[Show abstract][Hide abstract] ABSTRACT: Virus-host interactions are characterized by the selection of adaptive mechanisms by which to evade pathogenic and defense
mechanisms, respectively. In primary T cells infected with HIV, HIV infection up-regulates TNF-related apoptosis inducing
ligand (TRAIL) and death-inducing TRAIL receptors, but blockade of TRAIL:TRAIL receptor interaction does not alter HIV-induced
cell death. Instead, HIV infection results in a novel splice variant that we call TRAIL-short (TRAIL-s), which antagonizes
TRAIL-R2. In HIV patients, plasma TRAIL-s concentration increases with increasing viral load and renders cells resistant to
TRAIL-induced death. Knockdown of TRAIL-s abrogates this resistance. We propose that TRAIL-s is a novel adaptive mechanism
of apoptosis resistance acquired by HIV-infected cells to avoid their elimination by TRAIL-dependent effector mechanism.
[Show abstract][Hide abstract] ABSTRACT: TNF-related apoptosis inducing ligand (TRAIL) is a key mediator of the innate immune response to infection. While TRAIL-mediated apoptosis plays an essential role in the clearance of virus-infected cells, its physiologic role also includes immunosurveilance for cancer cells. Therapeutics that induce TRAIL-mediated apoptosis in cancer cells remain a focus of ongoing investigation in clinical trials, and much has been learned from these studies regarding the efficacy and toxicity of these interventions. These data, combined with data from numerous preclinical studies that detail the important and multifaceted role of TRAIL during infection with human immunodeficiency virus and other viruses, suggest that therapeutic exploitation of TRAIL signaling offers a novel and efficacious strategy for the management of infectious diseases.
[Show abstract][Hide abstract] ABSTRACT: HIV envelope glycoprotein gp120 causes cellular activation resulting in anergy, apoptosis, proinflammatory cytokine production, and through an unknown mechanism, enhanced HIV replication.
We describe that the signals which promote apoptosis are also responsible for the enhanced HIV replication. Specifically, we demonstrate that the caspase 8 cleavage fragment Caspase8p43, activates p50/p65 Nuclear Factor kappaB (NF-kappaB), in a manner which is inhibited by dominant negative IkappaBalpha. This caspase 8 dependent NF-kappaB activation occurs following stimulation with gp120, TNF, or CD3/CD28 crosslinking, but these treatments do not activate NF-kappaB in cells deficient in caspase 8. The Casp8p43 cleavage fragment also transactivates the HIV LTR through NF-kappaB, and the absence of caspase 8 following HIV infection greatly inhibits HIV replication.
Gp120 induced caspase 8 dependent NF-kappaB activation is a novel pathway of HIV replication which increases understanding of the biology of T-cell death, as well as having implications for understanding treatment and prevention of HIV infection.
PLoS ONE 02/2009; 4(3):e4875. DOI:10.1371/journal.pone.0004875 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Because effective antiretroviral therapy (ART) reduces immune activation, we hypothesize that early changes in immune activation are associated with subsequent virologic response to therapy.
Observational cohort study.
Institutional HIV clinic.
Thirty-four adult HIV patients with virologic failure on their current antiretroviral regimen.
Change to salvage regimen selected by patient's physician.
Measures of immune activation at baseline and at 2, 4, 8, and 24 weeks after enrollment. Data were analyzed by proportional hazards (PH) models.
PH models showed that reductions between baseline and week 2 in expression of CD38 (P = 0.02) or CD95 (P = 0.02) on CD4 T cells were associated with increased likelihood of achieving virologic suppression. Kaplan-Meier analysis demonstrated that patients who had reductions within the first 2 weeks of therapy in CD4 T-cell expression of CD38 (P = 0.003) or CD95 (P = 0.08) were more likely to achieve viral suppression than those who did not.
Reduced CD4 T-cell expression of CD38 and CD95 occurring within 2 weeks of salvage therapy is associated with subsequent viral suppression. Monitoring CD38 and CD95 may allow earlier assessment of the response to ART.
[Show abstract][Hide abstract] ABSTRACT: During uncontrolled HIV disease, both TNF-related apoptosis inducing ligand (TRAIL) and TRAIL receptor expression are increased. Enhanced TRAIL sensitivity is due to TRAIL receptor up-regulation induced by gp120. As a result of successful antiretroviral therapy TRAIL is down-regulated, and there are fewer TRAIL-sensitive cells. In this setting, we hypothesized that all cells that contain virus, including those productively- and latently-infected, have necessarily been "primed" by gp120 and remain TRAIL-sensitive, whereas uninfected cells remain relatively TRAIL-resistant.
We evaluated the immunologic and antiviral effects of TRAIL in peripheral blood lymphocytes collected from HIV-infected patients with suppressed viral replication. The peripheral blood lymphocytes were treated with recombinant TRAIL or an equivalent amount of bovine serum albumin as a negative control. Treated cells were then analyzed by quantitative flow cytometry, ELISPOT for CD4+ and CD8+ T-cell function, and limiting dilution microculture for viral burden. Alterations in the cytokine milieu of treated cells were assessed with a multiplex cytokine assay. Treatment with recombinant TRAIL in vitro reduced viral burden in lymphocytes collected from HIV-infected patients with suppressed viral load. TRAIL treatment did not alter the cytokine milieu of treated cells. Moreover, treatment with recombinant TRAIL had no adverse effect on either the quantity or function of immune cells from HIV-infected patients with suppressed viral replication.
TRAIL treatment may be an important adjunct to antiretroviral therapy, even in patients with suppressed viral replication, perhaps by inducing apoptosis in cells with latent HIV reservoirs. The absence of adverse effect on the quantity or function of immune cells from HIV-infected patients suggests that there is not a significant level of "bystander death" in uninfected cells.
PLoS ONE 02/2008; 3(8):e3096. DOI:10.1371/journal.pone.0003096 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Acute HIV-1 infection of CD4 T cells often results in apoptotic death of infected cells, yet it is unclear what evolutionary advantage this offers to HIV-1. Given the independent observations that acute T cell HIV-1 infection results in (1) NF-kappaB activation, (2) caspase 8 dependent apoptosis, and that (3) caspase 8 directly activates NF-kappaB, we questioned whether these three events might be interrelated. We first show that HIV-1 infected T cell apoptosis, NF-kappaB activation, and caspase 8 cleavage by HIV-1 protease are coincident. Next we show that HIV-1 protease not only cleaves procaspase 8, producing Casp8p41, but also independently stimulates NF-kappaB activity. Finally, we demonstrate that the HIV protease cleavage of caspase 8 is necessary for optimal NF-kappaB activation and that the HIV-1 protease specific cleavage fragment Casp8p41 is sufficient to stimulate HIV-1 replication through NF-kappaB dependent HIV-LTR activation both in vitro as well as in cells from HIV infected donors. Consequently, the molecular events which promote death of HIV-1 infected T cells function dually to promote HIV-1 replication, thereby favoring the propagation and survival of HIV-1.
PLoS ONE 02/2008; 3(5):e2112. DOI:10.1371/journal.pone.0002112 · 3.23 Impact Factor