Peripheral T Follicular Helper Cells Are the Major HIV Reservoir within Central Memory CD4 T Cells in Peripheral Blood from Chronically HIV-Infected Individuals on Combination Antiretroviral Therapy

Pallikkuth, Suresh; Sharkey, Mark E.; Babič, Dunja Z.; Gupta, Sachin; Stone, Geoffrey W.; Fischl, Margaret A.; Stevenson, Mario; Pahwa, Savita

doi:10.1128/jvi.02883-15

Cited by 113 publications

(118 citation statements)

References 53 publications

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“…7C). Of note, the frequency of p24-positive cells in reactivated CD4 T cells was similar to other previous reports (57)(58)(59). HIV RNA in the cell culture supernatant was not altered by venetoclax treatment compared to control (Fig.…”

Section: Treatment Of Gfpsupporting

confidence: 76%

Prime, Shock, and Kill: Priming CD4 T Cells from HIV Patients with a BCL-2 Antagonist before HIV Reactivation Reduces HIV Reservoir Size

Cummins

Sainski

Dai

et al. 2016

J Virol

105

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Understanding how some HIV-infected cells resist the cytotoxicity of HIV replication is crucial to enabling HIV cure efforts. HIV killing of CD4 T cells that replicate HIV can involve HIV protease-mediated cleavage of procaspase 8 to generate a fragment (Casp8p41) that directly binds and activates the mitochondrial proapoptotic protein BAK. Here, we demonstrate that Casp8p41 also binds with nanomolar affinity to the antiapoptotic protein Bcl-2, which sequesters Casp8p41 and prevents apoptosis. Intense activity is focused on identifying a clinical intervention that results in a long term, drug free remission of HIV-1 infection. Latently infected CD4 T cells harbor transcriptionally silent, replication-competent HIV. Because these cells persist long term and are unaffected by current therapies, the cells represent an HIV reservoir that remains undiminished by current approaches. Pilot clinical trials have tested whether reactivation of HIV-1 from latency will decrease the number of cells containing HIV DNA due to viral cytopathic effect or immune-mediated clearance. The latency reversal agents vorinostat, panobinostat, and romidepsin result in HIV reactivation, as measured by increases in cell-associated HIV RNA, but no change in cell-associated HIV DNA, indicating that the reactivating cells do not die (1-4). Multiple ongoing studies are testing augmentation of the anti-HIV immune response in combination with viral reactivation as a strategy for HIV eradication.In an effort to inform these attempts to eradicate the HIV reservoir, we and others have been examining the mechanistic basis for HIV-induced killing of CD4 T cells under different circumstances of activation and HIV replication. Although numerous pathways may contribute to the decline of uninfected CD4 T cells during uncontrolled HIV infection (5), fewer pathways have been implicated in the demise of cells directly infected by HIV. After HIV attachment, at least three distinct pathways can initiate the death of infected cells: (i) RIG-I-mediated sensing of HIV RNA (6, 7), (ii) IFI-16 sensing of unintegrated HIV DNA (8, 9), and (iii) DNA-PK-sensing of HIV integrase nicking of host DNA (10). Once integrated into host DNA, HIV can remain in a latent state

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Section: Treatment Of Gfpsupporting

confidence: 76%

Prime, Shock, and Kill: Priming CD4 T Cells from HIV Patients with a BCL-2 Antagonist before HIV Reactivation Reduces HIV Reservoir Size

Cummins

Sainski

Dai

et al. 2016

J Virol

105

View full text Add to dashboard Cite

show abstract

“…Memory T FH can be long-lived and primarily have a central memory phenotype, similar to the resting CD4+ T cell reservoir that harbors the majority of HIV DNA in treated individuals [50]. One recent study reported that the majority of HIV-1 DNA in peripheral blood was harboured by central memory T FH in subjects with sustained virologic suppression on ART [54]. Nevertheless, the precise phenotype of peripheral T FH is somewhat controversial [55] and until an accurate phenotype is determined, identifying the role of T FH in the latent HIV reservoir using peripheral blood will be challenging.…”

Section: Follicular Hiv Reservoirs During Treated Diseasementioning

confidence: 99%

T FH in HIV Latency and as Sources of Replication-Competent Virus

Brodie

Connick

2016

Trends in Microbiology

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During untreated disease, HIV replication is concentrated within T follicular helper cells (TFH). Heightened permissiveness, the presence of highly infectious virions on follicular dendritic cells (FDC), low frequencies of virus-specific cytotoxic T lymphocytes (CTL) in B cell follicles, expansions in TFH, and TFH dysfunction all likely promote replication in TFH. Limited data suggest that memory TFH play a role in the latent or subclinical reservoir of HIV during antiretroviral therapy (ART), potentially for many of the same reasons. A better understanding of the role of memory TFH and FDC-bound virions in promoting recrudescent viremia in the setting of ART cessation is essential. Studies that target follicular virus reservoirs are needed to determine their role in HIV latency and to suggest successful cure strategies.

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“…These new data demonstrate that lymph node cells harboring viral DNA permit productive infection even in the presence of suppressive cART. The very rare T FH in blood also contribute to the HIV reservoir in patients receiving cART (134).…”

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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Peripheral T Follicular Helper Cells Are the Major HIV Reservoir within Central Memory CD4 T Cells in Peripheral Blood from Chronically HIV-Infected Individuals on Combination Antiretroviral Therapy

Cited by 113 publications

References 53 publications

Prime, Shock, and Kill: Priming CD4 T Cells from HIV Patients with a BCL-2 Antagonist before HIV Reactivation Reduces HIV Reservoir Size

Prime, Shock, and Kill: Priming CD4 T Cells from HIV Patients with a BCL-2 Antagonist before HIV Reactivation Reduces HIV Reservoir Size

T FH in HIV Latency and as Sources of Replication-Competent Virus

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

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