Chronic inflammation means the immune system is imbalanced—a natural immune response has persisted, or immune regulation is not working properly. Research has shown that individuals living with HIV, even those with treatment-suppressed viral loads, have higher levels of inflammation than those who are HIV-negative. There is evidence too that inflammation and its effects become more exacerbated if individuals have experienced more pervasive immune system damage before antiretroviral initiation. Chronic inflammation in HIV-positive individuals has been associated with cardiovascular disease, cancers, and other non-AIDS-related conditions. Addressing chronic inflammation in treated individuals is especially important as they grow older and/or face premature manifestations of aging-related conditions.
In the article, “Systemic Effects of Inflammation on Health during Chronic HIV Infection,” published in Immunity (2013), researchers Steven G. Deeks et al. outline what may initiate inflammation, including but limited to T-cell activation caused by HIV replication/production or other pathogens; “HIV-mediated breakdown in the gut mucosa and chronic exposure to gut microbial products like lipopolysaccharide”; and immune-regulation dysfunction. “Antiretroviral therapy partially reverses many if not all of these proinflammatory pathways, but the effect is incomplete, and inflammation persists indefinitely,” the researchers state. Proinflammatory risk factors include antiretroviral toxicity, substance abuse, social isolation, and polypharmacy (using multiple drugs simultaneously to treat one illness or more).
A five-year $1.59 million NIH grant has been awarded to researchers at Case Western Reserve University, led by Dr. Pushpa Pandiyan, an assistant professor of biological sciences at the School of Dental Medicine, to study chronic inflammation in individuals living with HIV in the context of immune regulation dysfunction. The goal is to learn more about how to restore balance to immunity that has been changed by HIV and its treatment. How to replenish beneficial white blood cells while reducing dysfunctional ones remains one of the central questions, as well as what can be learned based on which cells are studied.
In an earlier article, “Mucosal Regulatory T Cells and T Helper 17 Cells in HIV-Associated Immune Activation,” published in Frontiers in Immunology (2016), Dr. Pandiyan and her team pointed out that “… the majority of research on immune activation has been derived from analysis of circulating T cells. How immune cell alterations in mucosal tissues contribute to HIV immune dysregulation and the associated risk of non-infectious chronic complications is less studied. Given the significant differences between mucosal T cells and circulating T cells, and the immediate interactions of mucosal T cells with the microbiome, more attention should be devoted to mucosal immune cells and their contribution to systemic immune activation in HIV-infected individuals.”
The new research continues a focus on T regulatory cells, one type of white blood cell, in particular (Tregs) located in oral tissue. In one earlier study, Dr. Pandiyan has shown that pathogens can affect Tregs in such a way that they prolong inflammation.
Controlling Tregs depends on understanding them. Notes Dr. Pandiyan about the oral-specific focus: “The whole idea is get information about tissue/mucosal Tregs. Oral mucosa and oral tissue biopsies are more accessible for studying mucosal immunity, than the gut, colon and rectal biopsies.”
Questions remain about mechanisms with Tregs that cause them not to function properly—producing too many or too few of certain Tregs—and disrupt immune balance. “There are a variety of immune factors that could influence their survival and functions. These factors can change depending on the location (for example, tissue vs. blood) and the type of disease. We currently have no understanding about this in context of HIV and other diseases. We are trying to address this in the context of oral tissue-related disease.”
Additionally, chronic inflammation in oral sites, if it persists, can cause pernicious, negative health outcomes, such as oral cancer, lesions, or viral infections that cause malnourishment because they make eating painful. Oral conditions produced by immune system imbalances, caused by HIV and its treatment, have been found in more than a third of individuals being treated for HIV.
“Previous research shows that oral health has significant effects on systemic autoimmunity and inflammation,” shares Dr. Pandiyan.
As the treatment paradigm has shifted beyond addressing immunodeficiency to include addressing the negative health outcomes associated with chronic inflammation, researchers seek to provide agents that extend and improve the lives of individuals living with HIV. Previous research by Dr. Pandiyan has shown how specific Tregs can be tailored in vitro to boost or suppress proteins’ that help the cells’ survival and then reintroduced to the body to help restore immune balance.
Notes Dr. Pandiyan:“We believe that studying local immunity will pave new and improved ways of disease treatment targeting specific tissue inflammation, and thus lead to precision medicine.”
Chael Needle is Managing Editor of A&U. Follow him on Twitter @ChaelNeedle.