By Zekerie Redzheb
Amsterdam, Netherlands. Jan van der Wolf/Shutterstock.com
Very few people with HIV can control the virus without treatment; some can suppress the virus from the outset, while others manage to control it with the help of initial antiretroviral therapy. This is the case of a man who has effectively controlled the virus for 23 years after a brief course of treatment. A team of Dutch researchers discovered that the virus is still present and intact in his cells and blood. They attempted to explore the mechanisms by which he could maintain this control and described their findings in the journal AIDS .
Those who can control the virus without any intervention are known as elite controllers, while those who achieve control after initial treatment are known as post-treatment controllers. What post-treatment controllers have in common is that most begin treatment very soon after acquiring the virus, during the stage known as acute HIV infection. This stage lasts about four weeks and is believed to be the time when the virus spreads to various tissues and establishes its hiding places.
So far, scientists have been able to reveal several ways in which some people with HIV can achieve partial or complete control over the virus. Some maintain this control for short periods, while others can continue for years and decades. It is important to note that in all these cases, these individuals still have the virus; in other words, we are excluding cases of natural resistance observed in Caucasians with the CCR5 gene mutation.
The case described in this study is that of a post-treatment controller; however, it is unique because the man has managed to maintain control for more than two decades while the virus is still present and intact. In other words, it resembles what scientists call a cure or functional remission, as opposed to HIV eradication (sometimes called a sterilizing cure), which can be difficult to achieve and perhaps riskier. Several pathways have been described that could lead to a functional cure in the future, and this could be one of them.
Case
A 49-year-old man experiencing symptoms such as swollen lymph nodes, headache, and fever was diagnosed with HIV in 1998 with a viral load of 2.7 million copies, 440 CD4 cells, and a positive antibody test. Two weeks later, he began a fairly complex antiretroviral regimen that included three NRTIs (stavudine, lamivudine, abacavir), one NNRTI (nevirapine), and one protease inhibitor (indinavir). His final regimen was based on efavirenz, which he decided to discontinue in October 2000.
He had already become undetectable seven months after starting therapy, so by the time he stopped, he was virally suppressed. However, he continued with his medical appointments, where his immunological and virological parameters were monitored periodically. This is where things got interesting: with the exception of a single episode (400 copies) seven months after stopping treatment, he remained undetectable for the next 23 years.
Genetic and virological analyses.
A series of genetic analyses were conducted to look for the presence of genes known to play a protective role in HIV control; these are typically present in elite controllers, for example. Interestingly, the man lacked almost all of the protective genes, with the exception of one genetic trait known to give CD8 immune cells the ability to recognize and fight HIV more effectively.
CD8 cells are often called cell-toxic because their primary function is to detect and destroy other cells that harbor a hostile agent. In fact, in recent years CD8 cells have been recognized as key players in HIV control.
Eighteen years after treatment was discontinued, researchers observed the presence of proviruses within their cells. Proviruses are the result of HIV converting its genetic material into a more compatible form that can reside within our own chromosomes and become an inextricable part of our genome.
The man had viable proviruses that, in theory, could produce thousands of HIV viruses. The virus had few mutations that did not hinder its viability and replication. However, there was a new mutation that partially slowed the virus's replication rate. It likely arose as a result of the virus trying to escape immune pressures; in a way, trying to change its "identity" so that it was no longer easily recognizable. However, this seems to have backfired, as the mutation decreased the virus's ability to make copies of itself. It is difficult to predict whether this made a significant contribution to virological control, but it must have helped the immune system since fewer copies of the virus would be produced.
Immunological analysis
Next, the researchers looked for antibodies that the man's immune system might have produced to neutralize the virus. Although he had antibodies, they were not broadly neutralizing (in other words, they were ineffective), so this could not explain his excellent virological control.
Finally, they observed the performance of their CD4 and CD8 immune cells. CD4 cells are essential for proper immune function, as they organize and orchestrate immune responses to any infectious agent. They are also the primary target of HIV.
The researchers discovered that the man's CD8 cells had a very strong response to the HIV coating protein, which is essential for the virus to infect new cells. Furthermore, his CD8 cells had a very high proliferation rate; they could multiply very rapidly to meet the body's demand in fighting the virus.
Conclusion
In this case, strong CD8 cell responses and perhaps slower viral replication appear to be the prerequisites that allowed for the exceptional 23-year virological control. For 23 years, the man continued to have very low, but detectable, levels of virus in his blood (fewer than 5 copies), and the virus in his cells was still viable. These are all circumstances that make this case unique.
At this point, it appears that instead of a single set of mechanisms necessary for virological control, many pathways have been discovered that can independently lead to control. It's like a math problem that seems to have many possible solutions, which is good news. Exploring these pathways gives us a clearer idea of what the immune system can do to control the virus and may prompt scientists to think about ways to harness and induce these immune system capabilities in those who are not controllers. References
van Paassen PM et al. “Virological and immunological correlations of post-treatment control of HIV following temporary antiretroviral therapy during acute HIV infection.” AIDS, online ahead of print, September 12, 2023.