as infection and death of more mature thymocyte subpopulations," Jenkins et al. wrote. "To the extent that this population of cells and/or its supportive microenvironment may be adversely affected by HIV-1 infection, resumption of thymopoiesis may be limited if present at all."
The mechanism of HIV destruction of the early progenitor cells remains unknown. Jenkins et al. suggested that HIV induced alterations in cytokine signalling pathways, dysregulation of other stromal developmental signals, and/or direct toxicity from HIV gp120 molecules may come into play.
"The data presented here suggest that destruction of progenitor cells at the thymic and/or prethymic stage may contribute to the failure to maintain normal CD4(+) T-cell counts in HIV-1 disease," they concluded. "Impaired progenitor capacity may contribute to peripheral CD4(+) depletion regardless of whether the rate of CD4(+) T-cell loss is high or low."
The corresponding author for this study is Joseph M. McCune, Gladstone Institute of Virology and Immunology, P.O. Box 419100, San Francisco, California 94141-9100.
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