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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 infec-tion 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 sepa-rate 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’ pro-file, and it has been suggested that these cells instead have immune-modulatory func-tions9. 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, dys-functional and incapable of killing virally infected cells10. Thus, the findings of the current study suggest that the relative exclu-sion 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.

The development of potent antiretroviral treat-ment (ART) strategies that are able to success-fully suppress HIV replication has greatly improved the prognosis for infected individu-als with access to care. However, once HIV establishes infection, the virus persists indefi-nitely 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 compart-mental location of the latent HIV reservoir in ART-treated individuals. Interestingly, even in the rare subset of HIV-infected individu-als who have a potent immune system with the ability to spontaneously suppress vire-mia 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 reemer-gence 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

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 nonhu-man 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 preferen-tially infected CD4+ T cell subset in the B cell follicle8. However, the underlying mechanism that causes resident TFH cells to be a pref-erential 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 shield-ing 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 non-TFH CD4+ T cells from the lymph nodes and analyzing the viral outgrowth of the respec-tive subsets. They found that in the ECs SIV infection was restricted to TFH cells within the B cell follicles, but in other animals with non-optimal 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

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

AIDS virus seeks refuge in B cell folliclesHendrik Streeck

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.

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FDCB cellfollicle

T cell zone

SIV-infectedTFH

Cortex

Para-cortex

Lymphnode

Medulla

CD8+ T cell

CD4+ T cell

FDCB cellfollicle

T cell zone

SIV-infectedTFH

TFH

TFH

CD8 T cell depletion

SIV-infectednon- TFH

that TFH cells represent only a small fraction of memory CD4+ T cells.

This finding that TFH cells within the B cell follicle may provide a sanctuary for HIV has major implications for potential cure efforts. Current curative strategies are focusing on a ‘flush-and-kill’ tactic, in which dormant cells infected with HIV are activated, for example by flushing agents such as histone-deacetylase (HDAC) inhibitors, thereby inducing changes in gene expression leading to presentation of viral proteins on the cell surface11. Virus-specific

The authors of this report further high-light the clinical importance of their findings for potential cure and eradication attempts3. By studying SIV-infected rhesus macaques that were treated with ART, and by compar-ing cell-associated SIV RNA and SIV DNA, 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. This is despite the fact

CD8+ T cells can then recognize and kill those reactivated infected cells. Although this approach sounds promising and it may par-tially work in latently infected cells that do not reside within the B cell follicles, the current study nevertheless suggests that the efficacy of this strategy may be limited, as the infected cells within an immune-privileged site may not be readily accessible by virus-specific CD8+ T cells, irrespective of virus epitope presenta-tion. In contrast, the results of this study may open up other possibilities for potential eradi-cation strategies. The authors show that virus-specific CD8+ T cells are incapable of clearing infection inside the immune-privileged sites, 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 (CD20-specific mAb) treatment, may be intriguing avenues to explore.

The study by Fukazawa et al.3 identifies TFH cells in lymphoid follicles as a reservoir for SIV in the setting of controlled SIV rep-lication, and it further establishes shielding from virus-specific CD8+ T cell recognition as a possible mechanism for this. Although these results demonstrate complications with current potential eradication strategies, they may rep-resent a major step forward in understanding viral reservoirs and allow for more-targeted approaches to virus elimination.

AcknowledgmentsH.S. is funded by a cooperative agreement (W81XWH-07-2-0067) between the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., and the US Department of Defense (DOD). 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.

comPetIng FInAncIAl InteRestsThe author declares no competing financial interests.

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2. Mens, H. et al. J. Virol. 84, 12971–12981 (2010).

3. Fukazawa, Y., Lum, R., Okoye, A., Park, H. & Matsuda, K.A. Nat. Med. 21, 132–139 (2015).

4. Lindqvist, M. et al. J. Clin. Invest. 122, 3271–3280 (2012).

5. Petrovas, C. et al. J. Clin. Invest. 122, 3281–3294 (2012).

6. Connick, E. et al. J. Immunol. 178, 6975–6983 (2007).

7. Folkvord, J.M., Armon, C. & Connick, E. AIDS Res. Hum. Retroviruses 21, 363–370 (2005).

8. Perreau, M. et al. J. Exp. Med. 210, 143–156 (2013).

9. Quigley, M.F., Gonzalez, V.D., Granath, A., Andersson, J. & Sandberg, J.K. Eur. J. Immunol. 37, 3352–3362 (2007).

10. Trautmann, L. et al. Nat. Med. 12, 1198–1202 (2006).

11. Siliciano, J.D. & Siliciano, R.F. J. Allergy Clin. Immunol. 134, 12–19 (2014).

Figure 1 Fukazawa et al.3 find that in ECs SIV is located in a specialized CD4+ T cell subset, TFH cells, in B cell follicles of the lymph nodes. CD8+ T cells are unable to access this region and thus are unable to carry out killer functions, resulting in TFH cell–specific infection. Upon CD8+ T cell depletion (bottom), the authors identified non-TFH SIV-infected cells outside the B cell follicle, indicating that TFH cell–specific infection is indeed reliant on CD8+ T cells.

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