Long-term Persistent Elite HIV-controllers: The Right Model of Functional Cure

Tarancón-Díez, Laura; Domínguez-Molina, Beatriz; Viciana, Pompeyo; López‐Cortés, Luis F.; Ruiz‐Mateos, Ezequiel

doi:10.1016/j.ebiom.2018.01.013

Cited by 6 publications

(5 citation statements)

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“…These results support that some EC are able to maintain stable CD4 + T cells and persistent control of viral replication for several years (>2–5 years) in the setting of high proviral diversity. Although HIV-1 diversity and other surrogate markers of viral replication (total HIV-1 DNA load, CD8 + T cell activation, and IP-10) were positively correlated among each other and with the cVL when EC and VC were taken as a whole, consistent with previous findings (Bello et al, 2005; Sajadi et al, 2007; Groves et al, 2012; Côrtes et al, 2015; Noel et al, 2015a; Platten et al, 2016; Canouï et al, 2017; Tarancon-Diez et al, 2018); we did not detect any significant association between the env proviral diversity and those biomarkers when EC were analyzed separately. Hence, the genetic diversity of the HIV-1 proviral reservoir in many EC is probably not driven by continuous residual viral replication (de Azevedo et al, 2017), which may explain why EC HD does not seem to display higher risk of immunologic or virologic progression in compared with EC LD in our cohort.…”

Section: Discussionsupporting

confidence: 90%

Proviral Quasispecies Diversity Is Not Associated With Virologic Breakthrough or CD4+ T Cell Loss in HIV-1 Elite Controllers

et al. 2019

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Elite controllers (EC) are able to control HIV-1 replication to extremely low levels (<50 HIV-1 RNA copies/mL) in the absence of antiretroviral therapy. However, some EC experience CD4 + T cell loss and/or lose their ability to control HIV-1 over the course of infection. High levels of HIV-1 env proviral diversity, activated T cells and proinflammatory cytokines were pointed out as relevant biomarkers for detection of EC at risk of virologic/immunologic progression. The aim of this study was to assess the importance of proviral diversity as a prognostic marker of virologic and/or immunologic progression in EC. To this end, we analyzed plasma viremia, total HIV DNA levels, T cells dynamics, and activation/inflammatory biomarkers in EC with low (EC LD = 4) and high (EC HD = 6) HIV-1 env diversity. None of EC LD and EC HD subjects displayed evidence of immunologic progression (decrease in absolute and percentage of CD4 + T cells) and only one EC HD subject presented virologic progression (≥2 consecutive viral loads measurements above the detection limit) 2–5 years after determination of proviral env diversity. Despite differences in proviral genetic diversity, the EC LD and EC HD subgroups displayed comparable levels of total cell-associated HIV DNA, activated CD8 + T (CD38 + HLA-DR + ) cells and plasmatic inflammatory biomarkers (IP-10, IL-18, RANTES, PDGF-AA, and CTACK). These results indicate that the genetic diversity of the HIV-1 proviral reservoir is not a surrogate marker of residual viral replication, immune activation or inflammation, nor an accurate biomarker for the prediction of virologic breakthrough or CD4 + T cells loss in EC.

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Section: Discussionsupporting

confidence: 90%

Proviral Quasispecies Diversity Is Not Associated With Virologic Breakthrough or CD4+ T Cell Loss in HIV-1 Elite Controllers

et al. 2019

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“…Together, these results suggest that PCs can serve as a premier model for understanding immune pathways responsible for spontaneous cures of HIV and for designing new HIV cure and treatment strategies (12). Nevertheless, the mechanisms that allow PCs to maintain viral control in the absence of ART have not been fully characterized.…”

Section: Resultsmentioning

confidence: 99%

The HIV-1 reservoir landscape in persistent elite controllers and transient elite controllers

Gasca-Capote,

Lian,

Gao

et al. 2024

Journal of Clinical Investigation

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BACKGROUND. Persistent controllers (PCs) maintain antiretroviral-free HIV-1 control indefinitely over time, while transient controllers (TCs) eventually lose virological control. It is essential to characterize the quality of the HIV reservoir in terms of these phenotypes in order to identify the factors that lead to HIV progression and to open new avenues toward an HIV cure. METHODS.The characterization of HIV-1 reservoir from peripheral blood mononuclear cells was performed using nextgeneration sequencing techniques, such as full-length individual and matched integration site proviral sequencing (FLIP-Seq; MIP-Seq). RESULTS.PCs and TCs, before losing virological control, presented significantly lower total, intact, and defective proviruses compared with those of participants on antiretroviral therapy (ART). No differences were found in total and defective proviruses between PCs and TCs. However, intact provirus levels were lower in PCs compared with TCs; indeed the intact/ defective HIV-DNA ratio was significantly higher in TCs. Clonally expanded intact proviruses were found only in PCs and located in centromeric satellite DNA or zinc-finger genes, both associated with heterochromatin features. In contrast, sampled intact proviruses were located in permissive genic euchromatic positions in TCs.CONCLUSIONS. These results suggest the need for, and can give guidance to, the design of future research to identify a distinct proviral landscape that may be associated with the persistent control of HIV-1 without ART.

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“…The size of the virus reservoir has been measured using different protocols, including qPCR of cell-bound virus DNA and mRNA, quantification of ex vivo reactivation of virus mRNA and proteins, as well as in ex vivo virus outgrowth assays. In HIV-1 long-term non-progressors (LTNP) and elite controllers (EC), that have been suggested as models for functional cure, the reservoir of latently infected cells is reduced compared with HIV-1 viraemic and treated individuals [49, 50]. Interestingly, conflicting results about proviral DNA levels in HIV-2 compared with HIV-1 infection have been reported.…”

Section: Hiv-1 and Hiv-2 Virology And Immunologymentioning

confidence: 99%

HIV-2 as a model to identify a functional HIV cure

et al. 2019

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Two HIV virus types exist: HIV-1 is pandemic and aggressive, whereas HIV-2 is confined mainly to West Africa and less pathogenic. Despite the fact that it has been almost 40 years since the discovery of AIDS, there is still no cure or vaccine against HIV. Consequently, the concepts of functional vaccines and cures that aim to limit HIV disease progression and spread by persistent control of viral replication without life-long treatment have been suggested as more feasible options to control the HIV pandemic. To identify virus-host mechanisms that could be targeted for functional cure development, researchers have focused on a small fraction of HIV-1 infected individuals that control their infection spontaneously, so-called elite controllers. However, these efforts have not been able to unravel the key mechanisms of the infection control. This is partly due to lack in statistical power since only 0.15% of HIV-1 infected individuals are natural elite controllers. The proportion of long-term viral control is larger in HIV-2 infection compared with HIV-1 infection. We therefore present the idea of using HIV-2 as a model for finding a functional cure against HIV. Understanding the key differences between HIV-1 and HIV-2 infections, and the cross-reactive effects in HIV-1/HIV-2 dual-infection could provide novel insights in developing functional HIV cures and vaccines.

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Long-term Persistent Elite HIV-controllers: The Right Model of Functional Cure

Cited by 6 publications

References 10 publications

Proviral Quasispecies Diversity Is Not Associated With Virologic Breakthrough or CD4+ T Cell Loss in HIV-1 Elite Controllers

Proviral Quasispecies Diversity Is Not Associated With Virologic Breakthrough or CD4+ T Cell Loss in HIV-1 Elite Controllers

The HIV-1 reservoir landscape in persistent elite controllers and transient elite controllers

HIV-2 as a model to identify a functional HIV cure

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