Australasian Science: Australia's authority on science since 1938

Infected: How HIV works at the cellular level to overwhelm the immune system

By Shane Huntington

Infectious diseases expert Prof Sharon Lewin explains how the HIV virus disarms our immune system and multiplies within it. She also discusses what these discoveries mean for research efforts into future treatment.

SHANE HUNTINGTON

I’m Dr Shane Huntington. Thanks for joining us. HIV or human immunodeficiency virus was for decades considered deadly regardless of where you lived or who you were. Despite the virus' complexity and initially limited research funding researchers have made extraordinary progress with finding treatments. Today, if you are fortunate enough to live in one of the world's wealthier countries, HIV can be kept in check indefinitely enabling healthy normal lives. The situation in less developed economies is very different. HIV is far from being under control and our ability to halt the spread and impact of the virus is limited by the usual political, social and financial restrictions that keep many populations in a state of poverty. Prevention and treatment are effective mechanisms in the developed world, but in developing countries finding a cure is paramount. Today on Up Close we ask why HIV is so much more difficult to stop than other viruses and we explore the possible pathways to finding an actual cure. We are joined by infectious disease physician Professor Sharon Lewin who has been on the frontline in the fight against HIV for decades. Professor Lewin is the Inaugural Director of the Doherty Institute at the University of Melbourne.

Welcome to Up Close, Sharon.

SHARON LEWIN

A pleasure to be here, Shane.

SHANE HUNTINGTON

Why don't we start with an explanation of HIV and how it actually works? How is it transmitted?

SHARON LEWIN

HIV is a virus and it's transmitted in bodily secretions, so through blood, semen and vaginal secretions. So it's transmitted sexually, through blood, through blood transfusions or sharing of infected injecting equipment and from mother to baby across the placenta and at the time of birth.

SHANE HUNTINGTON

What exactly is the virus doing once it enters the body?

SHARON LEWIN

Well the virus enters the body and attacks a key immune-fighting cell called the CD4 T cell which is a critical part of our immune system. It enters into that CD4 T cell, makes a copy of itself and then produces many more copies and kills the cell in the process. So, HIV is extremely efficient at replicating and in fact in someone infected with HIV not on treatment, billions of particles of HIV are produced per day. And in order to do that that virus hijacks the immune system and slowly eliminates these infection-fighting cells called CD4 T cells. It does it slowly over a long period of time. So on average after you get infected with HIV people stay extremely well for about 10 years even when the virus is replicating like crazy. But over time the virus is slowly chipping away at the immune system until the immune system or the CD4 T cell count gets to a low level and then a person starts getting sick.

SHANE HUNTINGTON

So if we compare that to something like the way ebola works it would seem that HIV is a lot smarter and more able to infect a larger number of people over a protracted period. Is that true?

SHARON LEWIN

Absolutely, it's a brilliant comparison actually. HIV's trick is that it is at very high levels in people while they are extremely well and they don't even know they are infected. Which means the virus has a chance to be transmitted over 10 years on average without the person even knowing. In contrast with ebola you are infections when you are symptomatic. So you are infectious when someone is unwell. In fact most people thought that that was the reason why ebola has never spread up until this outbreak. Ebola has never spread very far outside small pockets, largely rural pockets in Central Africa, and the biggest outbreak ever had 400 people involved. We are now seeing an outbreak in West Africa where over 8,000 people have been infected. But there is no evidence the virus has changed the way it's transmitted. But one would have normally thought that that is not a good strategy for survival of a virus.

SHANE HUNTINGTON

Now given those numbers for ebola by comparison how many people have HIV in 2014?

SHARON LEWIN

Well 35 million have HIV at the moment and about 25 million people have died since the beginning of the epidemic. An interesting statistic I just read accounting for the numbers of deaths in West Africa, currently about four a day from ebola and about 650 a day from HIV. So that doesn't at all mean that ebola is not important. It is critically important and there is no doubt this is an absolute global crisis at the moment. But we still see a lot of deaths from HIV.

SHANE HUNTINGTON

Now when the person is infected with HIV is every cell in their body essentially infected or is it just parts of the body that are actually affected by the virus itself?

