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AIDS virus seeks refuge in B cell follicles
Hendrik Streeck

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© 2015 Nature America, Inc. All rights reserved.

A study of SIV-infected rhesus macaques suggests that T follicular helper (TFH) cells, a specialized CD4+ T cell subset
within the B cell follicles, are a sanctuary for SIV that is largely inaccessible to CD8+ T cells. These findings may open
new avenues for research aimed at eradicating HIV.
The development of potent antiretroviral treatment (ART) strategies that are able to successfully suppress HIV replication has greatly
improved the prognosis for infected individuals with access to care. However, once HIV
establishes infection, the virus persists indefinitely as an integrated part of the genome in
a small population of latently infected CD4+
T cells. Cure or eradication attempts have so far
failed, and HIV remains a lifelong economic,
psychological and medical burden for infected
individuals.
One major hurdle impeding more-targeted
approaches to eradicating remaining HIV or
HIV-infected cells is the lack of knowledge
regarding the precise cellular and compartmental location of the latent HIV reservoir in
ART-treated individuals. Interestingly, even
in the rare subset of HIV-infected individuals who have a potent immune system with
the ability to spontaneously suppress viremia to almost undetectable levels (termed
elite controllers (ECs); <1% of the infected
population), the addition of ART does not
eradicate HIV but rather further suppresses
viral loads, suggesting a continuous reemergence of HIV from an unknown hiding
place1,2. In this issue of Nature Medicine,
Fukazawa et al.3 provide new insight into
potential mechanisms of HIV persistence
in elite controllers and individuals on
ART. By using a nonhuman primate model
for HIV infection, they found that in EC
rhesus macaques, SIV was restricted to the
TFH cell subset within the B cell follicles;
accordingly, they provide an intriguing
Hendrik Streeck is in the US Military HIV Research
Program, Walter Reed Army Institute of Research,
Silver Spring, Maryland, USA, and at the
Henry M. Jackson Foundation for the Advancement
of Military Medicine, Bethesda, Maryland, USA.
e-mail: hstreeck@hivresearch.org

explanation for why elite controllers are not
able to completely eradicate HIV or SIV
infection3.
TFH cells are a specialized CD4+ T cell
subset that is mainly found in the B cell
follicle, providing pivotal signals to B cells
that induce the generation and maturation
of antibody responses. Previous reports have
demonstrated that TFH cells expand during
chronic HIV (in humans) or SIV (in nonhuman primates) infection4,5. It is also known
that B cell follicles harbor high numbers of
HIV-infected cells6,7 but only recently have
TFH cells been implicated as being a preferentially infected CD4+ T cell subset in the B cell
follicle8. However, the underlying mechanism
that causes resident TFH cells to be a preferential reservoir of HIV and SIV remains
unclear. Several factors may account for this
observation, including a longer intrinsic life
span of TFH cells, preferential expansion of
TFH cells that harbor HIV/SIV or a shielding of TFH cells from CD8+ T cell–mediated
elimination in the follicles.
Fukazawa et al.3 first assessed the cellular
location of SIV in the lymph nodes of infected
rhesus macaques by sorting TFH cells and nonTFH CD4+ T cells from the lymph nodes and
analyzing the viral outgrowth of the respective subsets. They found that in the ECs SIV
infection was restricted to TFH cells within the
B cell follicles, but in other animals with nonoptimal immune control, SIV was also found
in non-TFH CD4+ T cells outside the B cell
follicle (Fig. 1)3.
The pattern of distribution of SIV-infected
cells in ECs suggests that CD8+ T cells have
the ability to control viral replication in the
paracortex and T cell zones of the lymph
nodes but are inefficient at eliminating
infected cells inside the follicle. To test the
hypothesis that the privileged nature of TFH
cells to harbor SIV within the lymphoid

nature medicine volume 21 | number 2 | february 2015

follicle in ECs is due to an inability of CD8+
T cells to access this anatomic site, the
authors first systemically depleted rhesus
macaques of CD8+ T cells by administering
CD8-specific antibodies3. The transient loss
of CD8+ T cell–mediated control resulted in a
re-distribution of SIV from TFH cells into other
non-TFH CD4 T cells outside the follicle (Fig. 1).
This suggests that the restriction of SIV infection to TFH cells within the follicles is driven
by a CD8+ T cell–mediated mechanism. To
confirm that the re-distribution of virus into
non-TFH cells in the absence of CD8+ T cells
is not driven by homeostatic proliferation
and activation of CD4+ T cells, in a separate experiment they injected SIV-infected
macaques with interleukin-7 to induce
T cell proliferation3. However, in this case
SIV remained restricted to TFH cells.
Previous studies have established that the
lymphoid follicles are immune-privileged
sites that exclude the majority of T cells with
the exception of the chemokine receptor
CXCR5–expressing TFH cell subset. Only
a certain small subset of antigen-specific
memory CD8+ T cells also express CXCR5
and can enter the follicles. However, these
cells do not possess a classical ‘killer’ profile, and it has been suggested that these cells
instead have immune-modulatory functions9. Moreover, during the chronic phase
of infection, the architectural integrity of
the lymphoid follicles changes, allowing
virus-specific CD8+ T cells to enter the B cell
follicles. However, at this stage of infection,
these cells are likely to be exhausted, dysfunctional and incapable of killing virally
infected cells10. Thus, the findings of the
current study suggest that the relative exclusion of functional CD8+ T cell effector cells
from the follicles may be partially responsible
for HIV persistence, even in the setting of
well-controlled viremia.
111

