Identification of a Potential Pharmacological Sanctuary for HIV Type 1 in a Fraction of CD4(+) Primary Cells

Author:

Valentin, A.

Morrow, M.

Poirier, R. H.

Aleman, K.

Little, R.

Yarchoan, R.

Pavlakis, G. N.
Author Address

[Valentin, Antonio; Morrow, Matthew; Poirier, Richard H.; Pavlakis, George N.] NCI, Human Retrovirus Sect, Vaccine Branch, Ctr Canc Res, Frederick, MD 21702 USA. [Aleman, Karen; Little, Richard; Yarchoan, Robert] NCI, HIV & AIDS Malignancy Branch, Bethesda, MD 20895 USA.;Pavlakis, GN, NCI, Human Retrovirus Sect, Vaccine Branch, Ctr Canc Res, POB B,Bldg 535,Room 210, Frederick, MD 21702 USA.;pavlakig@mail.nih.gov

Abstract:

We have identified a subset of HIV-susceptible CD4'CCR5' cells in human PBMCs that can efficiently exclude protease inhibitors (PI) due to high P-glycoprotein (P-gp) efflux activity. Phenotypically these cells are heterogeneous, include both T and non-T cells, and some display markers of memory cells. Cells with high P-gp represent 16-56% (median=37.3) of all CD4'CCR5' cells in healthy donors, and are selectively depleted in HIV-1-infected individuals (4.1-33%, median 10.1). A fraction of primary cells productively infected by HIV-1, in vitro, have high P-gp pump activity, demonstrating that infection does not inhibit P-gp function. In agreement with these data, HIV-susceptible cells expressing high levels of P-gp require higher levels of PI for complete inhibition of virus spread. We conclude that the PI concentrations achieved in plasma could be suboptimal for full inhibition of virus spread in high P-gp cells, indicating that they may represent a pharmacological sanctuary for HIV-1.

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