SHARON LEWIN

So, the virus affects a range of different cells but 99 per cent of the virus is in these infection‑fighting cells called CD4 T cells. In someone off treatment about one in a thousand CD4 T cells are infected but yet there are millions of copies of the virus. It's just because an infected cell is able to produce many, many, many copies of the virus. The virus is constantly infecting killing cells and making more and more copies of itself. But if you actually look where the virus is hiding it is in about one in a thousand CD4 T cells and it also has some special tricks that it uses to hide in certain organs such as the brain, the gastrointestinal tract and the genitourinary tract. So it sets up shop in some specialised long lived cells in those sites as well.

SHANE HUNTINGTON

The human immune system is an extraordinary piece of biological engineering to a degree. Why is it that it's incapable of handling something like HIV? It seems almost as though HIV benefits from that capability rather than the other way around?

SHARON LEWIN

Yes there are a few reasons for that. First of all people actually make a very good immune response to HIV. Everyone makes an antibody response. That is a protein that people produce that usually works against foreign pathogens. When you go along to your doctor and get an HIV test what the doctor is measuring is the presence of what is called an antibody to HIV. So everybody makes antibodies to HIV except the antibodies don't work efficiently. We call them non‑neutralizing so they don't actually kill off the virus but you make them. Pretty much everyone makes a T cell response that is the other arm of the immune system. But the virus is very smart because you do make a T cell response to that virus but at the same time it kills off those T cells. Then it has a special capacity to constantly change. Every time it replicates the virus makes a mistake so it undergoes very rapid evolution. So any time the immune system starts putting pressure on the virus and most people's immune system is putting pressure on the virus, the virus rapidly changes its surface coating or goes into disguise. We call that immune escape. That is another trick the virus uses to constantly outwit our immune system.

SHANE HUNTINGTON

Many of our listeners will have heard the terms HIV and AIDS often used interchangeably, can you describe the difference between these two descriptions?

SHARON LEWIN

Yes, HIV is the virus, human immunodeficiency virus. Being HIV positive means you have been infected with the virus and you have made an antibody and the blood test measures your antibodies. Having AIDS means you are sick from the virus. AIDS is really a clinical diagnosis. It stands for acquired immunodeficiency syndrome. And it was a way that we used to track people who were getting sick from the virus. So AIDS is actually a number of unusual infections or unusual cancers or a very damaged immune system to fit this diagnosis of AIDS. But AIDS essentially means you've become sick from the virus.

SHANE HUNTINGTON

What makes the determination in the body that you move from HIV to having AIDS itself? You mentioned that you can have the virus for quite a protracted period before you actually end up being sick. What is the transition that occurs?

SHARON LEWIN

The transition is because of the virus slowly chipping away at the immune system until the immune system or mainly this level of CD4 T cells reaches a critically low level at which you can no longer protect yourself against infections that would normally not cause a problem in people with a fully functioning immune system. And in fact AIDS was discovered in 1981 when young gay men were presenting in New York and San Francisco with these weird infections that no one had ever seen before in a previously healthy adult. They had seen them in the setting of cancer treatment or transplantation that is what made people think what the hell is going on here. Why are we seeing this weird pneumonia and weird skin cancers that we never see in healthy people? It's because you basically lose your CD4 T cells and therefore you can't fight off infections that usually don't cause any trouble in a person with a normal immune system.

SHANE HUNTINGTON

I'm Shane Huntington and you're listening to Up Close. In this episode we are talking about HIV with infectious disease specialist Sharon Lewin. Sharon, there are clearly three areas that we need to cover here in terms of the way we tackle HIV. There's prevention, there's treatment and there's cure. I'd like to start off with prevention. Presumably this is the best option overall if we could completely prevent the spread of the virus. How do we actually go about that though at the moment?

SHARON LEWIN

Well there are a number of tools that we now have that can effectively prevent HIV. The first that we've known about for years is condoms. So, barrier protection or condoms prevent the sexual transmission of HIV but getting people to use condoms all of the time we know is really very, very difficult. But condoms are very effective at preventing transmission. Access to clean needles is the other simple but highly effective way of preventing transmission through injecting drug use. And in fact here in Australia we have almost no HIV in people who inject drugs because we have had clean needles available to people who inject drugs from the very beginning of the epidemic. Many other countries have not done that and have very high rates of HIV in their communities of people who inject drugs. That's what we'd call behavioural ways of preventing HIV.

