By John Jesitus, MA
Also called “natural controllers” or “spontaneous controllers,” elite HIV controllers may seem like the winners of the HIV prevention, treatment, and research lottery. Once exposed to HIV, an elite controller’s immune system blocks the virus, so these extremely rare individuals maintain an undetectable viral load without antiretroviral therapy for years.
The study of these individuals has provided clues that could benefit other HIV-positive people. But further research is needed.
“The fact that someone can completely control this virus with their own immune system, without any treatment, is astonishing,” says Dr. Vincent Marconi. “It provides clues as to how we might design therapeutic vaccines or boost the immune system so that people who aren’t inherently elite controllers can control the virus with their own immune system.” Marconi is a professor in the Division of Infectious Diseases at Emory University School of Medicine.
What are elite HIV controllers?
Different studies have used different criteria to define elite HIV control. The most practical definition, according to Marconi, is having an HIV viral load below the detection limit of a standard commercial plasma RNA test (50 or, with the most recent tests, 20 viral copies/mL) for several years or several consecutive tests without antiretroviral therapy (ART). Viral load measures the amount of virus in the body. HIV immune response controllers (another name for elite controllers) also maintain normal CD4 T cell (CD4) counts (at least 500 cells/mm3). CD4 cells are key immune cells involved in fighting HIV. It is estimated that elite controllers represent less than 1% of people living with HIV worldwide. Even rarer are "super controllers," "exceptional" controllers, or long-term elite controllers, who maintain an undetectable viral load and normal CD4 counts and avoid clinical disease for at least a decade.
How HIV progresses
Typically, signs of acute HIV infection can appear up to two weeks after viral exposure. Acute HIV can last from a few days to several months. As the virus spreads rapidly throughout the body, HIV-positive individuals may experience flu-like symptoms. In most cases, however, acute HIV infection is asymptomatic.
During chronic HIV infection, the virus multiplies more slowly, so people may not experience HIV-related symptoms. But without treatment, the immune system eventually weakens. Dr. Monica Mercon explains, “The virus enters cells using the CC5 chemokine receptors (CCR5) on CD4 cells, creating persistent replication and establishing a reservoir.” Dr. Mercon is an attending physician specializing in infectious diseases at the Cook County Health Department in Chicago.
In other words, the virus integrates into a person's genome, remaining dormant but ready to replicate (or, in other words, make copies of itself) when CD4 cells replicate, or in response to stimuli such as another infection. Meanwhile, circulating HIV cells are constantly replicating.
If left untreated for several years, HIV infection usually progresses to acquired immunodeficiency syndrome (AIDS), meaning that CD4 cell counts have dropped below 200 cells/mm3. At this level, HIV-positive individuals are vulnerable to opportunistic infections and certain types of cancer.
What is a long-term non-progressor?
There is another group of HIV-positive individuals that is frequently studied: long-term non-progressors. These individuals can remain disease-free, with normal CD4 counts, for a period of seven to ten years and, at the same time, have a viral load below approximately 10,000 copies/mL.
Characteristics of HIV controllers and non-progressors
Elite HIV controllers and long-term non-progressors block HIV through a variety of mechanisms, including the following:
* Protective variants in the human leukocyte antigen (HLA)-1 molecule. These variants can better recognize HIV and direct the immune system to attack it.
* A strong synergistic relationship exists between CD4 helper T cells and CD8 cells. The latter are highly effective at finding and eliminating HIV-infected cells.
* Genetic mutation in the HIV CCR5 receptor, located on the surface of immune cells, including T cells. These mutations block HIV from entering the body. These mutations prevent HIV from entering cells.
* Exposure to defective HIV cells that cannot replicate. Another possibility is that the virus inserts itself into non-coding regions of the T cell's DNA and never causes damage.
Can elite air traffic controllers transmit HIV?
A recent review shows that even at 1,000 viral copies/mL, HIV transmission during sexual intercourse is virtually nonexistent. Given the consistently low viral load of elite HIV controllers, Marconi and Mercon agree that it is highly unlikely these individuals could transmit the virus.
In the past, people living with HIV were referred to as “HIV carriers” because it was believed that even elite carriers could transmit the virus, even if they showed no signs of HIV-related illness. TheBody no longer uses the term “carrier” because it stigmatizes people living with HIV.
Can HIV suppressants cause progression?
A landmark U.S. Department of Defense study, co-authored by Marconi, followed 25 elite air traffic controllers for an average of 7.8 years. During that time, none died, and only one developed AIDS. Mercon adds that very few people labeled as elite controllers have returned to his practice 30 years later with signs of disease progression.
However, not all elite drivers are the same. “Some may have other risk factors. In a single-center study that followed 59 elite drivers for an average of 17 years, only 16.9% did not experience any progression.”
HIV Control
Guidelines from the U.S. Department of Health and Human Services, as well as the British HIV Association, recommend that clinicians offer antiretroviral therapy (ART) to all HIV-positive individuals. Starting HIV treatment blocks many of the enzymes (proteins that accelerate biochemical reactions) that HIV uses to enter T cells and prevents HIV from multiplying.
Generally, Mercon says, achieving an undetectable viral load through ART is the best way to prevent HIV progression and transmission. “If you’re living with HIV,” he adds, “you already have a condition that creates an underlying inflammatory response in your body.” To reduce cardiovascular risk, you should avoid other triggers of inflammation, such as smoking and obesity. And don’t neglect routine cancer screenings.
Do HIV controllers need medication?
As our understanding of the dynamics of long-term HIV control increases, Marconi says, experts recommend treating elite HIV suppressants if:
* The viral load exceeds 1,000 copies/mL.
* The viral load ranges from 50 to 1,000 copies/mL, but the CD4 count or the CD4/CD8 ratio decreases.
* The viral load "jumps" or spikes to detectable levels and remains there, with a decrease in the CD4 count or ratio.
* Clinical HIV disease appears or inflammatory markers are elevated.
HIV controllers with undetectable viral loads and CD4 counts below 500 cells/mm3 need close monitoring and possibly treatment for non-HIV-related comorbidities, says Marconi. “You don’t necessarily have to start [HIV] treatment. But if you see cancer in that setting, start ART.”
Some research suggests that people with elite HIV control may have higher rates of comorbidities such as cardiovascular disease. Although research on this remains inconclusive, Marconi says that most of the elite controllers he knows have chosen treatment for such reasons. While he has no evidence that elite controllers transmit HIV, he adds, some might choose treatment for preventative purposes.
Future perspectives and treatments
For people living with HIV, prevention and treatment are becoming increasingly straightforward. Options under development include longer-acting oral and injectable medications, more immunotherapy and therapeutic vaccines, and targeted gene therapy, similar to that used in cancer, although that is still some way off, says Mercon.
Some approaches involve killing all affected cells, as chemotherapy does, and then introducing immunomodulatory drugs. Other strategies involve training the immune system to respond more effectively to HIV.
According to the National Institutes of Health, promising strategies include reactivating latent HIV so the immune system can attack it and permanently silencing HIV in infected cells. Other treatments under development include immune cells genetically modified to resist HIV infection.
Treatments based on broadly neutralizing antibodies (bNAbs) found in untreated HIV controllers are also being developed. While antiretroviral therapy cannot eliminate HIV from infected cells, bNAbs can block HIV replication and eliminate infected cells.
Thus, although very few people can control HIV spontaneously or naturally, these special people can provide a roadmap to HIV prevention, treatment, and cure for many other HIV-positive people.