At the 19^th Conference on Retroviruses and Opportunistic Infections (CROI) in Seattle last month there were three main areas of discussion. Prevention and hepatitis C (which we cover in News from CROI 2012 and in Full speed ahead to curing hepatitis C) were the first two.

The third hot topic was a permanent cure for HIV. We covered the approaches being explored in Towards a cure for all in HTU 204, a year ago, and followed with Matt Sharp’s account, in HTU 206, of being a pioneer participant in a trial of one of the ideas being explored: genetically altering people’s CD4 cells to make them resistant to HIV.

Many other avenues are being explored. In symposia, poster presentations and a community-sponsored meeting before the main conference, many of these were presented.

There are four key approaches being explored. They are largely in early stages so predicting their future importance is difficult, and an effective cure might need to combine more than one:

• Eliminating the ‘sleeper’ cells that contain latent HIV.
• Containing low-level viral replication without drugs.
• Enhancing HIV-specific immunity.
• Making cells resistant to HIV.

Researchers were calling the first approach ‘kick and kill’ at CROI. A small number of long-lived ‘reservoir’ cells in the body hold on to the instructions for making HIV in their genetic cores. As soon as you stop taking the HIV drugs that inhibit them, they start spewing out HIV again, which is why HIV infection is lifelong. They also appear to maintain smouldering HIV replication even in the presence of HIV therapy, which keeps the number of these cells constant.

The idea is to use drugs that stimulate the reservoir cells to come out of hiding (‘kick’) and then either hope the business of actively producing HIV will kill them and enable non-infected cells to take over or to use special molecular missiles to pick them off (‘kill’).

Several classes of drugs are being investigated for their ability to do this. A generalised immune activator could be highly toxic: you could both set off a lethal immune over-reaction and end up seeding a new generation of cells with HIV. So you need drugs that unblock the processes that suppress HIV reproduction by the cells, without overstimulating them. One example is the cancer drug vorinostat, which in one study¹ involving five people produced an up-to-tenfold increase in HIV expression within resting cells, despite their being on HIV treatment, but did not cause HIV to enter the bloodstream.

Drugs like vorinostat are like flooring the accelerator when it comes to HIV production within infected cells; another approach is more like taking the brake off. A cellular protein called PD-1 is responsible for keeping the HIV reservoir cells dormant and antibodies can be devised that neutralise the keep-quiet message that PD-1 sends round the immune system.

The results are similar to vorinostat, but with an added promising twist: it’s beginning to look as if HIV-infected cells won’t die off by themselves but will only do so if viral replication is accompanied by an increase in the CD8 cells that destroy HIV-infected cells. In one monkey study², giving previously ART-treated animals anti-PD-1 antibodies not only produced an increase in HIV production but also, while not increasing the number of anti-HIV CD8 cells, did increase their sensitivity.

A research consortium has been set up in the name of the late treatment activist Martin Delaney, and one of the avenues it is exploring is the development of aptamers: these are ‘flag’ molecules that stick to specific cell-surface molecules. The idea is that if you enticed HIV-infected cells out of hiding, you could inject aptamers at the same time and these would stick to the cells’ markers of immune activation. These would serve either as beacons for cell-killing drugs or contain cytotoxic compounds themselves.

A therapeutic vaccination that helps the body contain HIV replication has long been an unrealised ambition in cure research. A team from the Norwegian company Bionor Pharma, using a vaccine against the HIV p24 protein called Vacc-4x, produced a nearly threefold decline in the ‘set point’ average viral load of a group of participants taken off ART for a treatment interruption. Results like this have been seen before, but HIV usually manages to mutate its way round the immune response produced by the vaccine. However, a therapeutic vaccine could contain viral replication in people where the number of reservoir cells had been reduced to the bare minimum.

As well as scientific barriers to overcome, there are practical ones. Cure researcher Steven Deeks told the community symposium that, as there have been with HIV vaccine research, mechanisms needed to be put in place that achieve sustained funding for plausible but hard-to-achieve strategies, while also finding cash for left-field approaches and serendipitous discovery. And since a cure will probably combine several approaches, we need to start thinking now about ways highly disparate academics, companies and government bodies could work together.

There may be many wrong turns in cure research but at least we now believe it actually exists as a destination.