We have known for a long time that treatment can also reduce transmission from mother to baby. So if a pregnant mother is HIV positive the risk of transmitting the virus to her baby is about 30 per cent. If you give the mother treatments, so reduce the amount of virus in her body, that reduces down to less than one per cent. So they are three ways that we have known for a long time work. But in the last few years there has been an explosion of other ways to prevent HIV and probably the most dramatic is treating someone who is HIV positive. Someone who is HIV positive who takes antiviral medicines reduces their risk of transmitting the virus by 96 per cent. We call this treatment as prevention. And basically that's probably the main reason why numbers of new infections are decreasing each year in many parts of the world. Because as you treat more people there is less virus circulating in the community. We also know that if you treat people who are uninfected with anti‑HIV tablets, something we call pre-exposure prophylaxis or PrEP, it's a bit like taking the pill, you can actually prevent you getting infected with HIV and we can also use those same antiviral drugs as a topical gel. So a woman that inserts a gel that contains these anti-HIV drugs, something we call microbicides can also reduce transmission. Finally, the other very effective way is through circumcision. So a circumcised man has a reduced chance of acquiring HIV by about 70 per cent. So these are all the things that we call biomedical prevention and there has been an absolute explosion in effective biomedical prevention. The only thing we don't have and still really need, which is the classical and best and most cost effective way to prevent new infection, is a vaccine. So a vaccine we still don't have but that is something that is still a very important part of the toolbox that we need.

SHANE HUNTINGTON

You mentioned treatment a couple of times there. Let's talk about that. How do you go about treating an infected person with HIV and what are the goals of that treatment? Are they to eliminate the virus or just hold it back? How does the treatment function?

SHARON LEWIN

So we now have very good drugs that can block HIV replication at different points in the virus lifecycle. Over 25 different drugs now licensed in many parts of the world that are effective at inhibiting one part of the lifecycle. We call those drugs antivirals. In the mid-90s it was discovered that if we combined the antiviral drugs, give three drugs at the one time, something we call combination treatment you can basically stop the virus in its tracks. When you give someone antiviral drugs which is usually three different drugs, often co-formulated in just a single tablet, the virus levels in the blood plummet from in the order of hundreds of thousands of copies of virus down to undetectable levels or our current test measure down to about 20 copies of virus per ml of blood. In most people who start treatment now in 2014 with combination antiviral therapy the amount of virus in the blood goes from hundreds of thousands to less than 20 in about a month. The antiviral drugs keep the virus suppressed indefinitely actually. In fact we rarely see drug resistance, especially now with the newer drugs. If you take your tablets every day your virus effectively stays undetectable for years, indefinitely we think. At the same time your immune system has a chance to recover and the CD4 T cells I spoke about earlier in fact rebuild. In most people if you don't start treatment too late the CD4 T cells will rebuild over time and in many people go back to normal levels. The immune system often is not 100 per cent normal but pretty much the CD4 T cells come back and people no longer see AIDS-related illnesses. However, the catch is that treatment is lifelong and as soon as you stop treatment pretty much in everyone the virus bounces straight back up usually within two to three weeks of stopping the drugs.

SHANE HUNTINGTON

That's an incredibly fast return of the virus. Do we have an understanding of why it does come back so quickly? Presumably by the sounds of things you are absolutely beating this thing into submission to the point where you almost can't detect it and to the point where the immune system stops responding to it to a degree and yet it's coming back so fast.

SHARON LEWIN

Yes we have a pretty good idea now where the virus hides. If we use more sophisticated tests to measure the virus, we can actually always find it. It's always there at very low levels. What happens is the virus can go into this lockdown or silent mode. We call that HIV latency. It actually burrows into the person's DNA and goes into hiding. When it goes into hiding the infected cell is no longer visible to the immune system and not visible to the drugs. Actually many viruses have this what we call latent form - a silent form that lurks in the background, very smart.

SHANE HUNTINGTON

So, the person has to be on the drugs for their entire life. Are we seeing side effects at the moment to these drugs? I mean typically when we hear of people being on drugs for their entire life there are often significant side effects that end up being worse than the problem they are curing.

