498-M. Differential Gene Expression in Chronically Infected HIV Patients Initiating HAART and Long-Term HAART Recipients Interrupting Therapy

Abstract

E-mail Abstract Author

Add To Itinerary

Session

Search Abstracts

Program

Session 69 Poster Session
Immunopathogenesis Issues Addressed by Therapeutic Interventions
Session Time: 4:30-6:30 pm
Room 4E-F

498-M.

Differential Gene Expression in Chronically Infected HIV Patients Initiating HAART and Long-Term HAART Recipients Interrupting Therapy
G. Dennis*¹, J. Yang¹, M. Bosche¹, D. Hosack¹, B. 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, and R. A. Lempicki¹
¹SAIC, Frederick, MD; ²NCI and ³NIAID, NIH, Bethesda, MD

Background: HIV-1 infection is associated with a decline in CD4+ T-cell numbers and 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 more fully understand the molecular mechanism by which HIV-1 infection and HAART alter cellular function, the expression of ~7000 genes were followed longitudinally in PBMCs collected from patients before and after initiating or interrupting HAART.
Methods: Gene expression levels were determined using Affymetrix’s HuFL GeneChip. PBMCs were collected from 6 healthy control subjects, 5 protease inhibitor-naļve patients (NAĻVE) pre- and 6 months post-initiation of HAART, and in 6 long-term HAART recipients pre- and 1 month post-therapy interruption and following re-initiation of HAART (NOHRT). Differentially expressed genes were identified by using iterative permutations of the data to generate gene lists with <7.5% predicted false-positive rates.
Results: All patients receiving HAART for 6 months had viral loads below the limit of detection, whereas virus levels were >100,000 RNA copies/mL plasma in the NAĻVE patients prior to HAART initiation and in the NOHRT patients 1 month post-HAART cessation. Compared to healthy controls, genes involved in host defense, apoptosis, and lipid metabolism were differentially expressed in both NAĻVE and NOHRT patients while on or off therapy. Under high viral burden both NAĻVE and NOHRT patients upregulated ~25 interferon-induced genes whereas in NAĻVE patients there was also downregulation of 20 Type-I interferon-induced genes that returned to basal levels following HAART initiation. NAĻVE patients also modulated the expression of genes encoding cell cycle regulators and members of the TNF/TNFR superfamilies, including CD40L and OX40, to a much larger extent than did NOHRT patients.
Conclusions: These studies revealed that genes involved in host defense, apoptosis, and interferon responses are modulated by high viral burden. The modulation of genes in NOHRT patients following therapy interruption and viral rebound is more representative of a normal immune response than the genes modulated during chronic HIV-1 infection. The altered expression of genes involved in lipid metabolism such as leptin, CPT-I, LDLR, and PPAR-alpha and -gamma may prove useful in understanding the mechanisms behind HIV- and therapy-induced metabolic disorders.