HIV budding from a macrophage
HIV budding from a macrophage

The STEP anti-HIV vaccine trial  received a lot of press coverage last year, when the vaccine was pulled for fear that it actually worsened HIV disease. A number of mechanisms were proposed for the exacerbation.  One of those has now received some support.1

The STEP study used adenovirus vectors, expressing HIV proteins, to induce immunity to HIV. Adenoviruses are ubiquitous viruses in most human populations, usually causing fairly mild upper respiratory tract infections (i.e. cold-like symptoms), and most people have been repeatedly exposed to adenoviruses. As part of the adenovirus/HIV vaccine, people developed immunity to the HIV proteins, and also increased their immunity to the adenovirus component. Unfortunately, the preliminary analysis suggested that those vaccinees with high anti-adenovirus immune responses, were actually more susceptible to HIV, not more resistant. Obviously, that was a bad thing.

One suggestion at the time was that having immunity against adenoviruses might lead to increased activation of the immune system. There was already evidence at the time that activated T cells are more susceptible to HIV infection in several ways, and that evidence has been boosted by several studies since. For example, just the other day there was a paper showing that

… circulating microbial products can increase viral replication by inducing immune activation and increasing the number of viral target cells, thus demonstrating that immune activation and T cell proliferation are key factors in AIDS pathogenesis.2

In fact, in monkey species (e.g. sooty mangabeys) that don’t develop disease after SIV infection, you don’t see a lot of immune activation; whereas those species that do develop disease, show significant immune activation:

SIV-infected SMs3 do not manifest the chronic generalized immune activation that characterizes pathogenic SIV and HIV infections, a process that is thought to play a central role in driving CD4+ T cell depletion through bystander activation and loss of uninfected T cells. 4

HIV infecting a macrophage
HIV infecting a macrophage5

So there was theoretical support for the concept that immunity to adenoviruses could lead to immune activation, which in turn could lead to increased HIV replication, causing increased susceptibility to HIV. The paper I mentioned that provides more direct support 1   also spells out a mechanism in a little more detail, looking at antibodies against adenovirus and their effect on activation; as well as noting that at least one other potential problem might be that the anti-adenovirus response could indirectly cause a reduced anti-HIV response (by killing dendritic cells).

This study (and others) actually point to a couple of useful directions. For one thing, although in this case it seems that immune activation was bad, in most cases it’s just the opposite.6  The anti-HIV vaccine is actually a very special case where we might not want an activated immune response, and even there it’s not strictly activation we want to avoid, just off-target activation. (A strong, activated immune response against HIV is probably a good thing,4 because it can shut down the virus.) This adenovirus trick may be a fairly straightforward way of getting immune activation, if it can be harnessed.

Another point is that in this special case, where immune activation may be harmful, maybe blocking activation would be beneficial. It’s a little counterintuitive to try to suppress the immune response when you’re infected with a virus, but it’s probably worth looking at:

These data suggest that therapeutic strategies to reduce immune activation should be explored, in addition to the classic antiretroviral therapies, in preventing progression to AIDS in chronically HIV-infected individuals.2

Added note: The Michael Palm Treatment Action Group blog has commentary on the STEP vaccine trial conclusions published in The Lancet, as well as a previous series of commentaries on the vaccine trial. Highly recommended.

  1. M. Perreau, G. Pantaleo, E. J. Kremer (2008). Activation of a dendritic cell-T cell axis by Ad5 immune complexes creates an improved environment for replication of HIV in T cells Journal of Experimental Medicine DOI: 10.1084/jem.20081786[][]
  2. The Journal of Immunology, 2008, 181: 6687-6691.[][]
  3. SMs: Sooty Mangabeys[]
  4. J Immunol. 2008 May 15;180(10):6798-807[][]
  5. Gross, L., 2006. Reconfirming the Traditional Model of HIV Particle Assembly. PLoS Biology, 4(12), p.e445 EP []
  6. Bad.[]