SHARON LEWIN

The side effects from the drugs have got less and less and less over time. It's pretty spectacular. In the mid-90s when antiviral drugs first came on the scene, people were taking 20 tablets a day. They were a hassle to take and they had loads of different side effects. The drugs have got better and better over time. Many studies are now reporting both from high income and low income countries that if you start treatment at the right time your life expectancy is the same as someone without HIV. There are some side effects that we are seeing but they're a combination of the side effect of the drug, the fact that the immune system is not 100 per cent normal and probably because there are these very low levels of virus that persist. And together they give a person on long term treatment low level stimulation of the immune system, something we called immune activation. That's associated with an increased risk of heart disease, liver disease, dementia and cancer. So we're seeing all those of things at higher frequencies in people on long term antiretroviral therapy. But you can't compare the spectacular advances of the current treatments compared to the old treatments, compared to no treatment, no comparison.

SHANE HUNTINGTON

Sharon, the response to HIV at the very beginning was very poor for a number of reasons. One that the social stigma attached to the virus itself and people having it. How has that changed now when we look at the role that communities play across the world in tackling HIV and making sure that it is a virus that is addressed in the same way that any other virus is addressed?

SHARON LEWIN

Well what was unique about HIV was the incredible movement that grew out of community engagement and advocacy. I think that's been a real lesson for how we should respond to other diseases. Because in the early days it actually predominantly infected gay men many of whom were highly educated and articulate and really wanting a way to stop people from dying. The community rapidly became very mobilised and very, very effective in pushing scientists to work harder. Pushing regulatory bodies to make drugs more accessible. Pushing pharmaceutical companies, pushing governments. Really, really effective advocacy from the very early 80s and that translated into effective advocacy around getting treatments into lower income countries. It's even translating into advocacy around cure. A lot of the work we do now is still heavily involved with affected communities. They really are partners in progress, I think.

SHANE HUNTINGTON

When we talk about some of the low income locations and most vulnerable communities around the world, presumably the possibility of them picking up other things like Hep B for example are pretty high. How does that make the language we go after HIV more complicated?

SHARON LEWIN

In many parts of the world, both low and high income countries, co-infections with other infections are an issue for people with HIV. So we commonly see co-infections of people with HIV and hepatitis B about 10 per cent of the world's HIV positive population also carry Hep B. About 30 per cent also carry hepatitis C and then many, many also carry tuberculosis. That's probably the most important co-infection globally. So these co-infections present challenges in different settings. Hep B is an interesting one. Several of the drugs that work against HIV also work against hepatitis B even though hepatitis B is a totally different type of virus. But they share a similar step in their lifecycle. There's been great advances in the treatment of Hep B largely through advances in HIV. So, if we treat people who are infected with both with the right anti-HIV drugs we actually control both viruses at the same time.

SHANE HUNTINGTON

I'm Shane Huntington and my guest today is infectious disease specialist Sharon Lewin. We're talking about HIV and where we are in terms of treatment and cures here on Up Close. Sharon, let's talk about the idea of a cure now. I mean first of all I would like to know with all these amazing treatments and preventative options why is there still such a push for a cure.

SHARON LEWIN

The main reason for why we need a cure is that treatment needs to be lifelong. So that comes at considerable cost for both governments to support lifelong treatment, to support lifelong engagement in healthcare. That's quite a challenge in many parts of the world and quite a cost for an individual. So someone that's diagnosed with HIV in their 20s is on treatment for life. Added to that there are some side effects that we talked about earlier. The fact that the immune system doesn't quite go back to normal. Low amounts of HIV, some toxicity of the drugs, so there is associated what we call morbidity or other adverse effects of lifelong treatment. And also currently, although the numbers of new infections are decreasing globally, which is a spectacular advance, for every person in whom we start treatment there is one new infection. So we're constantly chasing our tail. I think the biggest concern is the cost of lifelong treatment and whether that's really going to be sustainable. So if we could find a way that you didn't have to treat for life, if you could just treat for five years instead of 60 years and you could stop the drugs without the virus coming back or if the person could keep the virus under control that could make a very big impact on the number of people we can treat and on the economics of how much treatment costs.

SHANE HUNTINGTON

What's the difference between a sterilising cure and a functional cure?

