Persistent Simian Immunodeficiency Virus Infection Drives Differentiation, Aberrant Accumulation, and Latent Infection of Germinal Center Follicular T Helper Cells

Xu, Huanbin; Wang, Xiaolei; Malam, Naomi; Aye, Pyone P.; Álvarez, Xavier; Lackner, Andrew A.; Veazey, Ronald S.

doi:10.1128/jvi.02471-15

Cited by 52 publications

(73 citation statements)

References 50 publications

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“…This raises the possibility that the local inflammation alone can induce this phenotype on GC-Tfh cells. Our results are also consistent with a recent study in macaques demonstrating that Th1 transcriptional factor T-bet is up regulated in Tfh cells isolated from the LN and spleen during chronic SIV infection (16, 18, 36, 37). In addition to GC-Tfh, we observed an increase for CXCR3 expression on all other memory CD4 T cells in the LN indicating that this effect is not restricted to GC-Tfh.…”

Section: Discussionsupporting

confidence: 93%

“…Similar to humans and mice, few studies defined Tfh in RM based on CXCR5 (16, 18, 36, 37), a key chemokine receptor required for homing of cells to B cell follicle/GC. In addition, it is important to characterize the expression of chemokine receptors that influence the migration and lineage relationship of CD4 T cells.…”

Section: Resultsmentioning

confidence: 99%

“…Multiple studies including our own have characterized the Tfh cells in the lymph nodes (LNs) during chronic HIV infection in humans (10–13) and SIV infection in rhesus macaques (RMs) (14–18). These studies used different combinations of markers to define Tfh.…”

Section: Introductionmentioning

confidence: 99%

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Induction of Th1-Biased T Follicular Helper (Tfh) Cells in Lymphoid Tissues during Chronic Simian Immunodeficiency Virus Infection Defines Functionally Distinct Germinal Center Tfh Cells

Velu

Mylvaganam

Gangadhara

et al. 2016

The Journal of Immunology

124

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Chronic HIV infection is associated with accumulation of germinal center T follicular helper cells (GC-Tfh) in the lymphoid tissue. The GC-Tfh cells can be heterogeneous based on the expression of chemokine receptors associated with T helper lineages such as CXCR3 (Th1), CCR4 (Th2), and CCR6 (Th17). However, the heterogeneous nature of GC-Tfh cells in the lymphoid tissue and its association with viral persistence and antibody production during chronic SIV/HIV infection is not known. To address this, here we characterized the expression of CXCR3, CCR4, and CCR6 on GC-Tfh in lymph nodes following SIVmac251 infection in rhesus macaques (RMs). In SIV naïve RM, only a small fraction of GC-Tfh expressed CXCR3, CCR4 and CCR6. However, during chronic SIV infection, the majority of GC-Tfh cells expressed CXCR3, while the proportion of CCR4+ cells did not change and CCR6+ cells decreased. CXCR3+ but not CXCR3− GC-Tfh produced IFN-γ (Th1 cytokine) and IL-21 (Tfh cytokine) while both subsets expressed CD40L following stimulation. Immunohistochemistry analysis demonstrated an accumulation of CD4+ IFN-γ+ T cells within the hyperplastic follicles during chronic SIV infection. CXCR3+ GC-Tfh also expressed higher levels of ICOS, CCR5 and α4β7, contained more copies of SIV DNA compared to CXCR3− GC-Tfh cells. However, both CXCR3+ and CXCR3− GC-Tfh delivered help to B cells in vitro for production of IgG. These data demonstrate that chronic SIV infection promotes expansion of Th1-biased GC-Tfh cells, which are phenotypically and functionally distinct from conventional GC-Tfh cells and contribute to hypergammaglobulinemia and viral reservoirs.

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Section: Discussionsupporting

confidence: 93%

Section: Resultsmentioning

confidence: 99%

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Induction of Th1-Biased T Follicular Helper (Tfh) Cells in Lymphoid Tissues during Chronic Simian Immunodeficiency Virus Infection Defines Functionally Distinct Germinal Center Tfh Cells

Velu

Mylvaganam

Gangadhara

et al. 2016

The Journal of Immunology

124

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“…It is also possible that infected T h 17 cells directly become T fh cells (32,33), which would then be capable of migration to secondary lymphoid tissues (Fig. 7), where they are capable of replication at high levels, despite their low expression of CCR5 (68,69). Our findings may aid in therapeutic intervention strategies aimed at preventing viral production during acute HIV infection or reducing the size of the viral reservoir in people living with HIV.…”

Section: Discussionmentioning

confidence: 94%

Human T _h 17 Cells Lack HIV-Inhibitory RNases and Are Highly Permissive to Productive HIV Infection

Christensen-Quick

Lafferty

Sun

et al. 2016

J Virol

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Human immunodeficiency virus (HIV) infects and depletes CD4 IMPORTANCE Our study compares the intracellular replicative capacities of several different HIV isolates among different T cell subsets, providing a link between the differentiation of T h 17 cells and HIV replication. T h 17 cells are of key importance in mucosal integrity and in the immune response to certain pathogens. Based on our findings and the work of others, we propose a model in which HIV replication is favored by the intracellular environment of two CD4؉ T cell subsets that share several requirements for their differentiation: T h 17 and T fh cells. Characterizing cells that support high levels of viral replication (rather than becoming latently infected or undergoing cell death) informs the search for new therapeutics aimed at manipulating intracellular signaling pathways and/or transcriptional factors that affect HIV replication.

