Naïve and Memory Cell Turnover as Drivers of CCR5-to-CXCR4 Tropism Switch in Human Immunodeficiency Virus Type 1: Implications for Therapy

Abstract

Early human immunodeficiency virus infection is characterized by the predominance of CCR5-tropic (R5)virus. However, in many individuals CXCR4-tropic (X4) virus appears in late infection. The reasons for this phenotypic switch are unclear. The patterns of chemokine receptor expression suggest that X4 and R5 viruses have a preferential tropism for naïve and memory T cells, respectively. Since memory cells divide approximately 10 times as often as naïve cells in uninfected individuals, a tropism for memory cells in early infection may provide an advantage. However, with disease progression both naïve and memory cell division frequencies increase, and at low CD4 counts, the naïve cell division frequency approaches that of memory cells. This may provide a basis for the phenotypic switch from R5 to X4 virus observed in late infection. We show that a model of infection using observed values for cell turnover supports this mechanism. The phenotypic switch from R5 to X4 virus occurs at low CD4 counts and is accompanied by a rapid rise in viral load and drop in CD4 count. Thus, low CD4 counts are both a cause and an effect of X4 virus dominance. We also investigate the effects of different antiviral strategies. Surprisingly, these results suggest that both conventional antiretroviral regimens and CCR5 receptor-blocking drugs will promote R5 virus over X4 virus.Human immunodeficiency virus type 1 (HIV-1) binding to and entry into cells are mediated by the interaction of the viral gp120 protein with cell surface CD4 molecules. Studies of HIV-1 infection have shown that the virus, in addition to binding to cellular CD4, also binds to a variety of chemokine receptors (3). Usually, in early HIV-1 infection, the virus shows a tropism for the CCR5 receptor (R5 virus). However, strains of virus that bind to the CXCR4 chemokine receptor (X4 virus) appear in late infection in at least 50% of patients (24). This change in viral phenotype is associated with rapid depletion of CD4 cells and disease progression (8). The reason for this phenotypic change in late disease is uncertain (41). It has been suggested that X4 virus may be more virulent than R5 virus. However, if this were the case, it is not clear why X4 virus should not dominate from early infection, since it must arise frequently due to the small number of mutations required to make the shift from CCR5 to CXCR4 tropism (11). It has also been suggested that R5 virus dominates early infection, because its tropism for CCR5 promotes infection of macrophages at the site of infection. However, R5 virus predominates even after parenteral infection (57), and CD4 T cells, not macrophages, are found to be the dominant cell type infected in both early and late infection (47,54). In addition, a recent study has shown that target cell availability, as measured by coreceptor expression, cannot be the driving force for R5-to-X4 viral evolution, since higher levels of CXCR4 expression among both total and CD45 ϩ R0 Ϫ CD4 ϩ cells ("naïve" cells) were associated with a delayed development of ...

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