Accelerated Aging, HIV Infection, Antiretroviral Therapies
Condition: HIV Infection; Aging Accelerated; Antiretroviral Therapies
MeSH terms: Infections; Communicable Diseases; HIV Infections; Acquired Immunodeficiency Syndrome
Study type: Observational

Summary: 
      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
    

Detailed description: 
      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.
    

Intervention name(s): Peripheral blood biological tests
Intervention type(s): Biological
Intervention description(s): A group and B group will be evaluated three 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.
Observational model: Case-Control
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        50 HIV1-infected naive patients (A group), apparied to 50 age- and sex-matched seronegative
        control (C group) subjects and 100 HIV1-infected patients in first line of antiretroviral
        therapy for at least 12 months (B group)
      
Keywords: Complementary Therapies