"Immune-based therapy" (IBT) has long been a buzzphrase among HIV researchers. Now that stronger anti-HIV drugs are available, the idea behind IBTs is to improve the function of the immune system. Although there was little new data on IBTs at the Sixth Conference on Retroviruses and Opportunistic Infections, currently available candidates break down into two categories. Non-specific IBTs attempt to improve the immune system's overall health. The best known example is interleukin-2 (IL-2). HIV-Specific IBTs try to improve the immune response to HIV specifically. Therapeutic vaccines like Remune® (HIV-1 immunogen) fall into this category.
There were many presentations on the cytokine IL-2 in Chicago. Cytokines are a group of chemicals released by immune system cells that carry messages between the cells. When IL-2 is released, it carries a message telling T-cells to copy themselves -- a process known as "proliferation." Researchers have long hoped that giving synthetic versions of IL-2 might increase T-cell counts in people with HIV.
The two major problems with IL-2 are how it is given (by either intravenous or subcutaneous injection) and its severe, flu-like side effects. Several studies at the Retrovirus conference tried different doses, dosing schedules and routes of administration for IL-2.
One research team looked at HAART with or without subcutaneous IL-2 at a dose of 7.5 million units (MU) twice daily for five days every eight weeks. Dose reductions of IL-2 were allowed if side-effects were problematic. The average T-cell count of study participants was 345. The average T-cell count increase was over 400 cells in the HAART + IL-2 group and 60 cells in the HAART-only group. However, since everyone had T-cell counts above 200 to start with, it is not known if the extra T-cells produced due to IL-2 will actually improve long-term health. IL-2 also produced significant side effects. Over half the IL-2 recipients experienced serious toxicities, compared to 16% of the HAART-only group.
Another study found that a lower dose given more regularly may cause less side effects. Three different dose schedules were tried, all given along with HAART: a) continuous intravenous infusion of 12 MU daily for five days every eight weeks (for two cycles) followed by subcutaneous (SC) 7.5 MU twice-daily for five days every eight weeks (for 4 cycles); b) 7.5 MU SC twice-daily for five days every eight weeks (for six cycles); and c) 3 MU SC twice-daily for five days every four weeks (for six cycles). T-cell increases of 600-700 cells were seen in the three groups, but side effects were only half as common in group C compared to groups A and B.
Perhaps the most widely publicized IL-2 presentation in Chicago was a case-control study. This study compared the results of 12 people taking HAART to 14 taking HAART + IL-2. The idea was to see if IL-2 helps eliminate HIV-infected cells that HAART can't get at. HIV-infected cells could be found in all 12 people taking HAART. In contrast, six of the 14 taking HAART + IL2 did not show evidence of HIV-infected cells.
The researchers looked at samples of up to 330 million cells in one of these individuals. It has been previously reported that long-lived memory T-cells may harbor HIV. The researcher presenting this study suggested that IL-2 may reduce the numbers of these HIV-infected memory cells, but couldn't explain how. Test tube studies have shown that IL-2 can interfere with the development of memory T-cells, but whether this explains these results is unknown.
Two of the people in the IL-2 cohort were reported to have stopped treatment, and after three weeks their HIV viral load remains undetectable. It is not yet clear if their immune systems are effectively suppressing any remnants of HIV, or if HIV has indeed been eradicated.
Several presentations focused on the importance of HIV-specific T-cell responses in controlling HIV replication. However, there were only two poster presentations on immune-based therapies designed to induce new HIV-specific T-cell responses. One poster was a further follow-up on a small 42-person study of HAART given along with a therapeutic vaccine called Remune, which is whole-killed HIV with the outer coat (envelope) stripped off. Removing the envelope means the vaccine induces immune responses to the core proteins of HIV. This may be important for stimulating antiviral immune responses.
The study found evidence of strong HIV-specific memory T-cell responses after just two vaccinations. No such T-cell responses were found in a control group of people taking HAART alone. Study leader Fred Valentine, MD, reported that he has received permission to stop HAART in willing study participants that have received Remune. This will hopefully show if their HIV-specific T-cell responses can control viral replication without any help from the drugs.
The only other HIV-specific IBT presentation used a new type of "naked DNA" vaccine. This vaccine uses bacterial DNA to produce dummy HIV proteins in the body. Unlike Remune, this vaccine uses both envelope and core HIV proteins. There was only a few weeks of follow-up of participants in this study. Most had evidence of some new memory T-cell responses to HIV. It was too soon to tell if these responses were helping their immune systems fight the virus.
Although there was no dramatic new information on IBTs at the Chicago conference, there is little doubt that this research will eventually bear fruit. In his state-of-the-art conference lecture on antiretroviral therapy, Italian expert Stefano Vella noted "it is important that we investigate all potential anti-HIV immune-based approaches." The focus seems to be turning towards the HIV-specific strategies, but there may still be room for combinations of non-specific and specific approaches.
Several studies of IL-2 combined with Remune® are ongoing, for example. A smattering of presentations at the conference did at least show that the immune system can be a potent weapon against HIV. Two individuals from an early David Ho study have now been off HAART for one to two years. Both have viral loads that remain below 500 copies, without any help from the drugs. With this kind of encouragement, the pace of research into immune-based therapies is likely to pick up significantly.
This article was provided by AIDS Community Research Initiative of America. It is a part of the publication CRIA Update. Visit ACRIA's website to find out more about their activities, publications and services.