474 Global Changes in Gene Expression During HIV Infection and Antiretroviral Therapy G. Dennis*1, J. Yang1, M. Bosch1, D.A. Hosack1, B.T. Sherman1, I.A. Sidorov2, D.S. Dimitrov2, J.W. Adelsberger1, J.A. Metcalf3, R. Stevens1, M.W. Baseler1, R.T. Davey3, M.A. Polis3, H.C. Lane3, R.A. Lempicki1 1Sci Applications Intl Corp, Frederick, MD; 2Natl Cancer Inst, Bethesda, MD; and 3Natl Inst of Allergy and Infectious Diseases, NIH, Bethesda, MD
Background: HIV-1 infection is associated with a decline in CD4+ T-cell numbers and a systemic immune activation that leads to a generalized immunosuppressive state. The advent of HAART has significantly improved immune function despite being linked to metabolic side effects. To better understand the transcriptional consequences of HIV-1 infection and HAART the expression levels of ~7,000 genes were followed longitudinally in PBMCs collected from patients (pts) before and after initiating or interrupting HAART.
Methods: PBMCs were collected from 6 healthy control subjects, 5 protease inhibitor-naïve pts (NAIVE) pre- and 6 months post-initiation of HAART and in 6 long-term HAART recipients pre- and 1 month post-therapy interruption and 6 months following re-initiation of HAART (NOHRT). To obtain a global view of consistent changes in gene expression, pts from both the NAÏVE and NOHRT cohorts were grouped as either ON (n = 17) or OFF (n = 11) HAART. Expression values were normalized using the model based probe selection algorithm of Li and Wong (2001) and differentially expressed genes were identified following 5000 random permutations of expression values that generated gene lists with < 7.5% false-discovery rates.
Results: Relative to healthy controls, HIV-1 viremia modulated the expression of genes involved in antiviral responses, immune activation, and antigen presentation. The induction of genes including IFNG, IFI6-16, IPI35, ISG15, and PRKR indicates the activation of an anti-viral response program during HIV-1 viremia. Likewise, induction of ADA, LY6E, CLECSF2, IgG3 and IgM reveals an activated state of the immune system that includes both the cell-mediated and humoral arms of immunity. Four (4) proteasome subunits, LMP7, LMPY, MECL1, and TBP1, were induced in viremic pts, whereas LMP2 was selectively down modulated.
Conclusions: These studies reveal that HIV-1 viremia results in the induction of a defense response program that includes genes involved in anti-viral, cell-mediated, and humoral immunity. Based on the uncoordinated expression of immunoproteasome complex subunits, the data suggests that the selective down-modulation of LMP2 may represent a novel mechanism that contributes to the ability of HIV-1 to evade the immune system by compromising MHC class I-mediated presentation of viral antigens.
