Project Inform, the country's longest serving community-based AIDS treatment information organization, has been sponsoring scientific think tanks on immune restoration since 1992. Their Immune Restoration Think Tank (IRTT) is also known as the "Dobson Project" in honor of the prime mover behind the early meetings, the widely respected and much-loved San Francisco AIDS activist Jesse Dobson, who died on September 23, 1993. After a hiatus since the last meeting in Chicago in 1999, Project Inform recently held the ninth IRTT at the Nikko Hotel in San Francisco. A full official report of the meeting, including recommendations regarding future research priorities, will be produced by Project Inform and made available on the IRTT section of their website. This article, by Richard Jefferys, will just touch on some of the interesting talks given particularly by immunology researchers attending the meeting.
Zvi Grossman from the National Institutes of Health shared some thoughts regarding pathogenesis, focusing on the conundrum that has faced the field since the very first Immune Restoration Think Tank meeting: HIV infection induces the activation of the immune system, yet also leads to immune deficiency.
Grossman was one of many immunologists to express skepticism about one of the most enduring yet erroneous theories of HIV pathogenesis, David Ho's "tap and drain" model (see TAGline, February 1997: "Dutch Research Team Challenges Ho/Shaw Pathogenetic HIV Model and Gives Cause for Pause"). Ho essentially posited that the virus destroys T cells and the immune system becomes activated to try and replace them but is eventually exhausted. Since this theory was first proposed in 1994, data from both humans and animal models has shown that immune activation is not a response to HIV-induced T cell depletion per se, as it affects not just CD4 T cells (HIV's preferred target) but also CD8 T cells.
In a typical immune response (to a virus such as influenza, for example), T cells that recognize the pathogen become activated and copy themselves (proliferate) in order to generate a swarm of short-lived "effector" T cells that all recognize the same pathogen. These activated effector T cells migrate out from the lymph nodes (where activation occurs) in order to hunt down and eliminate or control the pathogen. Within a few days, the vast majority of these cells (~95%) will automatically die in a process called apoptosis or activation-induced cell death. A minority of the effector T cells will survive and return to a resting (non-activated), long-lived "memory" state; these cells normally maintain the ability to proliferate and generate a new swarm of effector T cells if the same pathogen is subsequently reencountered. Grossman noted that when HIV replication is controlled by the initiation of HAART, the two-phase drop in viral load (a rapid decline in the first few days followed by a slower decline over several weeks to months) mirrors the initial rapid death of activated effector T cells followed by the return to rest of surviving memory T cells.
Grossman and immunologist William Paul have proposed that one effect of persistent HIV-induced immune activation is to slowly chip away the number of T cells that are able to deactivate and return to a resting state, thereby slowly depleting the T cell pool (see Nature Medicine, 8;4:319-323, 2002). Grossman also highlighted HIV's ability to persist in a latent state in some resting memory CD4 T cells, producing a reservoir of virus capable of renewed rounds of replication if the infected resting CD4 T cell gets reactivated.
A particularly novel aspect of Grossman's talk focused on memory T cell homeostasis. Homeostasis is a word used to encapsulate the ability of biological systems to generally maintain a balanced steady state; in the case of memory T cells this means maintaining a diverse pool of cells capable of responding to the many different pathogens that are encountered over a lifetime, within the limits of the total number of memory T cells that the human body can accommodate (which is thought to be around 1-2 trillion).
Because the memory T cell pool fills up rapidly in infancy, the new cells that are subsequently generated by encounters with new pathogens have to displace existing cells in order to survive. Grossman hypothesized that if the generalized immune activation seen in HIV infection generates memory T cells at an accelerated rate, one consequence would be that existing memory T cells -- such as those targeting common opportunistic pathogens like PCP, CMV, et cetera -- are at risk of being displaced. Such a phenomenon could potentially explain the decline in immunity to opportunistic infections that eventually leads to AIDS. On other hand, Grossman suggested it could be beneficial to look for ways to displace HIV-infected memory CD4 T cells with uninfected, functional memory CD4 T cells.
Scott Sieg from Case Western University discussed his research group's attempts to better to characterize the activated, short-lived T cells that are typically present in the setting of untreated HIV infection. Activation causes T cells to progress through a process called the cell cycle, which occurs in distinct phases:
Sieg used the radioactive label BrdU to identify S phase T cells in samples from HIV-infected individuals. He found that a greater proportion of CD4 T cells were in S phase than CD8 T cells, which may be an interesting finding given that when other markers of T cell activation are used more CD8 T cells appear to be activated than CD4 T cells. The frequency of S phase T cells correlated with viral load levels. Both the CD4 and CD8 T cells in S phase displayed similar external markers: the activation molecule CD38 (but not two other potential markers of activation, CD25 and CD69), CD62L and CCR7 (two molecules associated with trafficking to the lymph nodes and generally found on resting, not activated, T cells) and CD45RO (a marker commonly used to identify memory T cells).
The S phase T cells also expressed high levels of caspase 3 (an enzyme associated with apoptosis) and low levels of bcl2 (a molecule associated with T cell survival), suggesting that these cells are indeed short-lived. Preliminary efforts to evaluate the specificity of the S phase T cells (i.e., which antigens they respond to) are underway. According to Sieg, results so far indicate to be targeting antigens from HIV although these analyses may be complicated by the tendency of recently activated T cells to temporarily down regulate the receptor they use for recognizing antigens (the T cell receptor or TCR). Sieg stressed that this work is ongoing and more detailed results will eventually be presented and published.
San Francisco's redoubtable Steve Deeks gave a rapid-fire update on his work with individuals who appear to experience treatment failure (as defined by increasing viral load and drug resistance) without showing signs of immunological or clinical disease progression. Deeks is investigating the possibility that HIV-specific T cell responses are contributing to the lack of progression seen in this cohort, and planning studies designed to evaluate whether immunological control of HIV replication can be enhanced in individuals with multi-drug resistance and limited antiretroviral options.
Deeks followed up on recent reports indicating that HIV-specific CD4 T cells capable of producing IL-2 or IL-2 and interferon-gamma may play a role in controlling viral replication (see TAG's September 2003 Basic Science Review) by evaluating these responses in individuals with partial control of viral load and multi-drug resistant viruses who remain on HAART (which he calls "PCATs" for partial controllers on antiretroviral therapy). Compared to individuals with progressing disease, PCATs had significantly greater numbers of IL-2-producing HIV-specific CD4 T cells, as did untreated individuals with long-term non-progressing infection (LTNPs). PCATs also had significantly lower levels of T cell activation (as measured by CD38 expression).
Deeks compared the levels of T cell activation among 86 individuals with multi-drug resistant HIV compared to 13 untreated people with non-resistant or wild-type HIV; after controlling for viral load levels (and other factors known to impact activation such as hepatitis C co-infection), the degree of T cell activation was significantly lower for both CD4 and CD8 T cells in the individuals with multi-drug resistance. Taken together, Deeks results strongly suggest that -- at least in this cohort -- the maintenance of multi-drug resistant virus is beneficially altering the balance between the immune system and HIV. Deeks plans to conduct prospective studies to explore whether this apparent benefit can be further improved upon.
There were many other interesting presentations and discussions at the XI IRTT that will be included in Project Inform's full report, including "surprising suggestions" that some familiar but non-HIV-specific drugs (imatinib mesylate aka Gleevec, and valproic acid, for starters) may deserve to be studied for their potential to target the reservoir of latently infected CD4 T cells. TAGline will alert readers when the report becomes available.
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