The Botswana Federation of the Disabled recently held a seminar to commemorate the country’s “Youth Against HIV/AIDS” month, focusing on the role of disabled young people in efforts to curb the spread of HIV, Botswana’s php?NewsID=4908″ target=”_new”>Sunday Standard reports. About 60 disabled young people from across the country discussed HIV/AIDS-related issues and the vulnerability to HIV among disabled people. Participants called on the government to equally target the disabled population with information on HIV/AIDS prevention, according to the Standard. Shirley Keoagile, BOFOD vice chair, said that the group is primarily concerned about limited knowledge of issues that affect disabled youth, including HIV/AIDS prevention and other lifestyle issues.

Some advocates for the disabled community have said that government HIV/AIDS projects and initiatives have not addressed issues affecting the community. Keoagile said that a lack of communication means that disabled young people often are provided with little HIV/AIDS education, including information on prevention. “Realization to keep the promise and the human rights of people with disabilities in relation to HIV/AIDS is critical,” she said, adding that the seminar focused on abstinence, condom use and fidelity. In addition, the seminar focused on securing HIV/AIDS resources for disabled youth (Madibana, Sunday Standard, 5/10).

Reprinted with kind permission from http://www.kaisernetwork.org. You can view the entire Kaiser Daily Health Policy Report, search the archives, or sign up for email delivery at http://www.kaisernetwork.org/dailyreports/healthpolicy. The Kaiser Daily Health Policy Report is published for kaisernetwork.org, a free service of The Henry J. Kaiser Family Foundation.

© 2009 Advisory Board Company and Kaiser Family Foundation. All rights reserved.

Cytheris SA, a clinical stage biopharmaceutical company focused on research and development of new therapies for immune modulation, today announced publication of data from a study in a non-human primate model identifying a new critical function of Interleukin-7 (IL-7) that induces massive and rapid T-cell migration from the blood into various organs, including lymph nodes, parts of the intestine and the skin. The study points towards the importance of evaluating the potential of IL-7 in combination with highly active antiretroviral therapy (HAART) in stimulating the T-cell repopulation of the gut, known to be a latent HIV reservoir where the virus can continue to replicate and suppress immune function. The massive T-cell depletion of the GI tract early in the course of HIV infection opens the patient to the effects of opportunistic infections and malignancies which are frequently associated with a weakened immune system in this patient population.

The paper entitled “Injection of Glycosylated Recombinant Simian IL-7 Provokes Rapid and Massive T-cell Homing in Rhesus Macaques” is prepublished online in Blood, the Journal of the American Society of Hematology (Beq S et al, April 7, 2009;doi:10.1182/blood-2008-11-191288).

Studies such as the one described in this paper deal with the fundamental role of the gut in harbouring the HIV virus,” said Michel Morre, DVM, President and CEO of Cytheris. “This is the question that lies at the heart of the challenge for improving the efficacy of antiretroviral therapy in GI lymphoid tissue. It may also be key to developing vaccines that provide more than a peripheral blood response by addressing the critical issue of mucosal immunity.”

About the Study

In this study, conducted at the Institut Pasteur, Paris, and designed to measure early T-cell homing in the first hours post-injection, five healthy Rhesus macaques were subcutaneously inoculated with 80 micrograms/Kg of body weight of recombinant glycosylated simian IL-7 (R-sIL-7gly).

As observed in IL-7-treated human patients, all R-sIL-7gly-treated animals demonstrated a strong peripheral lymphopenia during the first day following injection. Notably, despite the fact that T-cell increase was not observed at Day 7 in one of the macaques (designated a poor responder), the initial decrease in lymphocyte counts was also observed in this animal. In contrast, two non-injected control animals sampled on the same schedule as the treated monkeys did not show a significant change in their circulating lymphocyte counts.

Four months later, when all the measured parameters had returned to baseline levels, a second injection of R-sIL-7gly given to two of the previously treated monkeys led to a similar drop in circulating lymphocytes.

