Theo Geijtenbeek on how HIV evades the immune system and ways to fight back
Could you tell us how you came to be working in the field of HIV?
After my PhD on phospholipid transfer proteins, I wanted to do something different and moved into immunology. At some point I embarked on a so-called Friday afternoon project involving immune cells known as dendritic cells (DCs) and an assay I had developed to study binding of adhesion molecules. Eventually I discovered a protein on DCs (which we called DC-SIGN) that plays an important role in sexual transmission of HIV. This turned out to be a very important discovery and led to several great papers. That’s really how it all started and how I became interested in viruses and the mechanisms they use to escape immunity.
Where are we now in terms of understanding how HIV infiltrates the immune system?
DCs are antigen-presenting cells that play a very important role in activating the immune response to pathogens, such as viruses. DCs are found in tissues that come into contact with viruses, such as the mucous membranes in the mouth and reproductive organs, as well as the skin. At rest, DCs in these tissues capture invading viruses that are subsequently broken down into smaller parts (antigens). The DCs then migrate to the lymph nodes where they present the viral antigens to T cells, leading to T cell activation, and these T cells then destroy the virus.
DCs also capture HIV, but, surprisingly, they don’t break it down. As a result, when the HIV-infected DCs migrate to the lymph nodes and interact with the T cells, they transfer the virus to T cells and the T cells become infected. This process is known as HIV transmission and you could say that DCs are a kind of Trojan horse. However, not all subtypes of DCs are equally susceptible to being misused by HIV. Although certain DC subtypes located in deeper tissue are easy targets for HIV and lead to high levels of HIV transmission, other DCs (known as Langerhans cells) actually form a barrier that is very effective in breaking down HIV and only become infected under specific conditions, such as sexually transmitted inflammation.
We know that when people acquire HIV they form antibodies to the virus and, as such, mount an immune response to HIV. However, this response is not sufficiently efficient and therefore does not clear the infection. This seems partially to be because the body is unable to detect the virus quickly enough and, as a result, the immune response is mounted too late. A crucial factor in achieving an efficient immune response is DC activation. Normally, when a virus enters the body, DCs are activated because certain proteins (or sensors) located on their surface are triggered. However, around 6 years ago it was suggested that, in the presence of HIV, DCs are not activated because they do not recognise HIV as a threat. This led to further research into understanding how HIV avoids triggering the sensors on DCs and it appeared that HIV uses several mechanisms in DCs to circumvent activation.
So HIV uses DCs for transmission, but also evades recognition by DCs to avoid stimulating an immune response. How does this work?
At present we know of two mechanisms in DCs that prevent activation of these cells and of which HIV makes good use. HIV uses the first mechanism to render HIV DNA unrecognisable. HIV is a retrovirus and therefore needs to convert its RNA into DNA to achieve infection. HIV DNA is made in the cytoplasm before being moved to the cell nucleus. Usually, excess DNA in the cytoplasm is recognised as a warning signal for DNA sensors and certain proteins, including one called Trex1, clear this excess DNA up. However, in the case of HIV, some of the DNA is transported to the cell nucleus so quickly that it goes undetected by the sensor proteins. HIV subsequently employs Trex1 to break down the remaining DNA in the cytoplasm, making it undetectable and thereby avoiding an immune response. The second mechanism is used by HIV to avoid recognition of viral RNA. During HIV replication, RNA is produced. This RNA is recognised by a particular sensor (DDX3), but HIV prevents DDX3 from transmitting its signal by activating a different protein on the cell surface (DC-SIGN). Consequently, despite HIV RNA recognition, DCs are not activated in response to HIV infection.
However, some people have a particular mutation that prevents HIV from suppressing the DDX3 trigger. When cells from these individuals are infected with HIV, we see very strong activation of DCs and a strong immune response. Using data from the Amsterdam Cohort Studies, we looked at how HIV infection progresses in people with this mutation. We found that these people are far better at keeping the virus under control and have a lower viral load. These findings suggest that a very early immune response would be good for people who acquire HIV and offer potential therapeutic opportunities. For example, if we can find a way to make DCs detect the virus immediately upon infection and stimulate them to mount a strong immune response, the virus would have less opportunity to replicate and patients would fare better because their viral load remains lower. As a result, patients may retain a more intact immune system, which may reduce their risk of HIV disease progression and non-AIDS comorbidity.
What concrete opportunities does all this offer in terms of improving treatment?
It confirms that early treatment is very beneficial, something that people at the AMC (such as Jan Prins, Godelieve de Bree and Peter Reiss) are working on. The idea is that if you start treatment early, lower reservoirs will form and, as a result, the immune system will be more resilient. This could help to better control the virus. I can also envisage possibilities in terms of developing drugs that improve the immune response to HIV by preventing the virus from blocking certain systems. Finally, I think that the work being carried out by Carla Ribeiro (who also spoke at NCHIV on this subject) is very interesting. She is looking at how to activate the HIV restriction factor Trim5α. At present this is only possible under certain circumstances in Langerhans cells. We would like to find out how to trigger the process in other cells, such as T cells, to make them resistant to HIV.