Implications of T-cell P-glycoprotein activity during HIV-1 infection and its therapy.
OBJECTIVE
P-glycoprotein (P-gp) may reduce antiretroviral efficacy by decreasing disposition of HIV-1 protease inhibitors into tissues and cells. In contrast, P-gp overexpression in vitro can inhibit HIV-1 replication, and some drugs induce P-gp expression. To explore which of these mechanisms predominate in vivo, this study characterized relationships between T-cell P-gp activity and clinical parameters in HIV-infected adults.


METHODS
P-gp activity was quantified in total and naive CD4+ and CD8+ T cells of HIV-infected adults by flow cytometry using the substrate dye DiOC2(3). Demographic, virologic, immunologic, and treatment factors were obtained from medical records. Factors associated with P-gp activity were identified using multivariate linear regression.


RESULTS
A total of 185 subjects (22% female; 34% African American) were studied, of whom 131 (71%) were receiving antiretroviral treatment. There was marked interindividual variability in P-gp activity. By multivariate analysis, higher CD4+ T-cell P-gp activity was associated with lower log10 HIV-1 RNA (P = 0.005), but not treatment or demographic factors. P-gp activity was correlated across T-cell subsets.


CONCLUSIONS
The inverse relationship between P-gp activity and plasma HIV-1 RNA is most consistent with an inhibitory effect on viral replication rather than drug disposition. Antiretroviral drug class did not independently predict P-gp activity.
Hulgan
Todd
T
Department of Medicine, Vanderbilt Medical School, Nashville, TN 37203, USA.
Donahue
John P
JP
Hawkins
Charlene
C
Unutmaz
Derya
D
D'Aquila
Richard T
RT
Raffanti
Stephen
S
Nicotera
Fred
F
Rebeiro
Peter
P
Erdem
Husamettin
H
Rueff
Melissa
M
Haas
David W
DW
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000097:blood* / Q000235:genetics; D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy / Q000276:immunology*; D000328:Adult; D018791:CD4 Lymphocyte Count; D024882:Drug Resistance, Viral; D005260:Female; D015497:HIV-1; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D012367:RNA, Viral / Q000097:blood; D013601:T-Lymphocytes / Q000737:chemistry*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D012367:RNA, Viral