10th Conference on Retroviruses and Opportunistic Infections Boston, MA USA - February 10 -14, 2003

Conf Retroviruses Opportunistic Infect 2003 Feb 10-14;10th: abstract no. 14
A. Owen, P. G. Hoggard, B. Chandler, S. H. Khoo, D. J. Back
Univ of Liverpool, UK

BACKGROUND: A differential expression of the drug efflux pump, P-glycoprotein (Pgp), has been observed during HIV infection and the functional ABCB1 (MDR1) gene polymorphism, C₃₄₃₅T, related to Pgp expression and immune recovery. A recent study using a cell line (CEM) selected for Pgp mediated drug resistance to vinblastine (VBL₁₀₀) indicated that Pgp modulates viral infectivity. In order to further examine this apparent modulation of infectivity we have examined the expression of HIV-1 receptors and Pgp in peripheral blood lymphocytes (PBLs) from a cohort of healthy volunteers and in cell lines (CEM, VBL₁₀₀). In addition, the effect of treatment with protease inhibitors (PIs) on receptor expression was studied, since there is evidence that in vitro, PIs induce Pgp via transcriptional mechanisms.

METHODS: Pgp, CXCR4, CCR5 and CD4 were measured in PBLs and cell lines by flow cytometry using specific antibodies. For PBLs (n = 16) linear regression was used in order to assess correlations between Pgp and receptors. Expression data are presented as mean fold increase ±s.d. [See table]

RESULTS: In PBLs, a significant positive correlation was observed between Pgp and CXCR4 expression (R² = 0.76; p < 0.0001 95%; CI = 0.66,0.95; Figure 1) and an inverse correlation was found when Pgp (R² = 0.26; p < 0.05; 95% CI = -0.80, -0.02; Figure 1) was compared to CCR5. PIs were shown to induce both Pgp and CXCR4. In cell lines, a statistically significant lower expression of CD4 (8.46 ± 0.71; p < 0.0005; 95% CI = 2.74, 6.59) and CXCR4 (3.5 ± 0.32; p < 0.01; 95% CI = 0.45, 2.52) were observed in VBL₁₀₀ compared to control CEM cells (13.13 ± 2.55 and 4.9 ± 0.75, respectively).

CONCLUSIONS: The relationship between Pgp and HIV-1 co-receptor expression in PBLs from healthy volunteers indicates that there may be similar mechanisms involved in the control of these proteins. This is an important finding since PIs are substrates for Pgp, raising the possibility that cells expressing higher levels of Pgp (and, therefore, virus sanctuary) may place a selective pressure in favour of X4 tropic virus. Furthermore, these host-virus dynamics may be influenced by current PI therapy. However, the CEM and VBL₁₀₀ data showing an inverse relation between Pgp and CXCR4 indicate that this may not be the optimum model for studying these interactions.

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