A small subset of HIV-infected patients do not progress to AIDS, even after decades of infection. What can we learn from these anomalies?
“It was a death sentence,” says Anthony Kelleher, an HIV researcher and Acting Dean of Medicine at the University of New South Wales. Kelleher was a junior doctor at St. Vincent’s Hospital in 1990, when the HIV epidemic was at its height. “At that stage, the ward had 18 beds. They were always full, and there were usually six people downstairs in the Holding Ward, waiting for a bed upstairs. If we kept people out of hospital for three months, that was a success.”
Human immunodeficiency virus (HIV) ceaselessly ravages the immune system, an insidious and relentless march towards a full breakdown of immune function. As the infection progresses, the ‘viral load’ — the number of viral particles in a measure of blood — increases, and the number of CD4 T cells, a type of white blood cell, decreases. “How CD4 cells die is complicated,” says Kelleher. “One, it’s a direct infection. Two, they become a target for CD8 T cells, which protect from viruses.” In essence, HIV turns the immune system against itself.
CD4 cells are partially responsible for adaptive, or acquired, immunity, the body’s ability to respond to new immunological threats. Without antiretroviral drugs, HIV will typically progress to acquired immune deficiency syndrome (AIDS) within 8 to 10 years. Patients with AIDS, because they lack enough CD4 cells, could expect to play host to any number of opportunistic infections, including cancers and pneumonia.
Beginning in 1981, a small group of people in Sydney were infected with HIV from blood transfusions. Screening of donated blood was not yet commonplace, and it was later discovered that all infected blood came from a single donor. This group became known as the Sydney Blood Bank cohort. While most people infected with HIV from blood transfusions had a very poor prognosis due to the large amount of the virus they received, it was noticed that all individuals in the Sydney Blood Bank cohort, along with the original donor, were taking a very long time to become ill, far longer than the typical 8 to 10 years. “These people had something special about them,” says Kelleher. When the blood was analysed, it was discovered that the virus from this particular donor had mutated into a form that was missing its ‘nef’ gene. This caused the virus to be attenuated, or weakened, like a muzzle on an aggressive dog.
This was significant for two reasons. “There was a lot of interest in this in terms of understanding pathogenesis,” says Kelleher, “but also in terms of developing this as a model for vaccines.” The measles and polio vaccines use attenuated viruses, and it was thought that a similar approach could be used with the attenuated virus from the Sydney Blood Bank cohort to create a vaccine for HIV.
Meanwhile, physicians around the world were noticing that many other people with HIV were exceeding the normal prognosis for progression of HIV and were maintaining a near-perfect bill of health. “If you spoke to the clinicians that saw large numbers of HIV patients, all of them had one or two people that weren’t deteriorating in an era where everybody was deteriorating” says Kelleher. Their CD4 T cell counts remained high while others’ plummeted. Collectively, this lucky few who were not succumbing to HIV, despite a lack of treatment, became known as long-term nonprogressors (LTNPs).
The mystery was why this phenomenon of nonprogression was not limited to the Sydney Blood Bank Cohort. The $64,000 question became: Is there a circulating nef-deleted strain responsible for other infections that creates nonprogressors?’ Kelleher is blunt: “There wasn’t.”
It is estimated that just 1 in 300 persons with HIV can control the virus to this extent. While most HIV-positive patients progress to AIDS within a matter of years, some LTNPs have kept the virus at bay for 30 years without intervention by antiretroviral medications, maintaining normal T cell counts and an otherwise clean bill of health.
Because there was no single strain of the virus that caused slow progression, this meant that there were other explanations at play, says Kelleher. “It’s multifactorial. We still don’t understand most of those factors.”
Genome-wide association studies, which analyse genetic variants to identify the genes associated with certain traits, have been undertaken in LTNPs to establish which genes are responsible for their resistance to the disease. Across these studies, there is one factor that stands out as a possible genetic cause of nonprogression: whether or not they possess certain human leukocyte antigen (HLA) types.
There are multiple classes of HLAs, but, broadly speaking, they are responsible for regulation of the immune system and in disease defence — they identify foreign objects in the body and present them to T cells to be killed off. Conversely, they are also a cause of transplant rejection. Two HLA types have been implicated in long-term nonprogression: HLA-B57 and, to a lesser extent, HLA-B27. In essence, both HLA types allow for a broader immune response to the HIV virus, but, as Kelleher explains, “with B57 no one really understands why it gives an advantage, they just know that it’s there.”
Unravelling the mystery was never going to be a simple task. Since research into LTNPs began, multiple mechanisms of control have been discovered, ranging from being infected with a weaker form of the HIV virus to genetic factors like gene mutation and receptor mutation. The latter is one of the most intriguing avenues of research.
