CROI 2016 Abstract eBook

Abstract Listing

Oral Abstracts

127

Visualizing the Early Events of Antigen Recognition by B Cells Facundo Batista , Francis Crick Inst, London, UK

B lymphocytes form an integral part of the immune system via the production of specific antibodies and by establishing immunological memory enabling a swift an effective response to pathogenic assault. To fully understand the processes whereby this is achieved, it is essential to gain a comprehensive understanding of the events involved in B cell activation and antibody production. This is initiated by the encounter with and acquisition of cognate antigen by the B cell receptor (BCR); processes occurring primarily in secondary lymph nodes (SLOs) such as the lymph node (LN) and which are regulated by complex systems. The functionality of these systems is strictly dependent on maintaining the architecture of the SLOs. During this talk I will describe how the LN structure enables the early encounter of B cells with antigen. Antigenic properties such as the size and nature of the pathogen affect the specialized lymph node antigen delivery systems that exist in readiness to deliver pathogen-derived antigen to B cells. This variability in the types of encounter enables the most appropriate response for that particular antigen to occur, giving the maximal protection to the host. Lastly, the consequences of the disruption of the LN architecture on the immune response will also be described. Its critical role in the immune response is evident following infection, which causes a temporary disruption in the cellular organization of lymphoid organs leading to a reduction in immune responses against subsequent challenge until such time as the LN architecture is restored. 128 Lymph nodes (LN) which are the sentinels of the immune system, are the site where lymphocytes engage cognate antigen and become activated. How antigen localizes to the lymph node and is “seen” by B and T cells is still not entirely clear; although it is apparent that follicular dendritic cells (FDC) are essential for retention of B cell antigens in germinal centers. Recently, we identified a novel mechanismwhereby FDC take-up complement opsonized immune complexes (IC) via the CD21 receptor and cycle the complexes in a non-degradative endosomal compartment ( Heesters et al 2013 Immunity ). Early studies identified Human Immunodeficiency Virus (HIV) viral particles associated with FDC in the B cell follicles; where they are bound via complement receptor 2 (CD21) and/or Fc Receptors; but are not thought to become productively infected. Whether FDC act as a reservoir for infectious virus has been debated in the literature for over two decades. We propose that FDC retain infectious HIV virus similar to that identified for complement opsonized IC. Despite the success of antiretroviral therapy (ART), it does not cure HIV as discontinuation of treatment results in viral rebound. We found that human FDC isolated from LNs of patients on ART retain infectious HIV within a non-degradative cycling compartment and transmit infectious virus to uninfected CD4+ T cells in vitro . Importantly, treatment of the HIV+ FDC with soluble complement receptor 2 Ig fusion protein (sCD21-Ig) purges the FDC of HIV virions and prevents viral transmission in vitro . Our results provide an explanation for how FDC can retain infectious HIV for extended periods and suggest a therapeutic strategy to limit this potential viral reservoir in HIV+ individuals. 129 Imaging Lymphoid Tissues to Understand Viral Persistence and Impaired Function Jacob D. Estes , Frederick Natl Lab, Leidos Biomed Rsr, Frederick, MD, USA A primary obstacle to curing HIV infection is the early establishment of long-lived viral reservoirs fromwhich infection rebounds if antiretroviral therapy (ART) is interrupted. There is currently considerable effort directed to devising strategies to eliminate or greatly reduce these reservoirs so it would be possible to discontinue ART for extended or indefinite periods of time, referred to as a functional cure. To date, these strategies have largely been assessed by monitoring changes in T cell HIV reservoirs from peripheral blood (PB), but the lymphoid tissues (LT) are the major tissue compartments where latently and persistently infected cells reside and infectious virus persists on the follicular dendritic cell network (FDCn) in lymphoid follicles. Because HIV is primarily a disease of lymphoid tissues, a detailed understanding of HIV reservoir establishment and persistence is particularly difficult to study in humans but can be readily studied in SIV nonhuman primate (NHP) models. These NHP models have been invaluable in understanding the timing of viral seeding, viral dynamics and