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What marks out HIV controllers from others?
Gus Cairns, 2017-08-03 09:50:00

What if we are asking the wrong, question, though? What if trying to destroy or at least expose and inactivate every cell containing HIV is not the way forward and instead the answer is to teach the body to simply either ignore HIV, or develop an immune response that controls it? One of the most widely-reported stories of the conference was the discovery of a South African child who had been born and started treatment early but who had now been off ART for five years without development of a viral load.

There has always been a very small proportion of adults who have either always been able to control HIV or who, like this child, started ART early but subsequently came off it, and found their HIV did not reappear, or did only after a prolonged period.

In the seminar, Nicolas Noël of the South Paris Hospital at Le Kremlin-Bicêtre talked about a French cohort of HIV controllers – people who maintain an undetectable viral load off treatment. He found 178 patients who controlled HIV with occasional ‘blips’ (transient detectable viral load results) and 52 patients who never had blips. The former group had an average viral load of 21 copies/ml by an ultrasensitive viral load test, while the non-blippers had a viral load lower than this test’s lower limit of detection at less than four copies/ml.

He found evidence that the ‘blippers’ had very slowly declining CD4 counts, while the non-blippers did not; their CD4s stayed resolutely stable, at an average count of 700, on the low side of normal.

The non-blippers had very low levels of anti-HIV antibodies of the type called IgG. This may appear to be a paradox, as in studies of HIV vaccines, a strong HIV IgG response has been found to be protective. But the point is that in most people with HIV, the IgG response is turned on all the time – even in people who take ART – and the virus learns very quickly to mutate around it. The battle between HIV and the antibodies that attack it is an arms race which HIV nearly always wins. What is needed is a situation where the ‘antigenic signal’ of the virus is so low that the IgG response, simply because it is rarely called on, remains effective when it is needed.

Another hint that this might be an ideal virus-controlling situation came from a study comparing the HIV response in Rhesus macaques with that in African green monkeys.

Michaela Müller-Trutwin of Paris’s Pasteur Institute told the Forum that Rhesus macaques can be infected with SIV, the monkey equivalent of HIV, develop high viral loads, experience CD4 cell declines, get sick, and die.

African green monkeys, on the other hand, can be infected with SIV, develop high viral loads, experience an initial loss of CD4 cells in their gut, but do not experience the chronic T-cell activation or inflammation that leads to immune system derangement and CD4 cell loss. The difference appears to be that African Green monkeys do not establish reservoirs: HIV remains a circulating virus but not an archived one.

How does this happen? The HIV appears to stop at the gut level: the central memory T-cells that live in the lymph nodes and whose infection is the last stage in the establishment of a chronic, integrated HIV infection are rarely infected by HIV and largely lack the CCR5 receptors on their surface that make them vulnerable to infection.

How are these lymph node cells protected? It appears that in the early stages of infection – we are talking about the first few days or even hours – a strong immune response snaps into action but then quickly closes itself down once its job is done. That response is characterised by a large proliferation of a different kind of immune cell, the natural-killer or NK cell, which has bears a large number of CXCR5 receptors. The job of cells with this receptor is normally to attract cells to the lymph nodes: but in this case, it may be to place HIV in proximity to the cells that are most likely to kill the cells it does manage to infect, and to do so most rapidly.

When cells with HIV do manage to get to the lymph nodes, they can only attach to the parts of lymph nodes that have high levels of the circulating immune chemical IL-15, and several monkey studies at the conference and the seminar found that treatments that combine either IL-15 or IL-21, another cytokine (immune system modulator) with alpha-interferon, produce animals with much fewer infected CD4 and CD8 cells and lower anti-HIV responses.

These results are very suggestive, especially as HIV vaccine researchers have found that an NK-type response is the one that may make all the difference between HIV infection and lack of it. However, they are probably more useful to people as vaccines to stop infection in the first place, as everything suggests that once the reservoir is established, it is much more difficult to generate an immune response that shrinks it.