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Immune Reconstitution and Control of HIV Conference
Reported by Mike Youle, MD, Director, Centre for HIV Medicine at Royal Free Hospital, London, UK
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The Regina Palace Hotel on the shores of Lago Maggiore at Stresa in Italy was the venue for this small but fascinating gathering, organised by the RIGHT Foundation in conjunction with the University of Pavia. The 'Great and the Good' in Immunotherapy and Immunopathogenesis had gathered from the four corners of the World to debate the effects that HIV has on host immunity and how this can be harnessed to improve therapeutic options.
Professor Lorenzo Minoli from the University of Pavia opened the meeting by noting that Structured Treatment Interruption had been a disappointment since it appears that re-presenting virus to the immune system by stopping HAART does not appear to substantially improve the ability to control HIV without the use of antiretrovirals. However the use of vaccines to augment the specific immune responses to HIV may be more promising. Franco Lori from RIGHT next introduced Jay Levy from the University of California, San Francisco, who enthralled the audience with an elegant description of the difference between adaptive immunity, which relies on the development of specific ways of targeting HIV, and innate immunity which is the first response to an external pathogen and which seems to be lost at an early stage for most individuals who acquire HIV. Long term non- progressors (LTNP) appear to retain many of the innate responses which disappear from the majority of people and make up only 5% of the final population, whereas in polio 95% of those infected remain well long-term. He posed the question "Can we bring back this innate response," i.e. that which keeps an individual as a LTNP.
It was Charles Janeway who defined the field in the late 1970's by describing the function of dendritic cells, which recognise antigen (foreign material) by their shape and respond by producing cytokines (soluble messenger chemicals), which then orchestrate the immune response. Further work in HIV by Siegal in 1986 showed that plasmacytoid dendritic cells (IPC - interferon producing cells) produce vast amounts of interferon gamma and that there is an inverse relationship between this and the development of opportunistic infections. These cells are a very small proportion, approximately 0.5%, of CD4+ cells, with no other surface markers and act as a bridge between immediate innate responses and the further development of adaptive immune responses. There is a direct relationship between the number of these cells found in LTNP and their ability to maintain high CD4 counts, and an inverse relationship with viral load during acute infection, which may explain the difference in progression rates that this produces. In addition, individuals who have very low CD4 cells but do not develop opportunistic infection seem to have preserved or even enhanced numbers of IPC's. It also seems that when these cells are infected they produce HIV instead of interferon, which leads to transfer of virus to activated T lymphocytes. So if strategies to improve IPC levels can be found it may be possible to induce long term non-progression.
He then showed further data on his ongoing quest to define the CD8 antiviral factor (CAF) which he has worked on for over 10 years. This naturally occurring factor relies on CD8 function, not number, and appears to work after integration but does not appear to be HIV specific. There is now evidence of CAF in HIV-2 as wells as feline immunodeficiency virus. It is found in those who are exposed but uninfected (EUI) but decreases rapidly if the exposure is removed, i.e. does not have induces or produce memory. In addition, IL-2 seems to increase its activity as does IL-15 and possibly interferon. So what is this magical agent? He has ruled out many types of cell, defensins, interleukins as well as growth factors and now, using microarray technology, seems to have isolated 7 possible compounds, 5 known and two that are novel. His suggestions for immune based therapies includes this agent, when isolated as well as IL-2, IL- 15 and interferon, some of which have or are being evaluated.
Mario Stevenson from University of Massachusetts Medical School then produced a fantastically complex slide denoting 20 years of work with all of the known regulatory factors in the HIV lifecycle. He picked two as new important potential therapeutic targets, CEM-1 which stops RNA at assembly and REF-1 which blocks entry.
Alan Landay from Rush Medical College, Chicago presented data on the possibility of using IL-7 for the treatment of HIV. He spoke of the changing of the immunological dogma that the thymus involutes or is non-functioning in adults. It now seems that T-cells can regenerate from the thymus in T-cell depleted states or that there may even be thymus independent pathways to produce these cells. IL-7 enhances this thymic output and also expands pre-existing cells. It would seem that this cytokine could be used as a support for vaccines as well as an immune therapy, although since it also highly expands B cell precursors it would seem prudent to be concerned over the possibility of enhancing the likelihood of developing of B cell tumours. It seems to enhance infections of PBMC's as well as increase levels of interferon. In primate studies already conducted IL-7 increased T cell cycling and mediated naive T cell production. There is an ongoing primate study with IL-7 plus ALVAC as well as a dose ranging study in cancer patients at the US National Cancer Institute (NCI).
Franco Lori showed new data on the utility of hydroxyurea (HU) as an adjunctive therapy with antiretrovirals. Having had problems with toxicity, mainly pancreatitis, in ACTG 5025 when a dose of 1000mg was used with the old formulation of DDI 400mg once daily, enthusiasm to develop HU had waned. However, in recent research such as the Jose Gatell's EARTH clinical study HU appeared to blunt the viral load rebound during treatment interruption, and CD4 loss during the interruptions was less with no impact on CD8 responses. RIGHT 702 showed that a dose of 600mg was significantly less toxic than 1200mg in a factorial design study with a backbone of d4t and EC-ddI given twice daily. Interestingly, the viral load benefit was better with the lower dose of HU and there was a significantly better AUC of RNA decline and rate of viral load <400copies/mL in the HU containing arms. Since the 3D study seemed to suggest some benefits of HU when given after week 12 in a d4t/ddi/efavirenz regimen, perhaps it is time to repeat this study but using HU from day one until week 24 in an attempt to maximise the benefit of the agent whilst reducing long-term toxicity.
