TAG HIV Basic Science, Vaccines, and Cure Project Blog

Bridging the Neurology-Immunology Barrier

The Cell Press journals Neuron and Immunity have collaborated to produce a timely free-access special issue focusing on the interrelatedness of neural and immune systems. The editors of Neuron write:

"The brain was once thought to be a largely 'immune-privileged' system. Traditionally, research has reflected this segregation, with neuroscientists focusing on the nervous system and immunologists focusing on the immune system. Yet as science in both realms has moved forward, it has become clear that the nervous and immune systems interact on many levels, in both disease states and under healthy conditions. It is also clear that molecules traditionally viewed as neural- or immune-specific play important and often distinct roles in the other system. Experimental evidence of interactions between the neural and immune systems continues to accumulate, and the two research communities are beginning to communicate more as well. In this same spirit, Neuron and Immunity have coordinated to bring together a compilation of articles on selected topics related to the interface between the nervous and immune systems."

The issue includes articles addressing "Immune Activation in Brain Aging and Neurodegeneration" and "Neuroimmune Crosstalk in HIV Infection."

Free Journal Issue on Immunology and Cardiovascular Disease

The January 2010 issue of the journal Clinical Immunology is offering free access to a series of articles addressing the immunology of cardiovascular disease. Among a range of related subjects, the reviews address data on the roles of innate and adaptive immunity in the development of atherosclerosis and the status of experimental immunotherapeutic approaches to treating the disease. 

PRO 2000 Microbicide Gel Doesn’t Pan Out

Earlier this year at the Conference on Retroviruses & Opportunistic Infections, Salim Abdool Karim presented data suggesting that a vaginally applied microbicide gel called PRO 2000 might offer some protection against HIV infection in high-risk women. The results were not statistically significant but represented a strong trend, and the suggested effect was a slight 30% reduction in risk of acquisition of the virus. Some commentators at the meeting noted that because this study had two separate control arms (a placebo gel and no gel), comparing the total number of control participants from both of these arms with the group that received PRO 2000 would render the result statistically significant. To his credit, Karim emphasized that such an analysis was not a pre-specified part of the protocol and was therefore inappropriate. He also pointed out that there was a larger, ongoing phase III study of PRO 2000 involving over 9,000 women that would provide a definitive answer as to the product’s efficacy.

The results from this trial, called MDP-301 and run by the UK Medical Research Council in close collaboration with Imperial College in London and investigators in four African countries, were announced today.  Disappointingly, the hint of efficacy seen in the smaller phase IIb was not duplicated: there were 130 HIV infections among the 3,156 women that received PRO 2000 gel, and 123 infections in the group of 3,112 women that received placebo gel.

The first news story reporting the result appeared in the Times of London yesterday and broke the embargo on the MRC releases by several hours; it was subsequently taken offline before being reinstated earlier today. The article dramatically - but erroneously - characterizes the PRO 2000 result as “a significant setback.” The whole purpose of large phase III efficacy trials is to definitively answer the question of whether an intervention works and, quite often, they don’t. In the case of PRO 2000, the microbicide is one of the last in a pipeline of products with relatively limited direct antiretroviral activity and, over the past several years, there has been increasing recognition in the field that more specific products are needed. Several such antiretroviral microbicides, such as the gel form of the drug tenofovir (Viread) are now in trials.

A number of informational resources on the MDP-301 trial are available on the web:

Background materials from the trial’s sponsor, the Microbicide Development Programme of the UK Medical Research Council

AVAC’s PRO 2000 resource page

Global Campaign for Microbicides

Disappointment as microbicide fails to protect against HIV

By Keith Alcorn (Aidsmap)

The Global Campaign for Microbicides is also hosting a tele-briefing for advocates tomorrow (Tuesday, December 15) at 9am EST to discuss the findings from MDP 301. Speakers on the call include the principal investigator for MDP 301, Sheena McCormack and the site investigator from the Africa Centre in South Africa, Mitzy Gafos. To participate, pre-registration is required at: https://cc.readytalk.com/r/usngsqfcqq0e 

IL-21 in HIV Infection

A slew of recent basic immunology papers have identified the cytokine interleukin-21 (IL-21) as playing a key role in the maintenance of antiviral T cell responses. One cross-sectional study in HIV infection has reported that IL-21 levels are lower in HIV-positive individuals compared to their seronegative counterparts, but no other data has been presented. A paper just published in the Journal of Immunology now offers a more comprehensive assessment of the impact of HIV infection on IL-21, showing that among individuals followed longitudinally, levels of the cytokine decline progressively and correlate with peripheral blood CD4 T cell counts. The researchers, led by Alexandre Iannello from the University of Montreal, also show that IL-21 levels do not appear to completely normalize after initiation of antiretroviral therapy. Analyses of HIV-specific CD4 T cells suggest a specific deficit in the ability of this population to make IL-21 that may be a consequence of their preferential infection with HIV.