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“…Lymph nodes thus play an important role in the dynamics of HIV reservoirs, in an intricate relation with CD4 T cell dynamics. Follicular helper CD4 T cells (T FH ) play an important role in the lymph node HIV reservoir and are infected during their differentiation (129). A recent study compared viral DNA levels in different cell subsets from lymph nodes of simian controllers and progressors.…”

Section: Lymph Nodesmentioning

confidence: 99%

Total HIV-1 DNA, a Marker of Viral Reservoir Dynamics with Clinical Implications

et al. 2016

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SUMMARYHIV-1 DNA persists in infected cells despite combined antiretroviral therapy (cART), forming viral reservoirs. Recent trials of strategies targeting latent HIV reservoirs have rekindled hopes of curing HIV infection, and reliable markers are thus needed to evaluate viral reservoirs. Total HIV DNA quantification is simple, standardized, sensitive, and reproducible. Total HIV DNA load influences the course of the infection and is therefore clinically relevant. In particular, it is predictive of progression to AIDS and death, independently of HIV RNA load and the CD4 cell count. Baseline total HIV DNA load is predictive of the response to cART. It declines during cART but remains quantifiable, at a level that reflects both the history of infection (HIV RNA zenith, CD4 cell count nadir) and treatment efficacy (residual viremia, cumulative viremia, immune restoration, immune cell activation). Total HIV DNA load in blood is also predictive of the presence and severity of some HIV-1-associated end-organ disorders. It can be useful to guide individual treatment, notably, therapeutic de-escalation. Although it does not distinguish between replication-competent and -defective latent viruses, the total HIV DNA load in blood, tissues, and cells provides insights into HIV pathogenesis, probably because all viral forms participate in host cell activation and HIV pathogenesis. Total HIV DNA is thus a biomarker of HIV reservoirs, which can be defined as all infected cells and tissues containing all forms of HIV persistence that participate in pathogenesis. This participation may occur through the production of new virions, creating new cycles of infection and disseminating infected cells; maintenance or amplification of reservoirs by homeostatic cell proliferation; and viral transcription and synthesis of viral proteins without new virion production. These proteins can induce immune activation, thus participating in the vicious circle of HIV pathogenesis.

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Persistent Simian Immunodeficiency Virus Infection Drives Differentiation, Aberrant Accumulation, and Latent Infection of Germinal Center Follicular T Helper Cells

Cited by 52 publications

References 50 publications

Induction of Th1-Biased T Follicular Helper (Tfh) Cells in Lymphoid Tissues during Chronic Simian Immunodeficiency Virus Infection Defines Functionally Distinct Germinal Center Tfh Cells

Induction of Th1-Biased T Follicular Helper (Tfh) Cells in Lymphoid Tissues during Chronic Simian Immunodeficiency Virus Infection Defines Functionally Distinct Germinal Center Tfh Cells

Human T _h 17 Cells Lack HIV-Inhibitory RNases and Are Highly Permissive to Productive HIV Infection

Total HIV-1 DNA, a Marker of Viral Reservoir Dynamics with Clinical Implications

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Persistent Simian Immunodeficiency Virus Infection Drives Differentiation, Aberrant Accumulation, and Latent Infection of Germinal Center Follicular T Helper Cells

Cited by 52 publications

References 50 publications

Induction of Th1-Biased T Follicular Helper (Tfh) Cells in Lymphoid Tissues during Chronic Simian Immunodeficiency Virus Infection Defines Functionally Distinct Germinal Center Tfh Cells

Induction of Th1-Biased T Follicular Helper (Tfh) Cells in Lymphoid Tissues during Chronic Simian Immunodeficiency Virus Infection Defines Functionally Distinct Germinal Center Tfh Cells

Human T h 17 Cells Lack HIV-Inhibitory RNases and Are Highly Permissive to Productive HIV Infection

Total HIV-1 DNA, a Marker of Viral Reservoir Dynamics with Clinical Implications

Contact Info

Product

Resources

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Human T _h 17 Cells Lack HIV-Inhibitory RNases and Are Highly Permissive to Productive HIV Infection