PURPOSE OF THE STUDY.
A small percentage of HIV-infected patients (elite controllers, EC) appear to be capable of controlling HIV replication, and this is most likely mediated by CD8+ cytotoxic T cells. T follicular helper cells (TFH) are antigen-specific CD3+ CD4+ “helper” T cells that are localized to B-cell follicles of peripheral lymphoid tissue, such as lymph nodes. They are characterized by specific surface antigen expression (PD-1, CXCR5, CD200, ICOS), a specific transcription factor (Bcl6), and specific functions (generation and maturation of antibody responses). In 2012, Perreau et al reported that TFH cells serve as the major CD4+ T-cell compartment for HIV infection, replication, and production (J Exp Med. 2013;210(1):143–156). The purpose of this study was to test in a simian model of HIV infection the hypothesis that immunologic control of retroviral replication depends upon CD8+ T-cell containment of simian immunodeficiency virus (SIV) replication, and that TFH cells present in B-cell follicles represent a primary reservoir for replicating retrovirus.
Fifty purpose-bred adult rhesus macaque monkeys were used in this study.
The equivalent of “elite controllers” was generated in a simian model by immunizing a population of monkeys with live attenuated SIV. The investigators then studied wild-type SIV replication in these EC monkeys and in monkeys infected with wild-type virus but treated with combination antiretroviral therapy.
The investigators confirmed the previous findings that restriction of SIV replication in EC monkeys was mediated by CD8+ T cells. Furthermore, replication-competent wild-type virus was highly restricted to a minor population of TFH cells. Histiologic analysis demonstrated that 95% of productively infected cells in the lymph nodes were localized within B-cell follicles from which CD8+ T cells were largely excluded. In EC monkeys depletion of CD8+ T cells with monoclonal antibodies resulted in markedly increased plasma viral loads that then decreased as CD8+ T cells recovered. Finally, it was shown that TFH cells within B-cell follicles are the primary source of ongoing productive infection in monkeys that are treated with combination antiretroviral therapy.
B-cell follicles constitute sanctuaries for persistent SIV replication in the presence of potent antiviral CD8+ T-cell responses, potentially complicating efforts to cure HIV infection with therapeutic vaccination or T-cell immunotherapy.
TFH cells, little known outside the immunology community, play a major role in the persistence of replicating retroviruses including HIV and SIV. “Sanctuaries” for replication competent HIV/SIV have long been known to exist, yet their location has not been identified definitively. The results of the present work suggest that TFH cells in B-cell follicles represent an important source of replication competent virus even when potent CD8+ T-cell immunity is present. This occurs because CD8+ T cells are essentially excluded from B-cell follicles as they lack the chemokine receptor required for trafficking to these areas. These findings have major implications for current attempts to cure HIV infection. For example, a strategy based on generating HIV-specific CD8+ cytotoxic T cells either through therapeutic vaccine or cytotoxic T-cell engineering must address the issues raised in this report.
- Copyright © 2015 by the American Academy of Pediatrics