The authors conclude that IL-21 may deserve evaluation as a potential immunotherapy for HIV infection. The patent on the therapeutic use of IL-21 is owned by a Seattle-based company called Zymogenetics who are currently evaluating it as a cancer treatment, but studies in HIV or other chronic viral infections have not yet been initiated. Interestingly, another recent paper published in the Journal of Leukocyte Biology (abstract also included below) suggests that IL-21 might have a role in promoting the expansion of functional CD28+ CD8 T cells over senescent CD28- CD8 T cells, which could conceivably add to the rationale for exploring its therapeutic potential in HIV. 

Published online November 30, 2009

The Journal of Immunology, 2009, doi:10.4049/jimmunol.0901967

Dynamics and Consequences of IL-21 Production in HIV-Infected Individuals: A Longitudinal and Cross-Sectional Study

Alexandre Iannello,* Mohamed-Rachid Boulassel, Suzanne Samarani,* Olfa Debbeche,* Cécile Tremblay, Emil Toma, Jean-Pierre Routy, and Ali Ahmad*

*Laboratory of Innate Immunity, Centre Hospitalier Universitaire Sainte-Justine Research Center,  Department of Microbiology and Immunology, and Division of Infectious Diseases, Centre hospitalier de l’Université de Montréal Hotel-Dieu, University of Montreal; and McGill University Health Center, McGill University, Montreal, Canada

IL-21 is a relatively newly discovered immune-enhancing cytokine that plays an essential role in controlling chronic viral infections. It is produced mainly by CD4+ T cells, which are also the main targets of HIV-1 and are often depleted in HIV-infected individuals. Therefore, we sought to determine the dynamics of IL-21 production and its potential consequences for the survival of CD4+ T cells and frequencies of HIV-specific CTL. For this purpose, we conducted a series of cross-sectional and longitudinal studies on different groups of HIV-infected patients and show in this study that the cytokine production is compromised early in the course of the infection. The serum cytokine concentrations correlate with CD4+ T cell counts in the infected persons. Among different groups of HIV-infected individuals, only elite controllers maintain normal production of the cytokine. Highly active antiretroviral therapy only partially restores the production of this cytokine. Interestingly, HIV infection of human CD4+ T cells inhibits cytokine production by decreasing the expression of c-Maf in virus-infected cells, not in uninfected bystander cells. We also show that the frequencies of IL-21–producing HIV-specific, but not human CMV-specific, Ag-experienced CD4+ T cells are decreased in HIV-infected viremic patients. Furthermore, we demonstrate in this study that recombinant human IL-21 prevents enhanced spontaneous ex vivo death of CD4+ T cells from HIV-infected patients. Together, our results suggest that serum IL-21 concentrations may serve as a useful biomarker for monitoring HIV disease progression and the cytokine may be considered for immunotherapy in HIV-infected patients.

J Leukoc Biol. 2009 Oct 1. [Epub ahead of print]

IL-21 preferentially enhances IL-15-mediated homeostatic proliferation of human CD28+ CD8 memory T cells throughout the adult age span. (free access to full text)

Nguyen H, Weng NP.

Laboratory of Immunology, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, USA.

An age-related decline in human immune response is marked by the accumulation of CD28(-) CD8 T cells, which is attributed to repeated antigenic stimulation and to homeostatic proliferation mediated by cytokines such as IL-15. However, the identity of the cytokines that are responsible for the maintenance of CD28 expression is less known. Here, we report the role of IL-21 in the regulation of IL-15-mediated growth and CD28 expression of CD8 memory T cells of young and old donors. We showed that IL-21 drives more IL-15-stimulated cells to enter cell division and to undergo apoptosis. Furthermore, IL-21 preferentially enhanced IL-15-induced proliferation of CD28(+) CD8 memory T cells over their CD28(-) counterparts, as CD28(+) cells expressed higher levels of IL-15R and IL-21R and greater pSTAT5 upon IL-15 and IL-21 stimulation. In addition, IL-21 reduced IL-15-induced CD28 down-regulation in CD8 memory T cells. Finally, the ability of proliferation and survival in response to homeostatic cytokines IL-15 and IL-21 of CD28(+) CD8 memory T cells was well-maintained with age. Together, these findings suggest that IL-21 enhances IL-15-mediated proliferation of CD8 memory T cells, particularly CD28(+) memory T cells, and also serves as an antagonist to the IL-15-induced increase of CD28(-) CD8 T cells.