How Chronic Inflammation Complicates HIV Infection

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Inflammation occurs in the presence of an agent, infection, or event that can hurt the body. With HIV specifically, it's a far more complex issue insofar as the condition has both a cause and an effect. On the one hand, inflammation occurs as a direct response to the HIV infection itself. On the other, a chronic inflammation—one that persists even when a person is on HIV therapy—can inadvertently cause damage to normal cells and tissues unaffected by HIV.

It's a catch-22 that continues to confound scientists and challenge the people living with the disease.

Inflammation Explained

Inflammation is a complex biological process that occurs in response to a pathogen (such as a virus, bacteria, or parasite), as well as exposure to toxic agents or an injury. It's a facet of the body's immune defense, one which aims to repair damaged cells and return the body back to its normal, healthy state.

When an infection or trauma occurs, the body responds by dilating small blood vessel to increase both the blood supply and the permeability of the vascular tissues. This, in turn, causes tissues to swell, allowing blood and defensive white blood cells to rush in. These cells (called neutrophils and monocytes) surround and destroy any foreign agent, thereafter allowing the healing process to begin.

Sometimes inflammation can be localized, as happens with a cut or an insect bite.

At other times, it can be generalized and affect the entire body, as can occur during an infection or certain drug allergies.

Inflammation is typically classified as being either acute or chronic. An acute inflammation is characterized by rapid onset and short duration. With HIV, for example, a new infection can trigger an acute response, often resulting in swollen lymph nodes, flu-like symptoms, and an all-body rash.

By contrast, chronic inflammation continues for prolonged periods of time. Again, we see this with HIV, wherein the acute symptoms resolve but the underlying infection remains. Even though there may be few, if any, symptoms during this chronic stage of infection, the body will continue to respond to the presence of HIV with a continuous, low-level inflammation.

Too Much of a Good Thing?

Inflammation is typically a good thing. But if it goes unchecked, it can turn the body on itself and reap serious damage. The reasons for this are both simple and not-so-simple.

From a broader perspective, the presence of any pathogen will spur an immune response, with the aim of targeting and killing the foreign agent. During this process, normal cells can also be damaged or destroyed. When the process is allowed to continue unabated, as happens with HIV, the inflammatory pressure placed on cells begin to mount.

Worse yet, even when a person is placed on fully suppressive antiretroviral therapy, there will remain an underlying, low-level inflammation simply because the virus is still there. And while this may suggest that inflammation is less of a problem at this stage, it's not always the case.

A recent study of HIV elite controllers (individuals able to suppress the virus without the use of drugs) demonstrated that, despite the benefit of natural control, there was a 77% greater risk of hospitalization due to cardiovascular disease and other illnesses when compared to treated, non-elite controllers.

That the same levels of disease were seen in untreated, non-elite controllers strongly suggest that the body's response to HIV can cause as many long-term consequences as the disease itself.

What we see in persons with a long-term disease are sometimes profound changes to the cellular structure, right down to the deterioration of the genetic coding. These changes are consistent with those seen in the elderly, whereby cells are less able to replicate and begin to experience what we call premature apoptosis (early cellular death). This, in turn, conforms to increased rates of heart disease, cancers, kidney disorders, dementia, and other illnesses commonly associated with older age.

In effect, chronic inflammation, even at low levels, can "age" the body before its time, often by as much as 10 to 15 years.

The Complex Link Between Inflammation and Illness

While researchers are still struggling to understand the mechanisms that cause these adverse events, a number of studies have enlightened us as to the association between chronic inflammation and illness.

Chief among these was the Strategies for Management of Antiretroviral Therapy (SMART) trial, which compared the clinical impact of early HIV treatment versus delayed treatment. One of the things that the scientists found was that, after starting therapy, inflammatory markers in the blood declined but never to the levels seen in HIV-negative people. Residual inflammation remained even when viral suppression was achieved, the levels of which were consistent with increasing rates of arteriosclerosis (hardening of the arteries) and other cardiovascular disorders.

A related study from the University of California, San Francisco further demonstrated a direct correlation between the thickness of arterial walls in people with HIV and the levels of inflammatory cells in their blood. While individuals on HIV therapy had thinner walls and fewer inflammatory markers when compared to an untreated counterpart, neither approached the "normal" arterial thickness seen in the general population.

Chronic inflammation was seen to have a similar impact on the kidneys, with increased rates of fibrosis (scarring) and kidney dysfunction, as well as on the liver, brain, and other organ systems.

Chronic Inflammation and Life Expectancy

Given the association between chronic inflammation and aging-related illnesses, is it fair to suggest that life expectancy might also be impacted for people living with HIV?

Not necessarily. We know, for instance, that a 20-year-old on HIV therapy can now expect to live into his or her early 70s, according to research from the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD).

With that being said, life spans can be significantly shortened as a result of these non-HIV-associated illnesses. Inflammation is a key contributor, as are treatment status, viral control, family history, and lifestyle choices (including smoking, alcohol, and diet).

The simple fact is this: Inflammation is linked in some way to practically every bad thing that can happen to our bodies. And while people with HIV are living longer and experiencing far few opportunistic infections than ever before, they still have higher rates of heart disease and non-HIV-related cancers than the general population.

By starting treatment early, taking it consistently, and living a more health-conscious lifestyle, many of these risks can be mitigated or even erased. In time, scientists hope to further these aims by finding the means to temper the immune response to better alleviate the long-term stresses of inflammation.

Sources:

Deeks, S. Tracy, R. and Doeuk, D. "Systemic Effects of Inflammation on Health during Chronic HIV Infection." Immunity. March 17, 2013; 39(4):633-645.

Crowell, T. Gebo, K. Blankson, J. et al. "Hospitalization Rates and Reasons among HIV Elite Controller and Persons With Medically Controlled HIV." Clinical Infectious Diseases. December 15, 2014; doi: 10.1093/infdis/jiu809.

Duprez, D. Neuhaus, J. Kuller, L. et al. "Inflammation, Coagulation and Cardiovascular Disease in HIV Positive Individuals" PLOS One. September 10, 2012; DOI: 10/1371/journal.pone.0044454.

Hogg, R. Althoff, K. Samji, H. et al. "Closing the Gap: Increases in life expectancy among treated HIV-positive individuals in the United States and Canada, 2000-2007." 7th International AIDS Society (IAS) Conference on Pathogenesis, Treatment and Prevention. Kuala Lumpur, Malaysia. June 30-July 3, 2013; Abstract TUPE260.

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