How HIV infects females

Say the word "pandemic", and most people immediately think of COVID-19. But while the coronavirus outbreak may be the worst pandemic we've ever faced in economic terms, it's certainly not the worst in terms of human cost. In the coming years we're going to recognise the 40th anniversary of the discovery of HIV, the virus that causes AIDS. 40 million are already dead, and about the same number are currently living with the virus. We still have no vaccine. It's surprising, then, that in 2020 we don't actually know the answer to a critical question about the disease, as Chris Smith heard from UCSF's Nadia Roan...

Nadia - The purpose of our study was to understand how HIV establishes infection in women. Surprisingly as a field we still have a very limited understanding of what happens during those initial early vital stages. This process occurs predominantly through the female reproductive tract as HIV is most often sexually transmitted. And so in our study, we wanted to essentially better understand this process.

Chris - Now the reproductive tract, isn't just one single entity, is it, especially in women, it's quite complicated, there's quite a lot of different anatomical areas. So which of them is the dominant player in the transmissions, do we think?

Nadia - Yeah. So it's thought that HIV can be transmitted through both the lower reproductive tract, as well as the upper reproductive tract. Now we decided to focus on the upper reproductive tract because it's lined by a single layer of epithelial cells that doesn't provide much of a barrier for pathogens, such as HIV to traverse. And so we think that this was a main portal of entry for the virus. And so we wanted to understand what are the cells specifically in the upper reproductive tract, specifically, cells of the endometrium that are most susceptible to HIV?

Chris - How do you think the virus gets there though? Because sperm can swim, but viruses can't. So how do you think the virus accesses the endometrium?

Nadia - Yeah. So that's a great question. There's something called peristalsis, basically movement of particles from the lower tract into the upper tract. And so that's one potential mechanism. There's also some suggestions that viruses such as HIV might even be able to somewhat hitch a ride along the sperm cells.

Chris - So this would ferry at least a proportion of the virus to this site, but what's there that the virus is going for then? Because these viruses are tropic for cells in the immune system.

Nadia - Yeah. So the primary targets of HIV are CD4 positive T cells, a type of immune cell also called a helper T cell. And so these are the main targets of HIV. And indeed in our study, we did find that these were the main targets, but interestingly not all CD4 positive T cells were infected. In our study we compared genital T cells to blood T cells and quite strikingly we found that genital T cells were about a hundred times more susceptible than their blood counterparts to infection. And the more susceptible genital T cells exhibited some distinguishing features, including high levels of a protein called CCR5 which HIV needs to infect cells. And they also exhibited some other defining features, including a heightened state of activation and a higher state of differentiation.

Chris - How did you actually do the study though? Blood that's easy to get hold of, but what about the endometrium? Did you actually get samples of that to look at what T cells were in there then?

Nadia - We did. Yeah. So as you might imagine it's very difficult, in fact, pretty much impossible to study the details of what occurs during actual HIV transmission in women. So we studied it in the lab by exposing endometrial biopsy specimens from uninfected women to HIV.

Chris - And what comes out of this is you see this population of T cells, which is there's something special about it in the endometrium that means they're much more likely to pick the virus up and they're much more likely to proliferate the virus compared with the source of T cells that are washing around in the blood.

Nadia - That's correct, but not only that, we also found that after HIV has infected a cell, that cell looks very different from any original uninfected cell. And so this phenomenon has a name. We call it viral induced remodelling, and consider these cells as quote unquote remodelled because they have changed quite a bit from their original state. And when we looked more closely at exactly how HIV was changing the cells, we found some really interesting results. And so first HIV seemed to modify the cell in ways that made it more difficult for the T cell to function properly and do its job. And so it did this by disrupting what's called signalling through the T cell receptor. Second HIV also seemed to modify the cell in ways that could make it leave the genital tract and migrate to lymph nodes where it's known that there's an abundant source of additional cells that are highly susceptible to HIV. And we think potentially this is a way for the virus to spread to the rest of the body. And finally, we also found that the virus increased levels of a particular protein called survivin, which as its name implies, promotes survival of the cells, and this could potentially serve to keep the infected cell alive long enough so that it can spread to the rest of the body to infect other cells.

Chris - Is there an equivalent to this in men?

Nadia - So we haven't studied for example, rectal mucosal cells, but that's something that we plan to do. I would guess that something similar would happen in a male derived cells.

Chris - I'm just wondering if, because circumcision is very powerfully protective against HIV infection, whether there are similar interesting subsets of T cells in that bit of the anatomy, which would facilitate infection via that route?

Nadia - Yeah, absolutely. So you're alluding to the fact that circumcision protects men from sexual transmission by about 60%, which is very effective. Interestingly, the mechanisms aren't well understood. It's thought that cells, perhaps in the foreskin, might be highly susceptible to infection. There's also thoughts that the microbiome might play a role, but that's a line of investigation that's actively going on at the moment.

Chris - And do you think that what you're doing in the dish is an accurate and faithful representation of what's really happening in the body?

Nadia - It's quite difficult to study what occurs in women, but there are in vivo animal models, in nonhuman primates. And so one important future direction will be to confirm what we found here in a MEVOL model.

Chris - And there must be some profound implications of this because if this is the main route by which the virus accesses the body and establishes itself, does this give us any insights into what other sorts of interventions might work?

Nadia - Yeah, so we think that our characterisation of the way the virus modifies cells may reveal some new targets for HIV prevention strategies. And given that HIV seems to change the infected genital cell in ways that promote its ability to spread to the rest of the body and to survive, we are interested in whether drugs that block these processes might limit the likelihood that HIV establishes that initial beachhead of infection. And so in our study, we actually found that there's a drug that specifically targets the survivin protein that HIV regulates to promote its survival, and that that drug preferentially kills HIV infected genital cells. And so we're very interested in whether that drug, when combined together with traditional antiretroviral drugs, could that be more effective in preventing HIV transmission in the context of microbicides.