Receptors are like doors to the cell. One such receptor, CCR5, is the door to white blood cells for which most strains of HIV hold a key. A small percentage of the caucasian population possess a mutation called the delta-32 mutation, which prevents HIV from entering the cell, rendering the individual resistant to HIV-1 infection. This mutation is present in some LTNPs, and partially explains their ability to control the infection. This mechanism led to the introduction of a type of medication called entry inhibitors, and an incredible success story in the battle against HIV: a patient known as the ‘Berlin patient’.
Timothy Ray Brown was diagnosed with HIV in 1995, and suffered a devastating double whammy when he was also diagnosed with acute myeloid leukemia in 2006. He underwent both radiation and chemotherapy, both of which were unsuccessful. It was then than his oncologist, Gero Hütter, had a brilliant stroke of insight, aiming to kill both birds with one stone.
Brown required a bone marrow transplant, and Hütter suggested that the transplant come from a donor with the CCR5-delta-32 mutation. Brown received the first of two transplants in 2007 and stopped taking his antiretroviral medication on the same day. As was hoped, his viral load did not return and he maintained his CD4 count. Several years afterwards, the virus remains completely undetectable in his body. Timothy Ray Brown is therefore the only known person to have been functionally cured of HIV with no traces of the virus left in his body.
However, bone marrow transplants have a high mortality rate, and the chances of finding a donor with the right type of CCR5 mutation are very low. Hence, Kelleher is quick to point out that this method of HIV treatment is unfeasible to roll out to the general population, and is therefore merely a “proof of principle”, albeit an astonishing one.
It has been known for some time that the optimal treatment of HIV involves a combination of drugs, not just a single one. The first generation of these drugs were quite toxic, inducing side effects that could be so bad that physicians would delay putting their patients on these drugs until the benefits would ostensibly outweigh the negatives. It’s only recently that the medical community has had an armamentarium of drugs that are both effective and relatively benign in terms of long-term side effects.
Normal CD4 counts are around 500 per microlitre of blood. Initially, it was recommended that a patient initiate antiretroviral therapy once their CD4 count hit 200, the point at which they are described as having AIDS and at which opportunistic infections become common. Some years later, the recommended CD4 count to start therapy became 350, and there was debate about whether that limit should be raised to 500.
In 2009, a clinical trial called START (Strategic Timing of AntiRetroviral Treatment) was developed, partially in Australia, to determine the best timing to initiate therapy. Approximately 4,600 HIV-positive patients with CD4 counts over 500 were recruited, and randomised into groups that started either immediately or at counts of 350.
The results were startling. Despite being projected to last for seven years, START was terminated ahead of schedule because the difference between groups was so significant. According to Kelleher, START showed “an unequivocal benefit for starting early” for impacts on survivability, while other studies showed dramatically reduced rates of transmission. “The current recommendations, WHO [World Health Organization] guidelines, the American guidelines, British guidelines, European guidelines, all now state that you start therapy immediately on diagnosis,” says Kelleher.
So what of our LTNPs now that all people diagnosed with HIV will immediately commence treatment? Keeping in mind that LTNPs are defined as people who progress slowly despite never having gone on therapy, Kelleher is blunt: “We’re never going to find another long-term nonprogressor.” In fact, after the START results were released, Kelleher closed off new recruitment to the LTNP study he is running. “We didn’t think it was ethical, and it was counter to guidelines, to continue to recruit.”
Not all of those in Kelleher’s study decided to go on therapy, however. Of the 30 in the study group, eight remain off therapy to this day. All are ‘elite controllers’, a subset of LTNPs who maintain both a high CD4 count and an extremely low viral load, who have been HIV-positive for 25 years or more but haven’t progressed.
Still, with almost all HIV patients now on treatment, the pool of LTNPs available to study is ever-diminishing. Further, Kelleher says that although blood samples taken from LTNPs are stored for later study, “there’s going to be a limit to what we can learn from that because there’s a limit to the material in the banks.”
While the door for research into LTNPs is closing, another, more pragmatic approach is providing opportunities for treating and eradicating HIV. Australia, and New South Wales in particular, is “leading the charge” in the treatment and eradication of HIV. Where the World Health Organization wants 90% of people with HIV on treatment by 2025, New South Wales has well exceeded that, aiming to have 95% of HIV patients with undetectable viral loads.
As Kelleher puts it, “the game has changed” after START. The only way to find out if someone is an LTNP is to delay therapy, and the insidious nature of HIV makes this inherently risky. The approach of the medical community now is one of pragmatism, as other avenues of research come up against brick walls time and time again. Even a vaccine, according to Kelleher, is “still beyond the wit of anyone on the planet.”
Edited by Andrew Katsis