AIDSWEEKLY Plus, Monday, 21 April 1997
Daniel J. DeNoon, Senior Editor
How do people with a mutation in only one of HIV's two coreceptors resist infection?
New studies suggest an answer, and provide a glimpse into the inner workings of the human immune system.
The recent discovery of the coreceptors required for HIV-1 entry into cells showed that macrophage-tropic (M-tropic) strains use the CCR5 receptor while T-lymphocyte-tropic (T- tropic) strains use the CXCR4 receptor (also known as fusin or Lestr).
M-tropic HIV strains predominate early in the course of infection; T-tropic strains predominate in the later stages of disease. Harvard researcher Conrad C. Bleul and colleagues have uncovered clues central to understanding why this is the case. They reported their findings in the Proceedings of the National Academy of Sciences ("The HIV Coreceptors CXCR4 and CCR5 Are Differentially Expressed and Regulated on Human T Lymphocytes," PNAS, 1997;94:1925-30).
"We identified the T-lymphocyte subsets expressing the two coreceptors and found them to be largely mutually exclusive," Bleul et al. wrote. "These findings suggest that in progression to AIDS during the shift from M- to dual- and finally T-tropic virus strains, the target cell population will shift to a different lymphocyte subset. This crucial point in AIDS pathogenesis is still poorly understood."
Bleul et al. used specific monoclonal antibodies (mAbs) to compare lymphocyte expression of CCR5 and CXCR4. They found that CXCR4 is found on naive, unactivated T cells while CCR5 is found on previously activated/memory T cells.
In an accompanying commentary, New York University researchers Derya Unutmaz and Dan R. Littman put this finding at the center of a model for HIV pathogenesis ("Expression Pattern of HIV-1 Coreceptors on T Cells: Implications for Viral Transmission and Lymphocyte Homing," PNAS, 1997;94:1615- 8).
According to the Unutmaz and Littman scenario, CCR5 is the key coreceptor during initial infection when M-tropic HIV strains encounter dendritic-cell (DC)/memory-T-cell conjugates (which are found in the skin and on the external linings of organs involved in sexual HIV transmission).
Infected and activated DC would then activate neighboring memory T cells, making them susceptible to infection.
"The eventual transition to T-tropic strains usually coincides with the dramatic reduction in CD4(+) T-cell counts and the development of full-blown AIDS," Unutmaz and Littman wrote. "It is, however, not clear wither the transition to T- tropic strains is the cause or the result of the sudden decline in the CD4(+) T-cell numbers."
Stromal cells in the secondary lymphoid organs produce high levels of SDF-1, the chemokine that is the natural ligand for CXCR4. This initially may limit the infectivity of T- tropic HIV strains. The disruption of the lymphoid architecture by HIV disease may eventually remove this limitation, however.
"Understanding the physiological role and regulation of HIV coreceptors on different subsets of T cells will not only pave the way for elucidating the interplay between these receptors and HIV and thus their role in the pathogenesis of AIDS, but will also guide future strategies for deploying therapeutics that block entry of HIV into target cells," Unutmaz and Littman concluded.
Beyond their implications for AIDS pathogenesis, the Bleul et al. findings also have implications for understanding the role of chemokines in T-cell migration patterns.
"The data suggest distinct functions for the two receptors and their ligands in the migration of lymphocyte subsets through lymphoid and nonlymphoid tissues," Bleul et al. wrote.
In particular, the findings implicate SDF-1 as a major chemoattractant involved in the migration of naive T cells to the lymph nodes.
The Bleul et al. study was supported by a grant from the Deutsche Forschungsgemeinschaft and by National Institutes of Health grant HL 48675.
The corresponding author for the study is Charles R. Mackay, LeukoSite Inc., 215 First Street, Cambridge, Massachusetts 02142.
Commentary authors Derya Unutmaz and Dan R. Littman may be reached at the Skirball Institute for BioMolecular Medicine and Howard Hughes Medical Institute, New York University Medical Center, New York, New York 10016.
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