Mapping the interaction of HIV with antiretroviral drugs in lymph nodes

Antiretroviral treatments have transformed HIV into a controllable chronic infection. Among the available options is dual therapy based on dolutegravir and lamivudine, which has been shown to be very effective in keeping the viral load undetectable in the blood. However, the fact that HIV is controlled in the blood does not mean that it has disappeared from the body: it remains in certain cells forming what is known as the viral reservoir, and the lymph nodes, control centers of the immune system, are one of the main tissues where these cells can persist. Now, the results of a clinical trial published in the Nature Communications journal and coordinated by IrsiCaixa –a center jointly promoted by the “la Caixa” Foundation and the Department of Health of the Government of Catalonia– and the Fight Infections Foundation, and in collaboration with the University of North Carolina at Chapel Hill and the Vaccine and Gene Therapy Institute in the USA, show that the combination of dolutegravir and lamivudine not only reaches the lymph nodes and is efficiently distributed in areas where virus-infected cells predominate, but also manages to rapidly reduce the HIV reservoir during the first year of treatment. 

“Lymph nodes have a very complex architecture, and it is not enough to know the amount of drug that reaches the tissue: it is necessary to know where it is distributed and if it reaches the areas where the HIV-infected cells are located. To answer this question, we have used, for the first time in humans, spatial imaging techniques that allow us to observe this relationship between drugs and infected cells directly within the human lymph node”, explains the co-leader of the study Javier Martínez-Picado, group leader at IrsiCaixa and ICREA researcher.

From how much to where 

The team analyzed lymph node samples from 39 people with HIV who had never received antiretroviral treatment. After starting treatment, lymph node cells containing HIV genetic material decreased rapidly in both groups: both those who received dual therapy (dolutegravir and lamivudine) and the triple therapy (dolutegravir, emtricitabine and tenofovir alafenamide). After one year after starting treatment, both therapies were associated with a substantial reduction in HIV genetic material in the lymph nodes, and reservoir levels were of the same order of magnitude in both groups. 

Measuring the amount of drug in a tissue does not allow us to know exactly where it is located or how it relates to infected cells. To address this problem, the team combined spatial imaging techniques –specifically, confocal microscopy of HIV genetic material and mass spectrometry of chemical molecules– to visualize the simultaneous distribution of viruses and drugs directly into sections of ganglion tissue. This approach showed that dolutegravir and lamivudine were mainly found in areas where T cells, the target cells of HIV, are concentrated. 

“The most interesting thing about this approach is that we can simultaneously study where HIV is located and where drugs reach within the lymph node architecture. This allows us to better understand whether there is exposure to antiretrovirals in the environment of infected cells and how the tissue itself can influence the distribution of treatments”, says study co-leader José Moltó, doctor and researcher at the Fight Infections Foundation. 

The architecture of the viral reservoir 

The main contribution of the study goes beyond demonstrating that the drugs reach the lymph node. The combination of the techniques used makes it possible to relate, in the same sample, three elements that until now were difficult to study together: where HIV persists, where antiretrovirals reach and how the tissue that surrounds them is organized. 

This information may be especially relevant to understanding why some tissues favor the persistence of HIV and how specific factors in its architecture, such as fibrosis, may influence drug distribution.  

The clinical trial is the first to longitudinally integrate spatial imaging of antiretrovirals with HIV reservoir analysis in human lymph nodes during the first year of treatment. Therefore, the results offer a new perspective to study HIV persistence in tissues and could contribute to the development of future strategies targeting viral reservoirs, a key aspect in research to achieve HIV remission and cure.