CD4 T follicular helper cell dynamics during SIV infection

Petrovas, Constantinos; Yamamoto, Takuya; Gerner, Michael Y.; Boswell, Kristin L.; Wloka, Kaska; Smith, Emily C.; Ambrozak, David R.; Sandler, Netanya G.; Timmer, Katherina J.; Sun, Xiaoyong; Li, Pan; Poholek, Amanda C.; Rao, Srinivas S.; Brenchley, Jason M.; Alam, S. Munir; Tomaras, Georgia D.; Roederer, Mario; Douek, Daniel C.; Seder, Robert A.; Germain, Ronald N.; Haddad, Elias K.; Koup, Richard A.

doi:10.1172/jci63039

Cited by 299 publications

(460 citation statements)

References 64 publications

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“…Recent studies with both humans and monkeys demonstrated that GC Tfh cells expand over the course of HIV or simian immunodeficiency virus (SIV) infection (8,23). Moreover, while these studies could not establish a direct link between individual viral loads and Tfh cell expansion, the presence of viremia was associated with an increased frequency of Tfh cells and a concurrent reduction of memory B cells in germinal centers, along with peripheral hypergammaglobulinemia (8).…”

Section: Discussionmentioning

confidence: 99%

Preservation of Peripheral T Follicular Helper Cell Function in HIV Controllers

Buranapraditkun

Pissani

Teigler

et al. 2017

J Virol

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The maturation process of high-affinity antibodies is a result of intricate interactions between B cells and follicular helper T (Tfh) cells occurring in lymphoid germinal centers. HIV infection induces significant chronic immune activation, phenotypic skewing, and inflammation driven by years of continuous viral replication. High levels of viremia as well as immune activation and dysfunction have been demonstrated to have a perturbing impact on the B cell memory compartment and contribute to B cell exhaustion. Counterintuitively, the factors associated with perturbation of the B cell compartment seem to be favorable for the generation of highly affinity-matured Env-specific antibodies in a minority of HIV-infected individuals. Thus, the impact of HIV antigenemia on B cells and Tfh cell interactions warrants further exploration. We therefore studied immunophenotypes of HIV-specific B cells in individuals with differing levels of viral control using HIV Env gp120 probes and characterized the functionality of matched T cells in peripheral blood. While CXCR5 ϩ CD4 ϩ T cells were significantly diminished in HIV progressors, we found that a small subset of gp120-specific interleukin-21 (IL-21)-secreting CXCR5 ϩ CD4 ϩ T cells were significantly associated with gp120-specific B cell frequencies. In contrast, neither bulk CXCR5 ϩ CD4 ϩ T cells nor other HIV antigen specificities were associated with gp120-specific B cell levels. HIV-specific B cells derived from elite controllers displayed greater amounts of gp120-specific B cells in the resting memory subset, whereas HIV-specific B cells in progressors accumulated in tissue-like and activated memory subsets. Furthermore, CXCR5 ϩ CD4 ϩ T cells from elite controllers showed a stronger ex vivo capacity to induce B cell maturation and immunoglobulin class switching than cells from HIV progressors.IMPORTANCE Dissecting the factors that are involved in B cell maturation and antibody development is important for HIV vaccine design. In this study, we found that HIV Env-specific CXCR5 ϩ CD4 ϩ T cells that secrete interleukin-21 are strongly associated with B cell memory phenotypes and function. Moreover, we found that the immune responses of HIV controllers showed intrinsically better helper activity than those of HIV progressors.

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Section: Discussionmentioning

confidence: 99%

Preservation of Peripheral T Follicular Helper Cell Function in HIV Controllers

Buranapraditkun

Pissani

Teigler

et al. 2017

J Virol

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“…Sustained LCMV replication in mice is also associated with expansion of GC Tfh cells, and here IL‐6 production has been shown to play a key role in driving Tfh cell differentiation during chronic infection 194, 195. GC Tfh cell expansion in chronic HIV‐1 infection is also associated with elevated IL‐6 production,189 but as IL‐6 is not such a potent stimulus of human CD4 + differentiation into Tfh cells, it can be speculated that upregulation of other Tfh‐differentiating cytokines, in the context of the reduction in IL‐2 expression known to occur in chronic HIV infection,196 may play a more important role in enhancing Tfh cell differentiation during HIV infection. Reduced control of Tfh cell numbers by regulatory T‐cell populations likely also facilitates expansion of Tfh cells during SIV/HIV infection; this is discussed further below.…”

