Our clinical research continues to address several important aspects of the following questions: how to optimally use and administer multi-class combination anti-retroviral therapy; how to integrate immune based therapies within a framework of ongoing antiretroviral therapy; how to determine the optimal time for initiation of antiretroviral strategy in order to preserve and reconstitute immune function while at the same time minimizing long-term antiretroviral toxicities, and how to optimize the potential use of immune-based therapies as a potential means both of decreasing exposure to antiretroviral drugs and of enhancing their efficacy. A major highlight of this project has been to characterize the immunologic abnormalities associated with HIV infection, develop safe, practical immunologic approaches to the adjunctive therapy of patients with HIV infection, and utilize these immune based therapies as tools for obtaining valuable insights into the pathophysiologic mechanisms present in patients at various stages of HIV infection. One of the specific tools employed in this endeavor has been the use of subcutaneous administration of interleukin-2 (scIL-2) in order to to reverse the CD4 T cell decline associated with progressive HIV-1 infection. A series of randomized phase I-II studies were carried out that established this as a feasible method for increasing the CD4 count in patients with HIV infection; these studies were then extended to optimize the dosing regimens for maximal immunologic and virologic benefit while minimizing side effects. Intensive efforts remain underway to better characterize the function, replication, and survival of lymphocytes following both acute and chronic stimulation by IL-2 therapy. Cohorts of patients are being followed who have received IL-2 treatment for periods that now extend to almost 19 years. A major finding of these studies, elucidated using two independent means of both in vivo and ex vivo lymphocyte labeling, has been the discovery that intermittent IL-2 therapy induces a marked prolongation of the survival of CD4 T cell subsets, particularly both naive and central memory cell subsets. Extensive phenotypic study of these CD4CD25 cytokine-expanded cells (CEN) shows them to express a unique pattern of surface markers distinguishable from other CD25 populations such as T regulatory lymphocytes. The laboratory remains engaged in an extensive series of collaborations with a large number of extramural colleagues, both in the US and abroad, in the context of two major randomized phase III international clinical endpoint trials of sc IL-2. The goal of these studies is to determine whether the favorable effects of IL-2 therapy on CD4 T cell number translate into a significant delay in the onset of AIDS-defining conditions and or death in such patients versus the recipients of antiretroviral therapy alone. Based upon the current frequency of clinical endpoints being observed in a blinded fashion in these two trials, it is anticipated that the data generated will meet the protocol-defined goals for formal analysis and conclusions within the coming 6 months. We are in the process of identifying and analyzing stored samples from one of these trials for the presence of elevated markers of inflammation and altered coagulation as potential predictors of CD4 decline. We also served as lead center in a multi-center exploration of the safety and potential immunologic efficacy of an interleukin-2 analogue that has a selectively enhanced binding affinity for the high-affinity IL-2 receptor and displayed a more favorable toxicity profile in preclinical studies. Interleukin-2 (IL-2) has also been studied for its potential role in supplementing ART therapy, specifically to determine whether it can be used as a ART-sparing regimen for those who experience an initial CD4 T cell increase from its use. In this regard we conducted a randomized, controlled trial of scIL-2 with and without ART interruption in an IL-2-experienced cohort with CD4 counts above 500 cells per cubic millimeter to determine how successful IL-2 therapy may be in eliminating the need for continuous ART with sacrificing CD4 cell numbers. Formal analysis of data from this trial revealed that over two sequential 6 month observation periods following interruption of ART the rate of CD4 decline exceeded that found in a comparison group who continued ART during this time frame, suggesting that IL-2 therapy alone may not be sufficient to prevent immunologic decline in the absence of concomitant antiviral suppression. We are also actively engaged in the design and implementation of similar exploratory studies of ART-sparing strategies with extramural collaborators to address different facets of this issue. In particular, we are the lead center in a randomized, controlled multi-center international trial designed to compare the effects of intermittent scIL-2 therapy with or without the use of peri-cycle antiretroviral treatment compared to control patients not receiving IL-2. The data generated during this multi-center trial are anticipated to meet protocol-defined criteria for analysis within the next 8 months. We also performed phase III work to determine the safety and preliminary antiviral efficacy of a novel CCR5 inhibitor compound. We are also assisting in the initial preclinical testing of a novel """"""""immuno-toxin"""""""", a monoclonal antibody linked with pseudomonas exotoxin, that may have direct antiviral activity by virtue of its affinity for HIV-infected cells. We are also preparing to serve as one of the trial sites for the """"""""START"""""""" study (Strategic Timing of AntiRetroviral Treatment) aimed at determining whether early introduction of ART in previously-untreated patients translates into better clinical outcomes. Finally, we also continue our efforts to improve access to clinical trials by local minority populations through an outreach that includes a close relationship with local clinics for medically under-served populations.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Intramural Research (Z01)
Project #
1Z01AI000865-09
Application #
7732553
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
9
Fiscal Year
2008
Total Cost
$2,059,757
Indirect Cost
City
State
Country
United States
Zip Code
Jagannathan, Prasanna; Osborne, Christine M; Royce, Cassandra et al. (2009) Comparisons of CD8+ T cells specific for human immunodeficiency virus, hepatitis C virus, and cytomegalovirus reveal differences in frequency, immunodominance, phenotype, and interleukin-2 responsiveness. J Virol 83:2728-42
Porter, Brian O; Anthony, Kara B; Shen, Jean et al. (2009) Inferiority of IL-2 alone versus IL-2 with HAART in maintaining CD4 T cell counts during HAART interruption: a randomized controlled trial. AIDS 23:203-12
Porter, Brian O; Shen, Jean; Kovacs, Joseph A et al. (2009) Interleukin-2 cycling causes transient increases in high-sensitivity C-reactive protein and D-dimer that are not associated with plasma HIV-RNA levels. AIDS 23:2015-9
Read, Sarah W; Lempicki, Richard A; Di Mascio, Michele et al. (2008) CD4 T cell survival after intermittent interleukin-2 therapy is predictive of an increase in the CD4 T cell count of HIV-infected patients. J Infect Dis 198:843-50
Penzak, Scott R; Busse, Kristin H; Robertson, Sarah M et al. (2008) Limitations of using a single postdose midazolam concentration to predict CYP3A-mediated drug interactions. J Clin Pharmacol 48:671-80
Healey, Letha M; Hahn, Barbara K; Rehm, Catherine A et al. (2008) The effect of continuous versus pericycle antiretroviral therapy on IL-2 responsiveness. J Interferon Cytokine Res 28:455-62
Davey, Richard T; Pertel, Peter E; Benson, Alice et al. (2008) Safety, tolerability, pharmacokinetics, and efficacy of an interleukin-2 agonist among HIV-infected patients receiving highly active antiretroviral therapy. J Interferon Cytokine Res 28:89-100
Robertson, Sarah M; Davey, Richard T; Voell, Jocelyn et al. (2008) Effect of Ginkgo biloba extract on lopinavir, midazolam and fexofenadine pharmacokinetics in healthy subjects. Curr Med Res Opin 24:591-9
Tilton, John C; Manion, Maura M; Luskin, Marlise R et al. (2008) Human immunodeficiency virus viremia induces plasmacytoid dendritic cell activation in vivo and diminished alpha interferon production in vitro. J Virol 82:3997-4006
Lifson, Alan R; INSIGHT Cause of Death Writing Group; Belloso, Waldo H et al. (2008) Determination of the underlying cause of death in three multicenter international HIV clinical trials. HIV Clin Trials 9:177-85

Showing the most recent 10 out of 54 publications