way of looking for correlates of protection is to study so-called ‘highly
exposed seronegatives’, people who do not acquire HIV despite frequent contact
In a study that looked at women who took part In the CAPRISA 004 study
of a vaginal tenofovir-gel microbicide, the researchers noted that while
younger age and genital herpes (HSV-2) infection were both associated with
infection with HIV in the study, factors such as the frequency of sex, number
of partners and condom use were not, and a large amount of the variation in
susceptibility to infection remained unexplained. They therefore compared
immune responses to HIV in 44 selected women who became infected (33 on tenofovir
gel and 11 on placebo) and 37 women who, despite higher levels of risk
behaviour, did not (22 on tenofovir and 15 on placebo).
infected women were on average younger (mean age 23.3 versus 27.6), but while
the non-infected women had sex on average 11 times month, the infected women
had it less than six times. These are baseline figures, but did not change
during the trial.
researchers found that women who were infected had higher levels of certain
cytokines (immune-modulating chemicals) including TNF-α, IL-2, IL-7 and IL-12.
They also found higher platelet counts in the blood of women in the visit
immediately before infection compared with non-infected women, even though
platelet counts were the same in both groups at baseline. All these factors point
to a higher state of immune activation existing in infected women shortly before HIV
they looked deeper, the researchers found that the cytokine and platelet increases were
manifestations of the activation of natural killer (NK) cells, a component of
the so-called innate immune system.
animals have three main branches to their immune system. They have the humoral
system (antibodies) and the cellular system (T-cells), collectively called the
acquired immune system, which are finely tuned to ‘remember’ specific
infections and recognise and defeat them again if re-encountered. But we also
share with all animals and plants the innate immune system, a less precise but
faster response, which recognises general characteristics of infected
cells and tissue damage. NK cells are central to this response; they send
signals that increase production of broad-spectrum antibodies called immunoglobulins, which
recruit acquired immune system cells to sites where the body’s defences are
broken. They also stimulate blood platelet production, which prepares the body for
wound healing and physically ‘tangles’ bacterial invaders in blood clots.
who were infected had higher levels of receptors (cell-surface proteins) called
HLA-DR and CD69 on the surface of their NK cells than uninfected women, and lower levels of CD38. In T-cells, high
levels of CD38 indicate activation, but in NK cells the reverse
differences were all significant in themselves, but when all three were lumped
together, as composite indicators of innate immune activation or quiescence,
they were much more so. In multivariate analysis, women with composite innate immune activation were eleven
times more likely to acquire HIV and women with composite immune quiescence 17 times less likely.
In terms of other variables, women on placebo were seven
times more likely to acquire HIV than women on tenofovir and HSV-2 positive women
22 times more likely. Women were also 28% less
likely to acquire HIV for every year older.
strength of correlation with particular immune indicators is not only good news
in terms of being able to predict who may or may not be vulnerable to HIV
infection, but, as the researchers point out, suggests new ways of making new
HIV prevention technologies more effective. The researchers point out that the
tenofovir-gel microbicide in CAPRISA 004 was only 54% effective even in women who claimed 100% adherence, but if it
could be coupled with therapies that dampened down NK-cell activity, many more
infections might be prevented.