SHARON LEWIN

Well you're obviously well-read and I'll talk about them. We've moved away a little bit from those terms actually because I think they're confusing for people. Sterilising cure basically means a complete cure. How we think of any infectious disease you go to your doctor with a cough or cold. You get some antibiotics or you don't and the following week you're completely disease free. That's what we mean by sterilising cure, so not finding HIV anywhere in any part of the body, completely gone. That would be fabulous. We haven't achieved that. In fact there is one person in the world currently who, I think, has had a sterilising cure. But he's been off drugs for about six years. He's a man by the name of Timothy Brown who received a bone marrow transplant from a donor who was naturally resistant to HIV. A very unusual case but a very inspiring and instructive case. A functional cure - a better way of thinking about functional cure is the virus being in remission. A bit like how we think about cancer. So we recognise that the virus might still be there at low levels when a person stops treatment but is under control and not causing any adverse ill health. We've now really moved towards talking about remission, putting people in remission because of this uncertainty of whether the virus ever comes back. I think it's a concept more familiar to people given that's how we think of it in cancer.

SHANE HUNTINGTON

So in a sense there you are talking about achieving the exact same goal that you would from treatment but with a single or a relatively short term dose of something. So rather than the person being on the treatment for an entire life they'd get that same viral load decreased to almost nothing in just a few shots?

SHARON LEWIN

I think a cure is always going to include antiviral treatment because you have to get the virus under control and someone not on antivirals there's so much virus in there causing havoc in the immune system, billions of copies of virus. You have to get that first under control and that would take maybe three to four years. Then we've reduced all of that havoc the virus is causing by reducing the amount of virus in the blood so that all that's left are these long lived, very rare, latent forms of the virus. The idea is then just to come in with some intervention whether it's tablets or injections or some intervention and then stop the treatment. The virus might be there at very low levels but it doesn't come bouncing back in two to three weeks like we see in people without that additional intervention.

SHANE HUNTINGTON

You mentioned earlier a lot about the idea of latency with HIV, the idea it can stay there dormant in our system for a protracted period. In terms of looking for a cure, does this particular function of HIV give us any advantage in terms of going after it and completely knocking it out?

SHARON LEWIN

Yes, a lot of the ideas around achieving remission or achieving a cure is through eliminating latently infected cells. We know on average latently infected cells occur about one in a million. One in a million of your infection fighting CD4 T cells carry this latent sleeping virus. So there's a lot of work in understanding how the virus gets in there, how it stays in there and how you could push it out as a way to eliminate the number of latently infected cells. We have a few tools already that we know can do that.

SHANE HUNTINGTON

Sharon, you mentioned Timothy Brown the so-called Berlin Patient earlier and the idea that a bone marrow transplant in a sense had presumably cured him of HIV. Do we know why that specifically occurred?

SHARON LEWIN

Timothy Brown was a man who was living with HIV; was on treatment and he developed a rare form of blood cancer which needed a bone marrow transplant. A bone marrow transplant is a bit deal about 20 per cent mortality but you need to have it if you have a blood cancer or leukaemia. So his doctor at the time, Gero Hutter, had the brilliant idea of saying why don't we transplant Timothy Brown with a bone marrow from someone that's naturally resistant to HIV. About one per cent of Caucasians are naturally resistant to HIV because they are born without the receptor that HIV needs to enter the cell, that receptor is called CCR5. So, one per cent of Caucasians are CCR5 negative. So, Gero Hutter managed to find a donor, which is not easy for a bone marrow transplant, who had all the right immune markers as well as being CCR5 negative. After the transplant was performed they bravely stopped his antiviral drugs and the virus never came back. There's a few different theories about what cured Timothy Brown. First is that he received a bone marrow from someone that was resistant to HIV. The bone marrow made all of his cells effectively HIV resistant. The second theory is that there was something around the transplant that led to a way of wiping out the residual latently infected cells. That's a plausible explanation. When you have a transplant you are giving a new immune system to someone. We try and make the two immune systems quite well matched so they don't react against each other. It's never identical because no one ever has an identical immune system. So there's always a level of what we call graft versus host. So the graft attacks the host immune system. That's a good thing because that helps eliminate disease because the graft also attacks the leukaemia. And maybe what happened was the graft attacked the latently infected cells that were still there and that was enough to wipe them all out. No one has been able to repeat the experiment. Not because they've done it and it hasn't worked. It's just that the capacity to find the right immunological match and also have that person CCR5 negative and that person survive their cancer has been a very tall order and no one has been able to replicate it yet.

