Why HIV Progresses Slower in Some People Than Others

Genetics, Demographics Provide Insights into Long-Term HIV Non-Progression

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In the presence of any infective agent (pathogen), our body can respond in two fundamental ways: it can either actively resist the pathogen or tolerate it. 

Pathogenic resistance implies an immune defense by which the body attacks and neutralizes the pathogen. By contrast, pathogenic tolerance is the state by which the body doesn't fight the pathogen but simply minimizes the damage done by it.

By actively tolerating the pathogen—in essence, living with the pathogen rather than lodging an all-out attack—the disease tends to progress very slowly in the infected individual even when the pathogen load is high.

In people with low disease tolerance, the body remains in a perpetual state of high alert, constantly producing antibodies and defensive T-cells in response to the pathogen (including CD4 T-cells which trigger the immune response).

By doing so, a disease like HIV can progress far more quickly since there are, among other things, more CD4+ T-cells to infect. Gradually, as HIV manages to wipe out these "helper" T-cells, the immune system is compromised to such a degree as to render it defenseless. 

People with high tolerance are able to modulate the immune response, often allowing for minimal or no expression of the disease over the medium to long term.

Understanding HIV Tolerance

HIV tolerance is still not very well understood but increasing research has given scientists a glimpse into why some individuals cope with the virus better than others.

In September 2014, researchers from the Swiss Federal Institute of Technology in Zurich reviewed data from the ongoing Swiss HIV Cohort Study, started in 1988, and looked specifically at 3,036 patients to establish the relationship between the patient’s set-point viral load (i.e., where the viral load stabilizes after acute infection) and their decline in CD4+ T-cells.

In doing so, the researchers were able to quantify both the individual’s resistance to HIV (as measured by the viral load) and tolerance to HIV (as measured by rate of CD4 decline). Simply put, the slower the rate of decline, the greater a person’s tolerance to HIV.

By combining these values with the patient's demographics and genetic makeup, the scientists hoped to find some commonalities by which to pinpoint the precise mechanism(s) associated with HIV tolerance.

What the Researchers Learned

While the research established no difference in how well men and women tolerated HIV (despite women having an almost two-fold lower viral set-point), age did play a significant role, with tolerance gradually waning as a person aged from 20 to 40 and then even further from age 40 to 60. In fact, by the time an individual reached the age of 60, the disease was seen to progress at almost twice the rate as that of a 20-year-old.

The research also demonstrated that there was no clear relationship between HIV resistance and tolerance in an infected individual—that tolerance and resistance would work either independent of each other or in tandem. In rare cases where they did operate in tandem, wherein a low viral set-point was accompanied by a slow CD4 decline, disease progression was often so slow as to define that person as a elite controller, able to tolerate HIV for years and even decades without the use of antiretroviral drugs.

In looking at hereditary factors, the researchers were also able to determine that genetics played absolutely no part in how well a person either tolerated or resisted HIV, confirming each as a distinct biological mechanism.

What they did find, however, was that one specific gene, the HLA-B, did have a strong association with HIV tolerance/resistance. The gene, which provides instruction for making proteins key to an immune response, was seen to vary considerably among the HIV-infected cohort. Some of the HLA-B variants (alleles) conferred to stronger resistance to HIV, while others variants correlated to greater tolerance.

Moreover, in individuals expressing the same variant of the HLA-B gene (homozygotes), disease progression was seen to be faster. The opposite was seen in those with two different genetic variants (heterozygotes). While the observational data is compelling, it is still not entirely clear how these hereditary factors influence this particular phenomenon.

The researchers also suggested that certain HLA-B alleles can cause faster disease progression by keeping the body in a state of ongoing immune activation, resulting in a persistent inflammation that can damage multiple organ systems over the long term.

By better understanding these genetic mechanisms, it is theorized that scientists may eventually be able to modulate them, allowing individuals to tolerate HIV infection better while minimizing the damage caused by persistent immune activation/chronic inflammation.


Regoes, R.; McLaren, P.; Battegay, M.; et al. "Disentangling Human Tolerance and Resistance Against HIV." PLoS|Biology. September 16, 2014; 12(9): e1001951.

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