scholarly journals Antiretroviral drug transporters and metabolic enzymes in human testicular tissue: potential contribution to HIV-1 sanctuary site

2016 ◽  
Vol 71 (7) ◽  
pp. 1954-1965 ◽  
Author(s):  
Yiying Huang ◽  
Md. Tozammel Hoque ◽  
Mohammad-Ali Jenabian ◽  
Kishanda Vyboh ◽  
Sana-Kay Whyte ◽  
...  
Keyword(s):  
Drug Transporters ◽  
Metabolic Enzymes ◽  
Testicular Tissue ◽  
Potential Contribution ◽  
Antiretroviral Drug ◽  
Hiv 1

scholarly journals HIV-1 Alters Intestinal Expression of Drug Transporters and Metabolic Enzymes: Implications for Antiretroviral Drug Disposition

2016 ◽  
Vol 60 (5) ◽  
pp. 2771-2781 ◽  
Author(s):  
Olena Kis ◽  
Sumathi Sankaran-Walters ◽  
M. Tozammel Hoque ◽  
Sharon L. Walmsley ◽  
Satya Dandekar ◽  
...  
Keyword(s):  
Protein Expression ◽  
Healthy Volunteers ◽  
Drug Transporters ◽  
Metabolic Enzymes ◽  
Efflux Transporters ◽  
Control Group ◽  
Cancer Resistance ◽  
Naive Group ◽  
Hiv 1 ◽  
Lower Expression

ABSTRACTThis study investigated the effects of HIV-1 infection and antiretroviral therapy (ART) on the expression of intestinal drug efflux transporters, i.e., P-glycoprotein (Pgp), multidrug resistance-associated proteins (MRPs), and breast cancer resistance protein (BCRP), and metabolic enzymes, such as cytochrome P450s (CYPs), in the human upper intestinal tract. Intestinal biopsy specimens were obtained from HIV-negative healthy volunteers, ART-naive HIV-positive (HIV+) subjects, and HIV+subjects receiving ART (10 in each group). Intestinal tissue expression of drug transporters and metabolic enzymes was examined by microarray, real-time quantitative reverse transcription-PCR (qPCR), and immunohistochemistry analyses. Microarray analysis demonstrated significantly lower expression ofCYP3A4andABCC2/MRP2 in the HIV+ART-naive group than in uninfected subjects. qPCR analysis confirmed significantly lower expression ofABCC2/MRP2 in ART-naive subjects than in the control group, whileCYP3A4andABCG2/BCRP showed a trend toward decreased expression. Protein expression of MRP2 and BCRP was also significantly lower in the HIV+naive group than in the control group and was partially restored to baseline levels in HIV+subjects receiving ART. In contrast, gene and protein expression ofABCB1/Pgp was significantly increased in HIV+subjects on ART relative to HIV+ART-naive subjects. These data demonstrate that the expression of drug-metabolizing enzymes and efflux transporters is significantly altered in therapy-naive HIV+subjects and in those receiving ART. Since CYP3A4, Pgp, MRPs, and BCRP metabolize or transport many antiretroviral drugs, their altered expression with HIV infection may negatively impact drug pharmacokinetics in HIV+subjects. This has clinical implications when using data from healthy volunteers to guide ART.

scholarly journals Multiple Mutations in the Human Immunodeficiency Virus Protease Gene Are Responsible for Decreased Susceptibility to Protease Inhibitors

1995 ◽  
Vol 6 (2) ◽  
pp. 80-88 ◽  
Author(s):  
R. W. King ◽  
S. Garber ◽  
D. L. Winslow ◽  
C. Reid ◽  
L. T. Bacheler ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Protease Inhibitors ◽  
Clinical Isolate ◽  
Protease Gene ◽  
Human Immunodeficiency Virus Protease ◽  
Fold Reduction ◽  
Antiretroviral Drug ◽  
Immunodeficiency Virus ◽  
Hiv 1

The protease (PR) of the human immunodeficiency virus (HIV) is essential for replication of the virus, and accordingly has become an attractive target for the development of an antiretroviral drug. We have previously reported that passage of HIV-1 in the presence of increasing concentrations of the C-2 symmetrical, linear diol P9941 resulted in the isolation of virus with a valine-to-alanine change at position 82 (V82A) of the PR, and reduced sensitivity to certain PR inhibitors. In this study, we passaged four different variants of HIV-1 in increasing concentrations of XM323, and isolated variants with reduced sensitivity to inhibitors of PR. Twenty-three passages of HIV-1 (RF) in the presence of XM323 resulted in a variant that exhibited an approximately 100-fold reduction in susceptibility to XM323 and that contained V82F and I84V changes. When two other viruses, HIV-1 (RF41D2) and HIV-1(RF41E4), previously derived from HIV-1 (RF) by passage in the presence of P9941, were passaged in the presence of XM323, variants with V82A/L97V and M46L/V82A/L97V changes, respectively, were obtained. The M46L/V82A/L97V variant showed a 6-fold reduction in sensitivity to XM323, whereas the susceptibility of the V82A/L97V mutant remained unchanged. Seventeen passages of a clinical isolate of HIV-1, HIV-1 (Pat.E), in the presence of XM323 produced a V82F/L97V mutant with an approximately 9-fold reduction in sensitivity to XM323.

scholarly journals Antiretroviral Drug Resistance Testing in Adult HIV‐1 Infection: 2008 Recommendations of an International AIDS Society–USA Panel

2008 ◽  
Vol 47 (2) ◽  
pp. 266-285 ◽  
Author(s):  
Martin S. Hirsch ◽  
Huldrych F. Günthard ◽  
Jonathan M. Schapiro ◽  
Françoise Brun‐Vézinet ◽  
Bonaventura Clotet ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Resistance Testing ◽  
International Aids ◽  
Antiretroviral Drug Resistance ◽  
Drug Resistance Testing ◽  
Antiretroviral Drug ◽  
Hiv 1

scholarly journals V2-Specific Antibodies in HIV-1 Vaccine Research and Natural Infection: Controllers or Surrogate Markers

Animals ◽  
2019 ◽  
Vol 9 (8) ◽  
pp. 526 ◽  
Author(s):  
Duerr ◽  
Gorny
Keyword(s):  
Vaccine Efficacy ◽  
Natural Infection ◽  
Vaccine Trial ◽  
Clinical Findings ◽  
Hiv Vaccine ◽  
Model Systems ◽  
Potential Contribution ◽  
Vaccine Research ◽  
Specific Antibodies ◽  
Hiv 1

Most human immunodeficiency virus (HIV) vaccine trials have lacked efficacy and empirical vaccine lead targets are scarce. Thus far, the only independent correlate of reduced risk of HIV-1 acquisition in humans is elevated levels of V2-specific antibodies identified in the modestly protective RV144 vaccine trial. Ten years after RV144, human and non-human primate vaccine studies have reassessed the potential contribution of V2-specific antibodies to vaccine efficacy. In addition, studies of natural HIV-1 infection in humans have provided insight into the development of V1V2-directed antibody responses and their impact on clinical parameters and disease progression. Functionally diverse anti-V2 monoclonal antibodies were isolated and their structurally distinct V2 epitope regions characterized. After RV144, a plethora of research studies were performed using different model systems, immunogens, protocols, and challenge viruses. These diverse studies failed to provide a clear picture regarding the contribution of V2 antibodies to vaccine efficacy. Here, we summarize the biological functions and clinical findings associated with V2-specific antibodies and discuss their impact on HIV vaccine research.

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