Prior to euthanizing the animals, the investigators observed a strong and rapid T-cell migration out of the blood, with 70 percent of the circulating T-cells disappearing, including recent thymic emigrants, naïve, CM and EM T-cells in both CD4+ and CD8+ populations. At the same time, these T-cells up-regulated several chemokine receptors implicated in homing mechanisms, while plasma concentration of a number of chemokines/cytokines specifically implicated in migratory phenomenon was significantly increased.

In order to confirm that R-sIL-7gly injection effectively triggers T-cell homing to the lymph nodes, gut and skin, tissue samples from two animals euthanized 24 hours after R-sIL-7gly injection, one animal euthanized at Day 7 and from a fourth non-injected animal were subjected to immunohistological labeling with anti-CD3 monoclonal antibodies.

In these tissue samples, T-cell infiltration was observed in the skin and the lamina propria of the ileum, the colon and the rectum. Quantifying CD3+ T-cells in 7 to 10 fields (0.09 mm2 each) randomly selected from four slides for each organ confirmed that the number of CD3+ T-cells per field was significantly increased by Day 1 in the skin (p=0.001), the ileum (p=0.003), the colon (p=0.018) and the rectum (p=0.05). In all organs but the colon, T-cell numbers remained significantly higher at Day 7 as compared to the control animal. In contrast, the density of CD3+ T-cells was not significantly modified in the lymph nodes.

These data confirm that R-sIL-7gly induces T-cell homing into various non-lymphoid organs including the lamina propria of several parts of the gut (ileum, colon and rectum) and skin. Moreover, the expression of CCR7 and CXCR4 on circulating T-cells, the increase of CXCL12 plasma concentration and the production of CCL19 and/or CCL21 mRNA in lymph nodes also suggest homing into secondary lymphoid organs.

Similarly, the production of CCL19 in the ileum and the rectum and that of CCL21 in the jejunum suggest that R-sIL-7gly injection also triggers T-cell migration into the lymphoid follicles of the gut, where massive T-cell proliferation subsequently occurs.

Human and Non-Human Primate Studies

The IL-7 induced T-cell proliferation indicated in the long-term follow-up to the Phase I/II study discussed in a recently published paper (”Enhanced T cell recovery in HIV-1-infected adults through IL-7 treatment” published online in The Journal of Clinical Investigation, Levy, Y et al, 2009, Vol. 119, No. 4) is now broadly confirmed by studies in non-human primates such as the one described here and others conducted by Cytheris in collaboration with the Seattle Biomedical Research Institute (SBRI), the Vaccine and Gene Therapy Institute (VGTI) and the Oregon National Primate Research Center (ONPRC) at Oregon Health and Science University, Emory University.

The focus of these non-human primate studies is the gastrointestinal tract, where the extraordinary size of the GI mucosa facilitates what is recognized as a fundamental role in the pathogenesis of HIV-1 infection. It is well known that the HIV virus is able to survive in these mucosal tissues of the human GI tract that effectively act as a viral reservoir. Current HAART therapy, which has been successful in reducing viral loads and increasing T-cells in the blood, has been largely ineffective in attacking the virus in the mucous membrane of the GI tract.

Left hiding in the gut lymphoid tissue, the HIV virus continues to replicate and suppress immune function by depleting its preferred target, the memory CD4+ T-cells which constitute the body’s defence against the invading virus and whose decline precedes the profound reduction in CD4+ T cells circulating in the blood. This then leaves the body potentially vulnerable to a variety of opportunistic infections and/or progression to full-blown AIDS.

Summary and Potential Implications

The findings based on animal models and human studies emphasize the potential stability of the IL-7 effect on the production of T-cells over time as well as its possible impact in stimulating T-cell proliferation in the lymphoid tissue layer in the mucous membrane of the GI tract. By stimulating the body’s immune response through T-cell migration into the gut mucosa where the viral reservoir hides, and thus taking the therapeutic battle directly into a known conduit for HIV entry, early infection and viral dissemination, IL-7 may eventually be shown to play an important therapeutic role in subverting HIV disease pathogenesis.