& Matsuda. Armon. the results of this study may open up other possibilities for potential eradication strategies. SIV-infected non. J. 8.D. Immunol. Med. and by comparing cell-associated SIV RNA and SIV DNA. J. 5. Okoye. irrespective of virus epitope presentation. Immunol. 21.S. and the US Department of Defense (DOD). All rights reserved. 9. Inc. 1443–1447 (2013).M. M. The authors show that virusspecific CD8+ T cells are incapable of clearing infection inside the immune-privileged sites. Folkvord. J. Lindqvist. et al. T. R.. Fukazawa. J. Although these results demonstrate complications with current potential eradication strategies. as the infected cells within an immune-privileged site may not be readily accessible by virus-specific CD8+ T cells. A. Siliciano. et al. 122. 3281–3294 (2012). & Siliciano. 12. C. 37. This is despite the fact 112 that TFH cells represent only a small fraction of memory CD4+ T cells. for example by flushing agents such as histone-deacetylase (HDAC) inhibitors. Upon CD8+ T cell depletion (bottom). et al. 210. the current study nevertheless suggests that the efficacy of this strategy may be limited. 10. is funded by a cooperative agreement (W81XWH-07-2-0067) between the Henry M. M. indicating that TFH cell–specific infection is indeed reliant on CD8+ T cells.TFH Figure 1 Fukazawa et al. 178. The authors of this report further highlight the clinical importance of their findings for potential cure and eradication attempts3. J. J.D. et al. 143–156 (2013). 3271–3280 (2012). Chun. 1. A. Park. V. Although this approach sounds promising and it may partially work in latently infected cells that do not reside within the B cell follicles. 122.K. & Sandberg. Clin. & Connick. they found evidence that residual viral replication occurs in relatively higher levels in TFH cells (higher SIV RNA but comparable SIV DNA) within the B cell follicles than in other CD4+ T cell subsets outside of the B cell follicles. 84. Gonzalez. E. CD8+ T cells are unable to access this region and thus are unable to carry out killer functions. The views expressed are those of the author and should not be construed to represent the positions of the US Army or the Department of Defense. Medulla FDC SIV-infected TFH T cell zone Acknowledgments H. Exp. 134.. 1198–1202 (2006). 11. TFH cells. Mens. Perreau. Inc. Connick. et al.F. 132–139 (2015). J. Cortex TFH Lymph node B cell follicle Paracortex FDC SIV-infected TFH CD4+ T cell CD8+ T cell T cell zone CD8 T cell depletion TFH B cell follicle Marina Corral Spence/Nature Publishing Group npg © 2015 Nature America.news and views CD8+ T cells can then recognize and kill those reactivated infected cells. 6975–6983 (2007). Trautmann. in which dormant cells infected with HIV are activated. R.. Allergy Clin. This finding that TFH cells within the B cell follicle may provide a sanctuary for HIV has major implications for potential cure efforts.. Jackson Foundation for the Advancement of Military Medicine. et al. Immunol. Nat. C. 7. By studying SIV-infected rhesus macaques that were treated with ART. 3. 363–370 (2005). H. Invest. Petrovas. Retroviruses 21. J. the authors identified non-TFH SIV-infected cells outside the B cell follicle. In contrast. AIDS Res. they may represent a major step forward in understanding viral reservoirs and allow for more-targeted approaches to virus elimination. thereby inducing changes in gene expression leading to presentation of viral proteins on the cell surface11. et al. Lum. L. Current curative strategies are focusing on a ‘flush-and-kill’ tactic.F. in B cell follicles of the lymph nodes. and thus strategies that either bestow follicular access to CD8+ T cells or lead to a disruption of the B cell follicles. for example through depletion of B cells with rituximab (CD20specific mAb) treatment. 4. resulting in TFH cell–specific infection. Andersson. J..3 identifies TFH cells in lymphoid follicles as a reservoir for SIV in the setting of controlled SIV replication. Infect. J. Hum.3 find that in ECs SIV is located in a specialized CD4+ T cell subset. J. Med. Virus-specific COMPETING FINANCIAL INTERESTS The author declares no competing financial interests. The study by Fukazawa et al. Quigley. Nat. Granath. Y. 3352–3362 (2007).. Invest. may be intriguing avenues to explore. Eur. 12971–12981 (2010). 208. and it further establishes shielding from virus-specific CD8+ T cell recognition as a possible mechanism for this. Clin. M.A. K.. Med. J. H. volume 21 | number 2 | february 2015 nature medicine . 6. E. 12–19 (2014).W. Virol.. 2. Dis.