Research Article: Low levels of SIV-specific CD8+ T cells in germinal centers characterizes acute SIV infection

Date Published: March 21, 2019

Publisher: Public Library of Science

Author(s): Shengbin Li, Joy M. Folkvord, Katalin J. Kovacs, Reece K. Wagstaff, Gwantwa Mwakalundwa, Aaron K. Rendahl, Eva G. Rakasz, Elizabeth Connick, Pamela J. Skinner, Guido Silvestri.

http://doi.org/10.1371/journal.ppat.1007311

Abstract

CD8+ T cells play an important role in controlling of HIV and SIV infections. However, these cells are largely excluded from B cell follicles where HIV and SIV producing cells concentrate during chronic infection. It is not known, however, if antigen-specific CD8+ T cells are excluded gradually as pathogenesis progresses from early to chronic phase, or this phenomenon occurs from the beginning infection. In this study we determined that SIV-specific CD8+ T cells were largely excluded from follicles during early infection, we also found that within follicles, they were entirely absent in 60% of the germinal centers (GCs) examined. Furthermore, levels of SIV-specific CD8+ T cells in follicular but not extrafollicular areas significantly correlated inversely with levels of viral RNA+ cells. In addition, subsets of follicular SIV-specific CD8+ T cells were activated and proliferating and expressed the cytolytic protein perforin. These studies suggest that a paucity of SIV-specific CD8+ T cells in follicles and complete absence within GCs during early infection may set the stage for the establishment of persistent chronic infection.

Partial Text

Most human immunodeficiency virus (HIV)-infected individuals fail to adequately control persistent high-level viral replication that results in gradual loss of CD4 T cells and ultimately AIDS in the absence of antiretroviral therapy (ART). B cell follicles in secondary lymphoid tissues have been identified as important sanctuaries that contain large amounts of virus-producing cells during chronic HIV and simian immunodeficiency virus (SIV) infection [1–5]. CD4+ T follicular helper (TFH) cells, a population that mainly resides in B cell follicles, serve as a major site of productive HIV and SIV replication during the chronic phase of infection [1,2,4,6–8]. In SIV-infected rhesus macaques that control viral replication, either via a natural highly effective immune response or receiving long-term, fully suppressive ART, residual productive SIV infection is strikingly restricted to TFH cells [9]. In HIV infected aviremic individuals treated with long-term ART, TFH also serves as a major reservoir for active and persistent virus transcription [10]. Therefore, understanding the immune activity needed to kill virus-infected TFH cells in B cell follicles is necessary for developing novel therapies to fully eradicate HIV or SIV infection.

Eradication of HIV-infected cells in vivo remains a critical obstacle to cure HIV infection. B cell follicles are major anatomical reservoirs that permit active HIV and SIV replication during chronic infection [2,3,9]. However, virus-specific CD8+ T cells generally fail to accumulate in high frequency in B cell follicles [2,3,20,21]. The ongoing viral replication in B cell follicles during chronic infection is likely due, at least partially, to the paucity of follicular anti-viral CD8+ T cell responses [1–3,9,44]. It is not known whether this phenomenon also occurs during early stages of infection. Here, we determined the location, abundance, and phenotype of SIV-specific CD8+ T cells in follicular and extrafollicular regions during early SIV infection. We found that few follicles had GCs at 14 dpi and many follicles had GCs at 21 dpi, suggesting that SIV infection induced the formation of GCs as part of the immune response to combat SIV infection. At 21 dpi, SIV-specific CD8+ T cells were largely excluded from B cell follicles, similar to what we reported during chronic disease [3]. Strikingly, and in contrast to chronic infection, we also discovered that follicular SIV-specific CD8+ T cells were entirely absent in 60% of GC areas examined. A complete absence of SIV-specific CD8+ T cells in most GCs at 21 dpi whilst during chronic infection there are equal numbers of SIV-specific CD8+ T cells in GC and non-GC follicular areas [20] suggests that during early infection, there is a temporal delay from the formation of nascent follicles and the entry of SIV-specific CD8+ T cells. Importantly, by 21 days dpi, the time in which we found most GC areas examined to be entirely devoid of SIV-specific CD8+ T cells, SIV has already seeded FDCs in GCs [45]. These findings indicate that the arrival of SIV-specific CD8+ T cells in GCs occurs after SIV has already seeded FDCs and infected follicular CD4 T cells. Thus, low levels or a complete absence of SIV-specific CD8 T cells in nascent GCs during early infection likely contributes mechanistically to the ability of SIV to become concentrated in lymphoid follicles during chronic stages of infection, and sets the stage for the establishment of persistent chronic infection.

 

Source:

http://doi.org/10.1371/journal.ppat.1007311