SHANE HUNTINGTON

Presumably from that perspective and the perspective of bone marrow transplants of this type having a 20 per cent rate of people not surviving, this is not a viable way to take on HIV in itself?

SHARON LEWIN

Not at all. But it's a way of teaching us some very interesting science. Just another fascinating story is the case of two Boston patients who were also men who were HIV infected on treatment needing bone marrow transplants because they both had another type of cancer, different to Timothy Brown but a form of blood cancer. But this time the Boston patients received a transplant from a susceptible donor, so not CCR5 negative, a susceptible donor. And the investigators looking after these two patients Timothy Henrich and Dan Kuritzkes in Harvard Medical School noted that they could no longer measure these latently infected cells. We can measure them quite easily with extra tests. They disappeared from the blood within about six months of these two men having transplants. There was a lot of excitement that maybe a regular transplant not a CCR5 negative transplant could work that it was all graft versus HIV. So all of their tests became negative and then they again had the bold but very careful intervention of stopping treatment. Everything looked pretty good for the first 12 weeks which is quite a long time given that we know the virus normally comes back in two to three weeks. After 12 weeks off treatment the virus suddenly re‑appeared in one patient and after 32 weeks in another patient. Now there are many reports of transplantation that's done for other reasons that are coming out showing that transplantation does lower the amount of latently infected cells we can measure. But no one has yet survived no virus for a long period of time off treatment. So the virus is still there at very, very low levels and it came back in both those patients. So that was a bit of a disappointment.

SHANE HUNTINGTON

With of all of this information coming in, I mean it's all helping us towards this final endpoint of a cure. What do you think will be that approach in the end? I mean obviously bone marrow transplants aren't it, but are we getting enough information now for us to be able to nail down what we think the approach to a cure for this virus will actually be?

SHARON LEWIN

Yes, well we've got much better tools now of measuring very low amounts of virus. Not perfect, a lot more work needs to be done on that area. There's another strategy that's being tested, it's an area that my own lab works quite a lot on it's something called shock and kill where you use ways to wake up the virus or shock it out of its latent form and then come in with something that's going to then kill the virus. We have lots of drugs that can shock the virus, at least in test tube models of HIV and then there's been several clinical trials now of these drugs. We did one of those clinical trials here in Melbourne a few years ago. We used a cancer drug, actually it’s a new class of cancer drugs that alter the way genes are expressed. It essentially wakes up the sleeping virus. We knew that in test tube models and we measured that in people. Since our study there's been some further studies with even more potent forms of this cancer drug showing that this drug definitely wakes up the virus. So we can shock the virus. What we haven't yet found is a way to kill it. So there's a lot of work now around what's the best way to kill it. Perhaps with antibodies, neutralising antibodies perhaps with an extra vaccine or a boost to the immune system.

SHANE HUNTINGTON

Sharon, are there any other viruses that we know of that are similar in the way they act that will - work in HIV will also benefit in terms of finding cures and ways to treat patients?

SHARON LEWIN

Yes there are. This capacity of a virus getting inside your DNA and going to sleep is a feature of a whole family of viruses called retroviruses and HIV is a member of the family of retroviruses. Our DNA is full of evidence of old retroviruses. So we have been living in harmony in a way with retroviruses for centuries. And so there are some other retroviruses that we may get some clues of. There are retroviruses that aren't as dangerous as HIV. But we call these retroviruses HERVs, or human endogenous retroviruses, they might give us some clues. Hepatitis B has a totally different but sort of similar way of hanging around forever, other viruses also do so. I think great discoveries in science or medicine often come left field, come from other disciplines. I think a real key to moving this field forward is to stay engaged with other disciplines and other advances in science because the cure might come through great advances in cancer therapy. Great advances in understanding gene regulation in the immune system, so not sitting with people that think the same as you is probably really important.

SHANE HUNTINGTON

Sharon, thank you very much for being our guest on Up Close today.

SHARON LEWIN

Pleasure, thanks a lot.

SHANE HUNTINGTON

Professor Sharon Lewin is an infectious disease physician and Director of the Doherty Institute at the University of Melbourne.