compartmentalization, and cell populations involved in viral persistence within LTs. These studies have highlighted B cell follicles in viral persistence both before and during ART, with infected T FH cells and viral particles bound to the FDCn as potentially important cells harboring infectious virus. Novel strategies to purge virus from these tissues may be hindered by the pathologic damage to these immune organs induced by persistent chronic inflammation and immune activation, which leads to a profound impairment of normal lymph node function. Adjunctive strategies to reverse LT damage will likely need to be considered to realize the full potential of HIV cure therapeutic approaches, which will need full access to these important immune organs where most HIV reservoirs reside. 130 The Lymph Node, Cytotoxic T cell, and HIV/SIV Infections Elizabeth Connick , Univ of Colorado, Denver, CO, USA HIV-specific CTL partially, but incompletely suppress virus replication in most infected individuals. Multiple mechanisms have been invoked to explain the failure of CTL to fully suppress virus replication including numerical and functional deficiencies. Whether there is an immune privileged site that is impervious to CTL has not been fully explored. In asymptomatic disease, HIV replication is concentrated in T follicular helper cells (TFH) located within B cell follicles (F) of secondary lymphoid tissues including lymph nodes, spleen, and GALT. In lymph nodes from untreated people, HIV-specific CTL fail to accumulate within F. In the SIV-infected rhesus macaque model, virus replication during chronic, asymptomatic disease is similarly concentrated in F of all lymphoid tissues and SIV-specific CTL fail to accumulate in large numbers. Compartmentalization of virus replication within lymphoid tissues appears related to CTL distribution. Frequencies of virus-specific CTL in F and extrafollicular (EF) compartments of lymph node and spleen of SIV-infected macaques predict SIV RNA+ cells within these compartments. In simian AIDS, when CTL are often numerically deficient, the follicular concentration of virus replication is attenuated. In acute infection, prior to when CTL exert substantial effects on virus replication, as well as in chronically infected animals after CD8 depletion, SIV RNA+ cells are wide spread and not concentrated in F. Thus, EF cells are capable of replicating virus, but virus replication is efficiently suppressed in themwhen CTL are present. Substantial differences in perforin or granzyme B expression are not evident between F and EF CTL in chronic SIV infection. Frequencies of SIV RNA+ cells increase modestly within F after CD8 depletion, suggesting that the few CTL present in F exert antiviral activity. Few SIV-specific CTL express the follicular homing molecule CXCR5 in the absence of the extrafollicular retention molecule CCR7, which likely accounts for their failure to home to B cell follicles and suppress virus replication. Thus, B cell follicles are immune privileged sites that shield TFH from CTL killing and are exploited by HIV and SIV, and likely other infections and malignancies. Strategies to induce migration of virus-specific CTL into B cell follicles, such as CTL transduction with CXCR5, could lead to improved viral control and possibly a functional cure for HIV. 131 Tuberculosis: Why Do I Have to Take So Many Pills? Eric J. Rubin , Harvard Sch of PH, Boston, MA, USA Tuberculosis has two characteristics that are central to the therapy of disease and the prevention of spread. One, latency, or infection without clinically apparent disease, creates a large reservoir fromwhich new cases of TB can appear and spread. The other, the slow response of active disease to treatment, creates a need for a large and expensive infrastructure to ensure completin of drug therapy. While both of these issues have long been recognized, new insights suggest possible underlying mechanisms and, perhaps, new strategies to subvert each of these problems. 132 The Evolving Epidemiology of HIV Infection in Persons Who Inject Drugs: Indiana 2015 John T. Brooks , CDC, Atlanta, GA, USA This session is directed to clinicians and scientists interested in the evolving epidemiology of HIV infection among persons who inject drugs. It is assumed participants are familiar with the principles of HIV transmission, its control, and the epidemiology of HIV infection in the United States. At completion of the session, participants will understand how to prevent potential outbreaks of HIV infection among new populations of persons who inject drugs, and to recognize and respond to an outbreak should one occur. Are Follicular Dendritic Cells a Reservoir for HIV? Michael C. Carroll , Harvard Univ, Boston, MA, USA

Oral Abstracts

49

CROI 2016