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15th International HIV Drug Resistance Workshop13-17 June 2006, Sitges, Spain |
ROLE OF HOST FACTORS IN DEFINING R5 VERSUS X4 DOMINANCE DURING PARTIALLY SUPPRESSIVE ANTIRETROVIRAL THERAPY
Antivir Ther. 2006, 11:S56 (abstract no. 48)
Z Grossman1, P Hunt2 and SG Deeks2
1Tel Aviv University, Tel Aviv, Israel and NIH, Bethesda, MD, USA; 2University of California and San Francisco General Hospital, San Francisco, CA, USA
BACKGROUND: CCR5-using HIV (R5) largely targets activated memory-effector CD4+ T-cells while CXCR4-using HIV (X4) targets naïve T-cells, resting memory T-cells and to a lesser degree activated T-cells. In untreated individuals, X4 typically emerges in very advanced disease. Recently, we and others found that X4 frequency is much higher in treated compared to untreated individuals. This difference persists at all CD4 levels and is partly predicted by pretreatment CD4 nadir. We offer a hypothesis to explain these observations.
HYPOTHESIS: There is growing evidence that R5 replication is driven by the high density of CCR5-expressing CD4+ T-cells generated in localized immune-activation bursts. We propose that progressive disorganization of lymphoid tissue leads to dilution of these localized aggregates of CCR5-expressing cells and that this in turn leads to the selection of X4 variants. We further propose that treatment does not restore, and may even diminish, these localized aggregates. This hypothesis is based on the following observations and deductions: (a) R5 and X4 compete for access to CD4 receptors. (b) R5 predominates when sufficiently large, dense clusters of activated, CCR5-expressing CD4 T-cells are abundantly generated through interaction with antigen-presenting cells. Binding of R5 (including defective virus) to CD4 blocks X4-CD4 binding such that infection by X4 is characterized by a reproduction ratio <1. X4 therefore persists only as “quasi-species”. (c) These conditions no longer exist once lymphoid-tissue organization is substantially disrupted. When the efficiency of local R5 replication is reduced, due to lower density of CCR5-expressing targets and/or diminished CCR5 expression, X4 variants, targeting a broader range of cells, can out-compete R5. (d) Partially effective HAART does not fully restore lymphoid architecture or CCR5-expression in lymph nodes and gut. (e) Treatment-mediated reductions in T-cell activation that further diminish CCR5 expression may enhance selection of the more virulent X4 but are also associated with slower lymph-node destruction. Such mixed effect might explain our recent observation that the presence of X4/dual/mixed virus in treated patients is not associated with rapid CD4 loss.
CONCLUSIONS: Several observations support the hypothesis that X4 dominance over R5 occurring during therapy reflects a diminished density of CCR5-expressing T-cells in lymphoid tissues.
2006-06-13
48
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