Attacking HIV from New Angles

Nico Pfeifer

Attacking HIV from New Angles

Visualization of a prediction result: In addition to the improved prediction method, a new visualization method was developed that shows which amino acids at which positions are most informative for the prediction. Many large red letters mean that the patient should rather not use the entry inhibitor, while green letters symbolize amino acids that can be found in viruses that are susceptible to the treatment. The above sequence is an example of a V3 loop sequence of a virus that should not be treated with the entry inhibitor.

According to the World Health Organization (WHO) 34 million people were living with an HIV infection worldwide in the year 2011. About 1.7 million died due to AIDS-related complications – including 230,000 children. The number of new HIV infections in 2011 was about 2.5 million according to WHO. Preventive measures are an important aspect of tackling these problems. There have been some significant breakthroughs over the past years in HIV vaccine research. For example, Walker et al. were able to extract broadly neutralizing antibodies that can neutralize many different HIV strains from patients with strong immune responses. Since there is no approved method of curing an HIV infection to date, a large part of HIV research is concerned with alleviating symptoms and extending the lifespan of infected patients with the help of antiretroviral drugs. Entry inhibitors are one new class of antiretroviral drugs against HIV that block HIV entry into human cells.

Prediction of HIV coreceptor usage from the genetic sequence

Before prescribing an HIV entry inhibitor it has to be determined whether the drug is effective on the viral population inside the particular patient or not. HI viruses bind to a certain protein on the surface of the host cell, a coreceptor, in order to be able to enter the cell. Different viral variants can use different coreceptors, but the most important coreceptor is the CCR5 coreceptor, which can be blocked by an entry inhibitor. Therefore, only patients with viral populations that exclusively use the CCR5 coreceptor can be treated with this kind of antiretroviral drug. To determine whether the virus harbored by the patient has this property, we follow the approach described in “Bioinformatical Support of HIV Therapy”, page 45. In this application scenario, it is general practice to use a part of the sequence of the envelope gene of HIV called the V3 loop, since this part of the corresponding viral envelope protein is mainly responsible for binding to the cellular coreceptor during cell entry. In our research, we could show how to train a statistical model that improves the prediction of coreceptor usage by the virus based on the complex data produced by new-generation sequencers. The better the coreceptor usage prediction model, the better recommendations it will give about whether an entry inhibitor is suitable for the patient. We were also able to craft a statistical model that uses the new-generation sequencing data to improve the prediction of coreceptor usage based on data produced by conventional sequencing machines. This is especially important since many clinics do not have access to the new-generation sequencing techniques. Additionally, we could identify important positions in the V3 loop, which are highly predictive of coreceptor usage. This could provide information on the mechanism of interaction between the V3 loop and the coreceptor and can potentially lead to new measures to attack HIV.

Analysis of different antibodies against HIV

An important step towards developing a vaccine against HIV is the analysis of the properties of antibodies that can neutralize the virus. To evaluate the potency of potential candidates, there exist laboratory tests that elicit how well a certain antibody can neutralize various different HIV strains. For these panels, several different HIV strains are used that are representative of the viral variation around the globe. Our analyses showed that a certain group of viral strains is less important, clinically, and that certain antibodies are significantly less effective in neutralizing these strains than other antibodies. Because current antibody panels treat all viral strains alike, they give the less important strains more attention than they should. We advocate targeting the antibodies to the important strains only, which gives room for making them more effective on these strains. Our results can be used to improve antibody tests and are consequently an important step on the way towards developing a universal vaccine against HIV.