HIV Infection Clinical Trial
Official title:
Accelerated Aging, HIV Infection, Antiretroviral Therapies
The main goal is to confirm, among HIV1-infected patients, data from in vitro studies showing that antiretroviral therapies induce an accelerated aging through the same mechanisms than genetic laminopathies or than "physiological " aging, that is through the synthesis and persistence of farnesylated prelamin A. The secondary goal is to measure the impact of HIV infection and of antiretroviral therapies on markers of cell ageing (proteasome, mitochondria, telomere). The perspective is to fix antiretroviral therapy side effects using the same drug combination that will be used in few weeks in Marseille to treat children suffering from progeria
Protease inhibitors block viral protease, as well as various other cell enzymes : ZMPSTE24
cliping off prelamin A into mature lamin A ; at least one of the Golgi proteases involved in
the release of SREBP, controlling the transcription of lipid metabolism regulating genes ;
mitochondrial proteases involved in the importation and further maturation of nuclear genome
encoded proteins ; proteasome regulating the transcription of several genes through NF-B ;
P450 cytochromes. Nucleosides inhibitors of the viral reverse transcriptase exhibit nuclear
and mitochondrial DNA toxicity, disrupt lipid and protein glycosylation and inhibit
telomerase. Therefore antiretroviral therapies target several pathways involved in
accelerated or normal aging. Their combined effects are added to viral infection direct
symptoms or to cell abnormalities induced by viral proteins.
Our multicentric (the 3 CISIH from Marseille, Nice and Montpellier) 3 year- long study will
analyse 50 HIV1-infected naive patients (A group), apparied to 50 age- and sex-matched
seronegative control subjects (recruited by CIC-UPCET of Marseille) and 100 HIV1-infected
patients in first line of antiretroviral therapy for at least 12 months (B group). Patients
of group A and B will be recruited in the 3 clinical unit. The HIV1- infected patients will
be evaluated four times, at baseline, then every 12 months during 3 years. In case of
initiation or changing of antiretroviral therapy, patients will be evaluated once more.
Control subjects will be only evaluated at baseline.
Peripheral blood biological tests will be the following [Laboratory designation] : i/ viral
load measurement, PBMC isolation, DNA extraction, proviral DNA measurement, cell and DNA
storage [Virology, Timone CHU, Marseille]; ii/ assays of CD4, CD8, glycemia, insulinemia,
HOMA, total-, LDL- and HDL-cholesterol, triglycerides [Biochemistry labs from the 3 CHU] ;
iii/ antiretroviral drug assay (mass spectrometry) [Pharmacokinetics, Timone CHU,
Marseille]; iv/ detection (western blotting, immunocytochemistry combined to image analysis
of nuclear abnormalities) of PBMC nuclear, cytosolic and mitochondrial targets of
antiretroviral drugs : A and B lamins, NF-B + I-B and proteasome activity assay, CD36
(glycosylation), mitochondrial Hsp70, ROS mitochondrial production, mitochondrial inner
membrane potential, cytochrome C oxidase subunits 2 and 4 [Cell Biology, Timone CHU,
Marseille] ; v/ genotyping the antiretroviral targets : lamin A (ZMPSTE24) and B (Rce1)
processing proteases, Golgi SREBP-releasing proteases (MBTPS1 and S2), mitochondrial
deoxynucleoside transporters (SLC25A4 to A6), mitochondrial proteases (MPPA, paraplegin)
involved in processing of nuclear encoded proteins during their mitochondrial import ;
quantitative PCR measurement of telomere length [Molecular Genetics, Timone CHU, Marseille].
Marseille's CIC-UPCET collaborated to the protocol design, will recruit control subjects and
will be responsible for statistical treatment of data.
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Observational Model: Case Control, Time Perspective: Prospective
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