AEGiS-14IAC: Natural killer cells and T cells infected by HIV contribute to long term viral reservoirs and to cellular sanctuaries for protease inhibitors.

14th International AIDS Conference

Barcelona, Spain - July 7-12, 2002

Natural killer cells and T cells infected by HIV contribute to long term viral reservoirs and to cellular sanctuaries for protease inhibitors.

Int conf AIDS 2002 Jul 7-12; 14:(abstract no. ThOrA1436)

Valentin A, Yarchoan R, Pavlakis GN
NCI-Frederick, Frederick, United States

BACKGROUND: We have shown that in addition to T cells, NK cells are persistently infected by HIV, and they can transmit infectious virus. NK cells are known to have a highly active P-glycoprotein (P-gp) pump, a member of the ABC family of transporters associated with therapeutic failure and multidrug resistance. Protease inhibitors are known substrates for P-gp. We hypothesized that high P-gp activity in some HIV-1 infected cells might account for a suboptimal pharmacological effect of protease inhibitors leading to treatment failure.

METHODS: GFP-tagged HIV-1 molecular clones were used to study P-gp activity in infected primary cells in vitro. We used Rh123 and TMRE, two fluorescent P-gp pump substrates, to study the P-gp activity in different subsets of primary cells by flow cytometry. This methodology allowed functional studies of pump activity combined with the immunophenotyping of different cell subsets. Live infected cells identified by GFP expression were compared to uninfected cells.

RESULTS: We have identified a population of CD4+CCR5+ primary cells with very high P-glycoprotein efflux activity. These cells are phenotypically heterogeneous and were identified as T lymphocytes and NK cells. They were found in both uninfected and HIV-1 infected individuals. Functional studies demonstrated that higher concentration of protease inhibitors is required to achieve the pharmacological effects of the drugs in these cells. Monitoring GFP-tagged infected cells demonstrated that very high P-gp activity is present in some cells actively replicating HIV-1.

CONCLUSIONS: Our results suggest the presence of pharmacological cellular sanctuaries resistant to the antiviral effects of protease inhibitors. The presence of these cells could be responsible for HIV-1 persistence in patients receiving HAART. New therapeutic interventions to eliminate these cells are required to successfully treat HIV-1 infected patients.

Keywords: AEGIS, Killer Cells, Natural, HIV Infections, HIV-1, Protease Inhibitors, HIV Protease Inhibitors, CD4-Positive T-Lymphocytes, HIV Seropositivity, Antiretroviral Therapy, Highly Active, Drug Resistance, Multiple, In Vitro, Human, virology

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ThOrA1436