Next Juliana Lisziewicz of RIGHT, Washington, DC opened her talk on Dermavir by stating that many agents we use to treat HIV such as ddI or tenofovir are given as pro-drugs. Thus the use of a therapeutic vaccine should also be seen as a pro-drug which exerts its action by harnessing the immune system to act as an antiviral. With this in mind she gave an update on Dermavir, the construct which essentially acts as a non-replicating non-integrating version of HIV in a novel construct of glucose and polyethyleneimine mannose (IPEM) and is designed to mimic a virion as a 100nm particle. This is presented to the immune system through the classic dendritic cell pathway by applying the Dermavir to abraded skin. The IPEM seems to prevent endosomal degradation of the construct and its delivery to the draining lymph nodes. Rich Pollard from University of California, Sacramento will be conducting the first human study through the ACTG (5176), which will assess Dermavir in 3 cohorts at doses of 0.1, 0.2 and 0.4mg DNA in subjects on HAART with nadir T4 counts above 350 and current viral loads <50copies/mL.
Hana Golding from the Food and Drug Administration, Bethesda, MD discussed the design of therapeutic vaccines for AIDS patients on HAART. She started by re-iterating many of the scientific points made by the speakers on the first day. There will be a huge difference in the criteria to judge therapeutic vaccines compared to preventative vaccines. The questions that are uppermost in the minds of the regulators and researchers alike are what are the possible endpoints that can be used in such studies? Also, how is it possible to define the best populations in which to test therapeutic vaccines? After her presentations I had a discussion with her in which she candidly accepted that for Human papilloma virus (HPV) vaccine studies, the FDA are going to accept surrogates markers of reduction in histological changes rather than waiting for a clinical endpoint of carcinoma. This stance, applied to HIV, would allow the use of viral or immunological surrogates to determine efficacy, although the excellent activity of current HAART would seem to suggest that treatment interruption or the use of activation markers such as CD38 would be required to show an additional benefit over and above that produced by drugs. What is not clear also is how frequently vaccination would be required to maintain or induce immune responses that would control viral replication, in those off drugs. In addition, the comparator arm must always be standard of care, which is getting more and more difficult to determine.
Rich Pollard gave a talk then on the role of immune enhancement in production of HIV- specific immunity and showed the studies that the ACTG machinery has produced and is undertaking in this area. He focused on the available data that suggests that the major candidates for this job are GMCSF, human growth hormone (HGH), IL-2 and IL-12. The first is an oft ignored agent since good placebo controlled data exists for the use of this agent in those with severely impaired immune function (T4 <50), Angel et al AIDS 2000;14:387-395. I suppose this may be due to the problems of cost and parenteral mode of delivery agent. We shall soon see if these disadvantages are seen in prescribing rates for T20. Certainly cost is the major inhibitory factor in the use of HGH, which in early studies has showed improvement in IL-2 levels and thymic size., ACTG 5176 is formally assessing these findings in a controlled manner. IL-12 has been used in two ACTG studies. The first, ACTG 325, assessed three doses (30, 100 and 300ng/kg) IL-12 s/c twice a week for 4 weeks in either T4<50 or 300-500 on HAART. Dose limiting toxicity was seen and no immunological improvement. In ACTG 5049 an attempt was made to vaccinate with the C4V3 vaccine with local injected IL-12 as an immunological adjuvant. This study suffered from huge administrative delays at the FDA and shows that sometimes regulatory controls mitigate against good science. The results of this study were inconclusive due to huge administrative delays in regulatory approval.
IL-2 is the subject of several large clinical endpoint studies (SILCAAT and Esprit). In ACTG 328, Wu et al. already presented tantalising data that showed a quality of life benefit for those in the IL-2 arm [Buenos Aires 2001; Abstract 102]. The study evaluated 150 subjects on HAART for 12 weeks. They were randomized to receive HAART alone (51), cycles of intermittent subcutaneous (SC) IL-2 (54) or cycles of continuous intravenous (CIV) infusion IL-2 (55) every 8 weeks for 52 weeks. At this meeting Pollard stated that there appeared to be a significant clinical benefit to IL-2 in this study even though it was not powered to assess this. Two further studies of IL-2 look interesting and are currently enrolling. ACTG 5024 will assess the utility of adding IL-2 to a regimen of ALVAC as a therapeutic vaccine, and in the second ACTG 5132 will evaluate the strategy propounded by Kendall Smith of using low-dose daily IL-2 is test with a dose of (2mIU daily) compared to cycles of 4.5miu twice daily before a treatment interruption in both arms.
This meeting was small enough for lively debate and had the quality of presentations that produced various new ideas worthy of researching. Immunotherapy against HIV seems to be one of the more fruitful new treatment fields, and if only the FDA and producers of potential vaccines and adjuvants could act with the speed that epitomised the early years of HIV drug development, then great strides could be made. An essential gear shift is to comprehend that therapeutic vaccines and immunomodulators are really pro-drugs which use the immune system, in some way, to elicit their action. In addition, many of the lessons learnt in this field will undoubtedly be useful in immunotherapy of other infections and vice versa.
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