CCR5 Inhibitor Treatment Intensification on CD4+ T-cell Recovery

Blunted CD4+ T-cell responses during viral control may be a consequence of on-going T-cell destruction in the regenerative phase of CD4 recovery from activation-induced apoptosis and/or reduced production from decreased thymic output. Maraviroc, a CCR5 inhibitor, may improve the clinical status of HIV-infected by two distinct mechanisms. First, by blocking HIV entry into CD4+ T-cells, CCR5 inhibitors have direct antiviral activity. Second, as the pro-inflammatory state of HIV infection up-regulates CCR5 ligands and receptors, this CCR5 receptor antagonist may abrogate immune activation and resultant T-cell apoptosis. Importantly, MVC binds CCR5 receptors without inducing intracellular signaling or altering cell-surface expression. Potentially, MVC intensification during viral suppression with ART may further decrease persistent activation-induced apoptosis and improve repair and remodeling of lymphoid tissue leading to increased CD4+ T-cell recovery and function. The aim of this study is to evaluate a potentially therapeutic immunomodulatory effect of MVC. Several measures of immune homeostasis will be determined in this study, including functional genomic analysis and extended T-cell phenotyping. Genes responsive to MVC therapy will be identified and categorized into functional groups. Based upon existing literature of the identified genes and observed immune responses (change in CD4/CD8 subsets) during MVC therapy, a model of CCR5 responsive-genes and potential impact on immune recovery will be outlined. Potentially, individuals experiencing immune discordance during suppressive ART may be better treated by MVC antiretroviral intensification. 1\. We hypothesize that expression will decrease among genes involved in immune activation (NF-kB, MAPK, nuclear factor of activated T-cells, MYD88 and STAT1), apoptosis (Fas ligand and TRAIL) and trafficking/repopulation of T-cells (CCR5, MIP-1α, MIP-1β and RANTES) and increase among genes involved in tissue repair (platelet-derived growth factor, insulin-like growth proteins and osteoblast-specific transcription factor). 1. The gene expression profiles induced by MVC will be associated with a favorable increase in the rate of CD4+ T-cell recovery. 2. The rate of CD4 recovery (cells/month) will be greater during MVC compared to before. 3. The proportion of cells expressing activation/ apoptosis markers will decrease from baseline and this decrease will be associated with improved CD4 recovery. 4. The proportion of naïve cells will increase from baseline and this increase will be associated with improved CD4 recovery. 5. The rate of CD4 recovery will be greater among those subjects receiving PI-containing treatment regimens compared to those receiving NNRTI-containing treatment regimen.