Mucosal Antiviral Immunity

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Left to right: Tim Borbet, Malu Robles, Benjamin Cohn, Shomyseh Sanjabi, Shahzada Khan, Julie Luong

Our vision:
In the Sanjabi Lab, our vision is an HIV-free world. To this end, we embrace the challenge of functionally curing infected individuals and generating an effective preventative HIV vaccine.

Our mission:
To better define the mechanisms and factors that govern the innate and adaptive immune responses in the female reproductive tract and the rectum, the portals of viral entry during sexual viral transmission.

The problem:
The HIV epidemic has posed one of the biggest social, economic, and scientific challenges of our time. We have come a long way to save many lives, but must now embrace the next set of challenges in this field: to functionally cure infected individuals and develop an effective HIV vaccine. However, after more than 25 years of focused research, only a handful of people have been cured and we still lack a successful HIV-preventative vaccine. Making a significant leap toward these goals will require testing new hypotheses and developing innovative tools.

The main barrier to complete elimination of HIV is a small proportion of latently-infected cells that harbor a transcriptionally silent but stably integrated HIV genome, thus allowing HIV to evade both the immune system and HAART. The reservoir of latent cells is long-lived and often resides in both lymphoid and non-lymphoid peripheral tissues. The field is now focused on discovering methods to specifically target and reactivate this latently infected pool in the hope of purging the virus and infected cells from the immune system. However, the exact identity of these latently infected cells remains unknown, which is posing a huge challenge to curing infected individuals.

The best solution to the HIV epidemic is to develop a protective vaccine. Protective immunity requires pathogen-specific neutralizing antibodies and systemic as well as resident memory CD8+ cytotoxic T lymphocytes (CTLs) in mucosal tissues to immediately clear infected cells before the virus systemically disseminates. In non-human primates, the natural CTL response is “too little and too late” to prevent systemic infection by simian immunodeficiency virus (SIV). Although the exact mechanism of this delayed and dampened antiviral immune response is unknown, vaccines that induce mucosal responses — in particular, strong CTL responses at the portal of viral entry — control viral replication and limit systemic dissemination. Thus, the goal of a protective vaccine in humans is to induce an immune response stronger than that elicited against natural infections.

Our approach:
To understand mucosal immunity in elite controllers
A small number of human immunodeficiency virus (HIV)-infected individuals called “elite controllers” maintain low levels of HIV RNA and high CD4+T-cell counts without antiretroviral therapy. Genome-wide association studies have correlated their immune response with certain human leukocyte antigen (HLA) class I alleles. As HLA class I molecules activate CD8 T cells by presenting viral peptides, the mechanisms governing elite HIV control are likely mediated at the level of antigen presentation and recognition by the immune system. In support of this, elite controllers have a more polyfunctional repertoire of CTLs specific for early viral antigens than other infected individuals. We believe that understanding how virus-specific CD8 T cells are primed and activated in the mucosal tissues of these individuals will inform the knowledge needed to develop a vaccine that can elicit a similar immune response in individuals without the protective genetic background. To this end, we are generating small-animal models that recapitulate the immune systems of the elite controllers and non-controllers. We hope to achieve this by generating human induced pluripotent stem (hiPS) cells from well-characterized HIV elite controllers and non-controllers and differentiating the hiPS cells into CD34+ hematopoietic precursor cells in vitro. The resulting cells will be engrafted into a new humanized mouse model, in which several mouse genes have been replaced with their human counterparts to promote human hematopoietic stem cell survival and differentiation. Our goal is to dissect the early innate and adaptive immune responses that are elicited after mucosal HIV transmission and to also determine how the latent reservoir is differentially formed in these small- animal models.

To define how the tolerogenic mucosal environment can act as a barrier to an effective immune response
Eliciting protective immunity in mucosal tissues is challenging, as these environments are inherently tolerogenic. As a first step toward a better understanding of how tolerance and immunity are induced at the portals of entry for sexually transmitted pathogens, we have established vaginal and rectal models of lymphocytic choriomeningitis virus (LCMV) infection in conventional mice. Using our mucosal LCMV models, we are comparing how mucosal and systemic LCMV infections differ in terms of innate and adaptive immune activation. We are further dissecting the role of transforming growth factor beta (TGFβ), an abundant and immunosuppressive cytokine in mucosal tissues, in mucosal anti-viral immune responses. Understanding how anti-viral immunity surpasses the inherent mucosal tolerance and how CD8 T cells are activated in this environment will pave the way for enhancing mucosal immune responses during vaccination and for developing novel therapeutics against sexually transmitted pathogens.