While there are various antiretrovirals which can control HIV, they don’t cure the infection and this is a matter that a team from the Africa Health Research Institute (AHRI) are trying to unpack by investigating where exactly HIV hides in the body.
Based at the University of KwaZulu-Natal’s Nelson R. Mandela School of Medicine, they are are working in collaboration with the Massachusetts Institute of Technology (MIT) to find where HIV hides with the aim being to extend virology slightly by not targeting the virus itself, but rather the cells that it's hiding in.
AHRI Faculty member, Dr Alex Sigal, explained: “When somebody stops taking the drugs (antiretrovirals), the infection rebounds within several weeks. It’s unclear why exactly that happens. If you have a bacterial infection and you take antibiotics for a couple of weeks, that infection clears. But that’s not the case for HIV. It's hiding somewhere and this hiding place is called the HIV reservoir. This is the cell type where HIV is able to persist despite the drug pressure.”
He said they believe HIV hides in cells in a body compartment called lymph nodes. “Lymph nodes are a place where the body identifies infection. There are a lot of immune cells that are packed in there and this is actually something that HIV preys on. So it attacks precisely those cells that are meant to protect us. But which of those cells is actually the one where HIV is hiding, we don't know. This is what we are trying to identify.”
PhD student, Isabella Ferreira, explained how exactly they are trying to do this: “We take cells from the lymph nodes of infected people and we profile the cells using a new technology called single-cell RNA-Seq to determine which cells are harbouring HIV infection. This technique detects messenger RNAs in each cell. Messenger RNAs are translated to proteins by the cell. So by knowing which messenger RNAs are present, we know what proteins the cell is planning to make, including HIV proteins.”
Sigal explained how having the information will this help in moving forward with treating or possibly curing HIV: “Each cell has a signature, which we can pick this up using this technique of single-cell RNA sequencing. By picking up the signature, we know what cell it is and which cell type is infected. Now if we know the cell type, we’re treating HIV like cancer. So it’s not the virus anymore that we want to target, but the infected cell itself. So it’s kind of a different thinking to normal virology. If you can get rid of the cell, you get rid of the infection.”
Jessica Hunter, also a PhD student, said at this stage the team is at the early stages of their research. “At this stage, we are beginning to sequence the RNA, but it’s still at a fairly early stage. Research takes time because these techniques are very finicky. You are asking a lot from a single cell. The single cell has the information we need, but we need to be able to read what’s inside it and this is very difficult to do. So we need to do a lot of work before we can actually do that. This kind of procedure is called calibration - basically setting up your experiment. We received a grant from the National Institutes of Health for five years and we expect that by the end of it we’ll have some answers.”
Sigal said HIV infection has been around for a while now without any idea of where HIV is hiding, so it’s something that will take time to do. “However, technology that is around now hasn’t been around before, and this is especially true of being able to analyse a lot of data. Each cell has thousands of these transcripts - the pieces of RNA that we’re looking at. And the only reason we can analyse it now is that we have all this computer power. 20 years ago, you couldn't do anything like that. So we’re progressing with technology and this really should help us get a new perspective on where HIV is hiding in the face of antiretroviral therapy.”
Watch Dr Alex Sigal, and AHRI Laboratory Technologist, Yashica Ganga in the process of Cryo storage and retrieval of HIV infected cells to investigate the cell type in which HIV persists in the face of antiretroviral therapy.