Section: T Follicular Helper Cells and Their Role In Bnab Inductionmentioning

confidence: 94%

“…Despite the susceptibility of Tfh cells to infection with SIV/HIV, the frequency of GC Tfh cells begins to increase within a few months of infection188 and elevated Tfh cell numbers are routinely observed in LNs during chronic SIV and HIV infections,168, 173, 189, 190, 191 although Tfh cells are eventually depleted as progression to acquired immunodeficiency syndrome (AIDS) occurs 192. The expansion in Tfh cells is associated with an increase in GC B cells and plasma cells and elevated IgG production, suggesting that Tfh cells contribute to the dysregulation of B cells and antibody production that occurs during HIV‐1 infection 191.…”

Section: T Follicular Helper Cells and Their Role In Bnab Inductionmentioning

confidence: 99%

“…The expansion in Tfh cells is associated with an increase in GC B cells and plasma cells and elevated IgG production, suggesting that Tfh cells contribute to the dysregulation of B cells and antibody production that occurs during HIV‐1 infection 191. The magnitude and duration of antigenic stimulation are known to be important determinants of the GC Tfh cell response,193 and although GC Tfh cell frequencies do not generally show a direct correlation with viral load, the increase in GC Tfh cells during chronic SIV/HIV infection is dependent on ongoing antigenic stimulation, as GC Tfh cell frequencies decline when viral replication is contained by antiretroviral therapy 168, 189, 191. Sustained LCMV replication in mice is also associated with expansion of GC Tfh cells, and here IL‐6 production has been shown to play a key role in driving Tfh cell differentiation during chronic infection 194, 195.…”

Section: T Follicular Helper Cells and Their Role In Bnab Inductionmentioning

confidence: 99%

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Immunologic characteristics of HIV‐infected individuals who make broadly neutralizing antibodies

Borrow

Moody

2017

Immunological Reviews

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SummaryInduction of broadly neutralizing antibodies (bnAbs) capable of inhibiting infection with diverse variants of human immunodeficiency virus type 1 (HIV‐1) is a key, as‐yet‐unachieved goal of prophylactic HIV‐1 vaccine strategies. However, some HIV‐infected individuals develop bnAbs after approximately 2‐4 years of infection, enabling analysis of features of these antibodies and the immunological environment that enables their induction. Distinct subsets of CD4+ T cells play opposing roles in the regulation of humoral responses: T follicular helper (Tfh) cells support germinal center formation and provide help for affinity maturation and the development of memory B cells and plasma cells, while regulatory CD4+ (Treg) cells including T follicular regulatory (Tfr) cells inhibit the germinal center reaction to limit autoantibody production. BnAbs exhibit high somatic mutation frequencies, long third heavy‐chain complementarity determining regions, and/or autoreactivity, suggesting that bnAb generation is likely to be highly dependent on the activity of CD4+ Tfh cells, and may be constrained by host tolerance controls. This review discusses what is known about the immunological environment during HIV‐1 infection, in particular alterations in CD4+ Tfh, Treg, and Tfr populations and autoantibody generation, and how this is related to bnAb development, and considers the implications for HIV‐1 vaccine design.

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“…T FH cells are infected at higher frequencies in macaques and humans than in SMs [155]. In contrast to most other CD4þ T cells, this subset is expanded and accumulates in lymph node germinal centres during HIV and SIVmac infections [153,[156][157][158]. Whether T FH in HIV infection shows an altered function that could impact anti-HIV antibody development is unclear.…”

Section: (B) Adaptive Cellular Responses (I) Cd8þ T Cell Responsesmentioning

confidence: 99%

Immune responses during spontaneous control of HIV and AIDS: what is the hope for a cure?

Sáez‐Cirión

Jacquelin

Barré‐Sinoussi

et al. 2014

Phil. Trans. R. Soc. B

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International audienceHIV research has made rapid progress and led to remarkable achievements in recent decades, the most important of which are combination antiretroviral therapies (cART). However, in the absence of a vaccine, the pandemic continues, and additional strategies are needed. The 'towards an HIV cure' initiative aims to eradicate HIV or at least bring about a lasting remission of infection during which the host can control viral replication in the absence of cART. Cases of spontaneous and treatment-induced control of infection offer substantial hope. Here, we describe the scientific knowledge that is lacking, and the priorities that have been established for research into a cure. We discuss in detail the immunological lessons that can be learned by studying natural human and animal models of protection and spontaneous control of viraemia or of disease progression. In particular, we describe the insights we have gained into the immune mechanisms of virus control, the impact of early virus-host interactions and why chronic inflammation, a hallmark of HIV infection, is an obstacle to a cure. Finally, we enumerate current interventions aimed towards improving the host immune response

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CD4 T follicular helper cell dynamics during SIV infection

Cited by 299 publications

References 64 publications

Preservation of Peripheral T Follicular Helper Cell Function in HIV Controllers

Preservation of Peripheral T Follicular Helper Cell Function in HIV Controllers

Immunologic characteristics of HIV‐infected individuals who make broadly neutralizing antibodies

Immune responses during spontaneous control of HIV and AIDS: what is the hope for a cure?

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