An exciting answer to a persistent question

February 23, 2015

February's featured paper is called "B cell follicle sanctuary permits persistent productive simian immunodeficiency virus infection in elite controllers," published in Nature Medicine. The paper is published by a team from the Picker Lab.

The Human Immunodeficiency Virus (HIV) causes acquired immunodeficiency syndrome (AIDS), a condition characterized by progressive failure of the immune system.

HIV infects important cells in the immune system, particularly CD4+ T cells. Loss of CD4+ T cells leads to loss of cellular immunity and increased susceptibility to opportunistic infections. HIV cannot be immunologically cleared from the system and in the absence of anti-retroviral therapy (ART), the vast majority of infections will ultimately lead to AIDS. ART can stop HIV replication but cannot eliminate the virus; cessation of ART invariably leads to a rebound of the infection.

A very small fraction of individuals, sometimes called "elite controllers," do not suffer from falling CD4+ T cell levels after infection with pathogenic HIV, even in the absence of ART. Rather, these individuals develop immune responses to the virus that lower the level of viral replication by as much as 10,000-fold compared to typical infections. 

Despite this robust immune response, the virus is still able to manifest continuous rounds of productive infection, albeit at much lower levels than in typical infections. This residual viral replication, however, causes persistent inflammation, which over time can be deleterious to multiple organ systems, and provides for viral evolution with the potential for immune escape and resumption of progressive infection.   


Role of B cell follicles

Why do these strong immune responses fail to establish a fully latent infection? This month's selected paper provides new evidence that the answer may be hiding inside B cell follicles. Published in the journal Nature Medicine, the article "B cell follicle sanctuary permits persistent productive simian immunodeficiency virus infection in elite controllers" provides an exciting answer to this persistent question.

Louis Picker, M.D., associate director of the OHSU Vaccine and Gene Therapy Institute, has been studying HIV using a monkey analog Simian Immunodeficiency Virus (SIV). "We previously demonstrated that monkeys infected with live attenuated SIV (LAV) developed a very effective immune response that brought LAV replication down to very low levels," said Dr. Picker.  "When exposed to wildtype SIV, these monkeys were protected against infection. Despite this remarkable response, the monkeys were unable to completely eradicate LAV from their systems."

Previous work by the Picker laboratory had shown that LAV replication persists in a particular type of CD4+ T cell, called follicular helper T cells (TFH), located in the B cell follicles of the lymph node.  "While there might be many reasons for the restriction of LAV replication to follicular helper T cells," said Dr. Picker, "one intriguing possibility is that the B cell follicles in which TFH are located provide the virus with a protective barrier against virus-specific CD8+ cytotoxic T cells."

"We found that during the first several weeks of LAV infection, viral infection was distributed in both CD4+ TFH and non-TFH cells (e.g., both inside and outside the B cell follicle). Restriction of viral replication to the TFH occurred only after the onset of immune control," said Dr. Picker. "Next we showed that among monkeys with typical progressive infection with pathogenic SIV, productive infection was again found in both CD4+ TFH and non-TFH cells, implying that there was no viral reason for preferential TFH infection."   

Major step forward

The Picker lab confirmed this when they found that "elite controller" monkeys with enhanced CD8+ T cell mediated control showed stringent restriction of productive infection to the CD4+ TFH within B cell follicles.  "This suggests that potent anti-viral CD8+ T cell responses present in elite controller monkeys are able to stop productive infection in CD4+ T cells outside, but not inside, of the B cell follicles," said Dr. Picker.  "In fact, depleting CD8+ lymphocytes with an antibody resulted in a dramatic re-distribution of productive SIV infection to CD4+ non-TFH cells, and when CD8+ T cells recovered the productive infection was once again restricted to CD4+ TFH cells. This indicates that B cell follicles are 'sanctuaries' for persistent SIV replication in the presence of anti-viral CD8+ T cell responses."     

"This study identifies TFH as the location of productive AIDS virus infection in the setting of immunologically controlled viral replication – more importantly, it represents a major step forward in understanding viral reservoirs and will help us develop more targeted approaches to virus elimination," said Dr. Picker.

"How can you not be excited by this work?" said Mary Heinricher, Ph.D., assistant dean for basic research.  "This paper makes me appreciate the years and years of basic science work that came together in this truly translational and transformational finding," she added. 

So what exactly does this mean for future treatment of HIV? The Picker study also found that residual productive infection in SIV-infected monkeys treated with highly effective ART  was also preferentially found in B cell follicles.  "This indicates that the 'sanctuary' will almost certainly complicate efforts to cure HIV infection with vaccination or T cell immunotherapy," said Dr. Picker.  "We will need to identify mechanisms to circumvent the B cell follicle sanctuary so that CD8+ T cells can more effectively eliminate all productively HIV/SIV-infected CD4+ T cells. The overall goal is development of approaches that will contribute to HIV cure." 



B cell follicle sanctuary permits persistent productive simian immunodeficiency virus infection in elite controllers

Yoshinori Fukazawa, Richard Lum, Afam A Okoye, Haesun Park, Kenta Matsuda,   Jin Young Bae, Shoko I Hagen, Rebecca Shoemaker, Claire Deleage, Carissa Lucero, David Morcock, Tonya Swanson, Alfred W Legasse, Michael K Axthelm, Joseph Hesselgesser, Romas Geleziunas, Vanessa M Hirsch, Paul T Edlefsen, Michael Piatak Jr, Jacob D Estes, Jeffrey D Lifson & Louis J Picker

Nat Med. 2015 Feb;21(2):132-9. doi: 10.1038/nm.3781. Epub 2015 Jan 19.

More Published Papers

Pictured above from left to right: Yoshinori Fukazawa, Louis Picker

About the School of Medicine Paper of the Month

The OHSU School of Medicine spotlights a recently published faculty research paper each month. The goals are to describe to the public the exceptional research happening at OHSU as well as inform our faculty of the innovative work underway across the school’s departments, institutes and disciplines. The monthly paper is selected by Assistant Dean for Basic Research Mary Heinricher, Ph.D.