Joint TAG-AmFAR Scientific Think Tank Assembles Eradication Experts for Marathon Brainstorming Session
Tissue samples could be key
The Treatment Action Group and the American Foundation for AIDS Research held a groundbreaking scientific workshop 2/27-3/1 on clearing lingering reservoirs of HIV from patients on highly active antiretroviral therapy (HAART). The following are highlights from the meeting. A full report of the conference will be available soon. Gregg Gonsalves, who organized the scientific think tank on behalf of TAG, prepared this brief overview of the meeting.
The Central Nervous System as a Reservoir for HIV
The central nervous system (CNS) is one of the least understood reservoirs for HIV and may have an important role in the persistence of HIV infection in patients on HAART. The CNS is seeded by virus early in the disease. In monkey studies, HIV's cousin, SIV, appears in the CNS within two weeks after infection. The CNS is also a site partially sequestered from immune surveillance and the action of many antiretroviral drugs by the blood-brain barrier. There are many unanswered questions about the role of the CNS in HIV disease:
- When does HIV reach the CNS?
- How much virus is present in the CNS as opposed to the cerebrospinal fluid which is outside the blood brain barrier?
- What cell types are infected? Are microglia, astrocytes or microvascular endothilial cells infected?
- How does the virus get past the blood brain barrier?
- How do we get drugs into the CNS?
- Is virus replication in the CNS self-sustaining or is it replenished from outside the brain?
How will the answers to these important questions be resolved? One of the primary difficulties in understanding the role of the CNS in viral persistence is the inability to collect and study CNS tissue from people with HIV infection. Researchers at the TAG/AmFAR think tank called for the National Institutes of Health to establish a new tissue repository that would collect brains from patients with HIV infection who have died from other causes. Similar brain banks have been established for other neurological conditions, including Alzheimer's disease and schizophrenia. The participants in the conference also called for the development of antiretroviral drugs and adjunctive therapies that will penetrate the blood brain barrier.
Antigen Presenting Cells as a Reservoir for HIV
The macrophage is an important reservoir for HIV infection. These cells can maintain a productive infection with HIV without being killed and have a long life span. These cells may also provide a lingering reservoir for HIV under HAART because many protease inhibitors may achieve less than 99% viral inhibition in chronically infected macrophages. There are many unanswered questions about the role of macrophages in HIV infection:
- What tissues are harboring chronically infected macrophages in patients on HAART?
- What period of time on HAART is sufficient to eradicate these cells?
There may be the opportunity to use adjunctive therapies to clear virus from this compartment. The Immunex Corporation is investigating the use of granulocyte-macrophage colony stimulating factor (GM-CSF) for this purpose. GM-CSF (and also tumor necrosis factor (TNF) and interleukin-12) stimulates macrophage reproduction, essentially "unmasking" the cells for recognition and destruction by the immune system.
T-Cells as a Reservoir for HIV
The role of T-cells in the persistence of HIV infection under HAART has been the subject of intense investigation over the past few months. Recent studies of people on HAART have shown that although productively infected T-cells are killed relatively quickly after the initiation of therapy, resting T-cells harbor infectious virus which is not likely to be cleared from patients for many years, if at all. In order to further dissect the fate of these latently infected resting T-cells, participants in the meeting called for the development of non-invasive technologies which would allow investigators to track these cells without requiring extensive biopsies of lymph nodes and other tissues.
Several investigators discussed ways of expediting the clearance of latently infected resting T-cells. There are currently two possible approaches to this problem. The first involves activating these cells using antibodies directed to the T-cell receptor or cytokines that activate T-cells. Once these cells are activated and begin to produce virus they become a target for elimination by the immune system. The second approach involves boosting immune responses to the virus which might allow clearance of infected cells by cytotoxic T-cells. Immune responses to HIV generally weaken in patients chronically infected with HIV on HAART. It may be possible to use HIV vaccines to boost the immune response in these patients. While the initial immune response to the virus in early HIV infection is not successful in clearing the billions of virions present at this stage of disease, a reinvigorated immune response may be able to clear the substantially fewer viral particles present in patients on HAART.
The Thymus, the Genital and the Gastrointestinal Tract
Along with the CNS, the thymus and the testes are relatively isolated from immune surveillance and the action of antiretroviral drugs by a tight barrier of endothelial or epithelial cells. T-cells, macrophages and dendritic cells in the thymus are infected with HIV. This site may have particular importance in children infected with HIV because the thymus generally atrophies and shrivels away by early adulthood. There is little known about the fate of infected cells in the thymus in patients under HAART. Once again, there is a dire need for tissue samples of thymus from children infected with HIV on HAART to resolve the question of whether or not this site is an important reservoir for HIV.
The gastrointestinal mucosa is the largest lymphoid organ in the body. It also has the largest concentration of macrophages and is the busiest site for cell trafficking in the body as well. The gut is a prime site for HIV replication because of its important role in the immune system. In patients on HAART, the pathology of the gut has generally mirrored that of the lymph nodes: productively infected cells expressing RNA are rapidly cleared from this site with latently infected, resting T-cells expressing HIV DNA remaining.
|Resting T-cells||OKT3, anti-IL-15|
|Macrophages||GM-CSF, TNF, IL-12|