Istwas this conundrum that Dr Michael Lederman sought to review in his presentation to delegates at the International Aids Society (IAS) meeting in Sydney, Australia, last week. Specifically, is viral replication sufficient to explain the loss in CD4 T cells seen in HIV patients. And if not, what other factors contribute? Lederman thinks that through a combination of research within his group and other scientists' work, he might finally have an answer - immune activation. Counter-intuitively, this finding could mean drugs that suppress the immune system will prove to be valuable weapons in the fight against HIV. "If we could learn how HIV causes AIDS, we could open up new treatment options for HIV sufferers," he said. "There is growing evidence that immune activation is a better indicator of disease progression that viral replication." Dr Lederman has himself been studying the virus for nearly a quarter of a century and is now the director of the Center for AIDS Research at Case Western Reserve University (CWRU), US. According to Lederman, it is often forgotten that the original scientific papers describing HIV recognised that the remaining CD4 cells had a high level of immune activation. The late Janice Giorgi also saw that immune activation predicted the risk of HIV disease progression independently of viral load. By immune activation, Lederman explained that he was referring to the fact that activated cells produce activation markers (such as CD38), produce more 'stuff' (cytokines in the case of T cells) and, also, enter cell cycle with the 'intent' to divide. Levels of T cell activation can be measured in various ways and scientists such as Dr Joseph Kovacs at the US National Institutes of Health (NIH), have used BrdU labelling to do this. According to Lederman, Kovacs found that if HIV is left untreated, there is high turnover of both CD4 and CD8 T cells, which is then "dramatically attenuated" by antiretroviral therapy. Lederman later discovered that when the immune system becomes activated, the CD4 cells enter cell cycle. However, crucially, they don't complete this process, and instead die while trying to divide. . And this leaves the body chronically short of T cells, eventually causing the immune deficiency associated with AIDS. However, more questions remained - namely, what made the T cells start to divide? And, importantly, could whatever was causing it be stopped using drugs? T cells can be induced to begin dividing in two ways: when their receptors encounter antigen in order to expand the immune response to that particular antigen; or through so called 'bystander' mechanisms, such as on exposure to certain cytokines. Cytokines, Lederman explained, are simply proteins made by one type of cell as a means to communicate with, and activate, another cell at a distance. Lederman, and his group of scientists at CWRU, found that most of the circulating T cells in HIV patients are actually memory T cells (as opposed to naïve or effector T cells), which look to be activated by bystander mechanisms. So where are the cytokines that activate the T cells? Lederman considered the possibility that this activation takes place in lymph nodes, since this is where memory T cells 'live'. Lymph nodes are also filled with many effector T cells, which produce large numbers of cytokines. Indeed, when Angelique Biancotto recently examined lymph nodes from 12 HIV positive patients and 10 HIV negative controls, she found that several cytokines were found in much higher levels in HIV positive patients - especially interleukins 2 and 15 (IL-2, IL-15). But there is another force at work in activating CD4 cells. Jason Brenchley recently discovered that in chronic HIV infection, a diminished gut barrier allowed legions of microbes to spill out into the body. These microbe fragments are recognised by Toll-like receptors (TLRs), and Lederman's group discovered that these TLR ligands activate CD4 cells. Adding weight to this theory was Angela Meier and colleagues, who reported this year that strands of HIV RNA can activate T cells indirectly via TLR7 and TLR8. So, according to Lederman, the answer to the original question of how HIV causes AIDS appears to be that infection by the virus both directly and indirectly drives immune activation and also damages the gut lining which drives further immune activation. This activation increases both viral replication and, crucially, causes CD4 T cells to enter cell cycle. However, this cell cycle isn't successfully completed and the T cells die. This is how the immune deficiency is caused. In separate research, Dominik Wodarz, a biologist from the University of California, Irvine (UCI), has shown that multiple HIV particles must team up to infect individual cells, called co-infection, in order for the most deadly strains of the virus to emerge. "If this is true, a new approach to therapy could be to block the process of co-infection in cells," said Wodarz, who used a mathematical model to draw his conclusions. "This would prevent deadly HIV strains from emerging and the patient would remain healthy, despite carrying the virus." In his calculations, he showed that deadly, slower-spreading strains emerge over time and trigger the onset of AIDS, rather than strains that spread in the body more efficiently, as might be expected. The results of the study were published in the online July 31 edition of Proceedings of the Royal Society B. However, the theory needs to be tested experimentally before drug developers could create molecules that block HIV co-infection. In the nearer term, based on the immune activation research, Lederman posed the question: "Should HIV patients be given immune suppressants?" Although he admits he doesn't know the answer to that question, what is certain is that the work of many scientists, including Lederman, has opened up a new area of interest for HIV researchers. Drug developers may now begin to look at attacking the mechanisms through which the virus causes damage to humans, rather than simply attacking the virus itself. After all, levels of the virus might not be the accurate picture of disease progression it has always been taken as: in a study at his clinic, Lederman showed that even after five years of treatment, 20 per cent of HIV patients still have below normal CD4 cell counts despite having low levels of virus.