The sustained immunological efficacy seen in the long-term follow-up of the previously published Phase I/II trial (Levy, Y et al, 2009. The Journal of Clinical Investigation, Vol. 119, No. 4) suggests that IL-7 may provide an important avenue for reconstituting the immune system and inducing broad spectrum proliferative activity of CD4+ and CD8+ T-cells in the blood, lymph nodes and small intestine, a key therapeutic effect in achieving long term disease stability in HIV-infected patients.

About Interleukin-7

Investigational recombinant human Interleukin-7 (r-hIL-7) is a critical growth factor for immune T-cell recovery and enhancement. Cytokines that signal via the common gamma chain (gamma c) represent promising therapeutics based upon their potential to augment T cell expansion and increase the effectiveness of immune based therapies. Within this family, IL-7 is a prototypic homeostatic cytokine, produced constitutively by non-lymphoid cells. Its receptor (IL-7R alpha) is expressed on resting T cells, then rapidly down-regulated following T cell activation or IL-7 signaling.

IL-7 is essential for T cell development in mice and humans and for T cell homeostasis since it is required to maintain naïve CD4+ and CD8+ T cells in vivo. IL-7 levels rise in serum and tissues following T cell depletion and fall upon recovery.

In preclinical studies, IL-7 therapy exerts marked effects on T cell immune reconstitution in mice and primates. IL-7 augments effector and memory responses to vaccination in mice with preferential enhancement of responses to weak subdominant antigens. In preclinical models, IL-7 therapy augments anti-tumor responses leading to improved survival when combined with anti-tumor vaccines.

Clinical trials conducted on more than 110 patients in Europe, North America and Taiwan suggest the potential of IL-7 in expanding and protecting CD4+ and CD8+ T-cells. Cytheris is currently conducting multiple clinical studies of IL-7 in HIV, HCV and cancer.

Source
Cytheris

The network “Grandmothers 4 Grandmothers” in Regina, Canada — the local effort of the Stephen Lewis Foundation’s network of grandmother organizations called Grandmothers to Grandmothers — has “emerged as a force to be reckoned with” among the 70,000 Canadians supporting the foundation, the Regina Leader-Post reports.

Lewis, chair of the foundation and head of AIDS-Free World, at a recent Grandmothers 4 Grandmothers fundraising event said grandmothers “have become the most auspicious, most formidable, most loyal and most overwhelming” advocates against HIV/AIDS. The group has brought grandmothers from across Canada together to contribute to efforts to address HIV/AIDS among women in Africa. According to Lewis, the group of grandmothers has become a core aspect of his foundation, raising more than $6 million and becoming active participants in lobbying efforts. In addition, they have helped educate and recruit new participants, adding to the current list of 10,000 grandmothers in more than 200 chapters nationwide.

Lewis said, “[Y]ou cannot imagine the grandmothers in Africa, how overwhelmed they are, that in a country they know nothing of, there are all these grandmothers who are supporting them and working with them.” While Lewis said he appreciates the grandmothers’ efforts, he also hopes fundraising events will begin to have a larger focus on “understand[ing]” HIV/AIDS in Africa. He noted that the treatment of HIV/AIDS in Africa remains “criminally incremental” and progress in fighting the disease remains slow. He also pointed to new challenges, including an increase in the number of tuberculosis cases; drought; food shortages; and economic crises that are causing many governments to back-track on funding commitments. The Leader-Post reports that the foundation plans to raise $100 million over the next five years for HIV/AIDS efforts in Africa (Pruden, Leader-Post, 5/11).

Reprinted with kind permission from http://www.kaisernetwork.org. You can view the entire Kaiser Daily Health Policy Report, search the archives, or sign up for email delivery at http://www.kaisernetwork.org/dailyreports/healthpolicy. The Kaiser Daily Health Policy Report is published for kaisernetwork.org, a free service of The Henry J. Kaiser Family Foundation.

© 2009 Advisory Board Company and Kaiser Family Foundation. All rights reserved.