The Catch-22 of HIV and Immune Activation

Heightened Immune Response Potentiates HIV by Providing It Targets for Infection

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HIV-1 virions (in yellow) budding from an infected CD4+ T-cell. Photo credit: National Institute of Allergy and Infectious Diseases (NIAID)

When the body is faced an invading pathogen, it usually triggers an immune defense, either innate (meaning non-specific or "first line") or adaptive (acquired after fighting a previous infection). While an immune response is generally considered natural and good, it can actually potentiate HIV by providing it cellular targets for infection.

HIV is unique in its ability to destroy the immune system the more the body tries to defend itself, first by infecting, and then gradually depleting, the very cells meant to spur the attack.

These cells, called CD4+ T-cells, function by signalling defensive, "killer" cells (CD8+ T-cells) to neutralize the invading viruses. While CD4+ T-cells are vital in mounting an immune response, they are also preferentially targeted by HIV, putting into motion a vicious cycle that promotes, rather than inhibits, viral replication.

Known as chronic immune activation, the condition is caused when HIV essentially overstimulates the immune system. Even when viral activity is fully suppressed by way of antiretroviral therapy, the presence of non-replicating HIV in hidden, cellular reservoirs keeps the immune system in this constant, exaggerated state of alert.

The consequences of immune activation are many. Persistent activation can accelerate a T-cell's life cycle to such an extent that it can die prematurely, undergo apoptosis (programmed cell death), or lose its ability to replicate. Moreover, the chronic inflammation associated with prolonged activation not only directly damages tissues, but contributes to the premature aging of cells and the early development of non-HIV-related conditions such as cancer, heart disease and diabetes.

What Are the Exact Causes of Immune Activation?

The precise mechanisms for chronic immune activation are not fully known, but it is strongly believed that a number of interconnected factors contribute to the state.

Many investigators have begun to focus on the impact of HIV on the cells of the intestine, known as the gut.

During early-stage infection, the largest depletion of CD4+ T-cells occurs within the gut, with most of the cells effectively wiped out completely, never to recover. Depletion of these cells allows for pathogenic (disease-causing) bacteria to leak from the intestines, further burdening the immune system.

Others suggest that HIV directly interferes with so-called "regulatory" T-cells (Tregs), which are meant to dampen the immune response once an infection is controlled. It is widely known that, during an HIV infection, there is often an unsteady balance between the beneficial and detrimental effects of Tregs. On the one hand, Tregs can suppress generalized T-cell activation, preventing an exaggerated response. On the other, they can inadvertently contribute to immune deficiency by inhibiting an HIV-specific response.

It is these and other paradoxes that make chronic immune activation the subject of increased medical research. By better identifying the mechanisms for activation, investigators believe that they may one day find the means to not only mitigate the impact of early-stage gut infiltration, but prevent aging-associated morbidities seen in long-term infection.

Sources:

Appay, V. and Sauce, D. "Immune activation and inflammation in HIV-1 infection: causes and consequences."  Journal of Pathology. 2008; 214(2):231-241.

Chevalier, M. and Weiss, L. "The split personality of regulatory T cells in HIV infection." Blood. January 3, 2013; 121(1); doi :10.1182/blood-2012-07-409755.

Deeks, S. and Philips, A. "HIV infection, antiretroviral treatment, ageing, and non-AIDS related morbidity." British Journal of Medicine. January 26, 2009; 338:a3172.

Vásquez-Castellanos, J.; Serrano-Villar, S.; Latorre, A.; et al. "Altered metabolism of gut microbial contributes to chronic immune activation in HIV-infected individuals." Mucosal Immunology. November 19, 2014; doi: 10.1030/mi.2014.107.

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