A Possible Sterilizing Cure of HIV-1 Infection Without Stem Cell Transplantation

Turk, Gabriela; Seiger, Kyra; Lian, Xiaodong; Sun, Wei‐Zen; Parsons, Elizabeth M.; Gao, Ce; Rassadkina, Yelizaveta; Polo, María L.; Czernikier, Alejandro; Ghiglione, Yanina Alexandra; Vellicce, Alejandra; Varriale, Joseph; Lai, Jun; Yuki, Yuko; Martin, Maureen P.; Rhodes, Ajantha; Lewin, Sharon R; Walker, Bruce D.; Carrington, Mary; Siliciano, Robert F.; Siliciano, Janet D.; Lichterfeld, Mathias; Laufer, Natalia; Yu, Xu G.

doi:10.7326/l21-0297

Cited by 42 publications

(30 citation statements)

References 17 publications

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“…In this sense, Loucif et al. found an association between lipophagy (degradation of endogenous lipids via autophagy) as a critical immune mediator to induce functional antiviral CD8 + T-cell responses that have an important role in the natural control of HIV-1 infection in ECs ( 27 ). Concretely, enhanced lipophagy leads to fuel mitochondrial metabolism due to glutaminolysis and restores protective CD8A T-cell immunity during persistent HIV-1 infection in an IL-21-dependent manner ( 28 , 29 ).…”

Section: Discussionmentioning

confidence: 99%

Elevated α-Ketoglutaric Acid Concentrations and a Lipid-Balanced Signature Are the Key Factors in Long-Term HIV Control

et al. 2022

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Long-term elite controllers (LTECs) are a fascinating small subset of HIV individuals with viral and immunological HIV control in the long term that have been designated as models of an HIV functional cure. However, data on the LTEC phenotype are still scarce, and hence, the metabolomics and lipidomics signatures in the LTEC-extreme phenotype, LTECs with more than 10 years of viral and immunological HIV control, could be pivotal to finding the keys for functional HIV remission. Metabolomics and lipidomics analyses were performed using high-resolution mass spectrometry (ultra-high-performance liquid chromatography–electrospray ionization–quadrupole time of flight [UHPLC-(ESI) qTOF] in plasma samples of 13 patients defined as LTEC-extreme, a group of 20 LTECs that lost viral and/or immunological control during the follow-up study (LTEC-losing) and 9 EC patients with short-term viral and immunological control (less than 5 years; no-LTEC patients). Long-term viral and immunological HIV-1 control was found to be strongly associated with elevated tricarboxylic acid (TCA) cycle function. Interestingly, of the nine metabolites identified in the TCA cycle, α-ketoglutaric acid (p = 0.004), a metabolite implicated in the activation of the mTOR complex, a modulator of HIV latency and regulator of several biological processes, was found to be a key metabolite in the persistent control. On the other hand, a lipidomics panel combining 45 lipid species showed an optimal percentage of separation and an ability to differentiate LTEC-extreme from LTEC-losing, revealing that an elevated lipidomics plasma profile could be a predictive factor for the reignition of viral replication in LTEC individuals.

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Section: Discussionmentioning

confidence: 99%

Elevated α-Ketoglutaric Acid Concentrations and a Lipid-Balanced Signature Are the Key Factors in Long-Term HIV Control

et al. 2022

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“…Further studies with other HIV cohorts are needed to corroborate these findings. Of special interest would be to study the group of elite controllers that spontaneously control viral replication [ 31 ].…”

Section: Discussionmentioning

confidence: 99%

An Abnormal Inflammatory Pattern Associated with Long-Term Non-Progression of HIV Infection Impacts Negatively on Bone Quality

Soldado-Folgado

Chillarón

Cañas-Ruano

et al. 2022

JCM

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Introduction. Long-term non-progressors (LTNPs) are HIV-infected individuals (HIV+) whose viral replication is controlled. However, these individuals experience complications associated with HIV, among them, bone remodeling impairment. This study aims to perform a comprehensive bone health assessment and its association with the inflammatory status of HIV+ LTNPs. A cross-sectional study was conducted comparing bone strength components (bone mineral density and bone tissue quality) between age-, sex-, and comorbidities-matched groups of HIV+ LTNPs, HIV+ progressors, and HIV-negative individuals. A panel of bone turnover and inflammatory biomarkers was measured in fasting plasma using ELISA. Bone tissue quality was assessed by bone microindentation, a technique that directly measures the bone resistance to fracture and yields a dimensionless quantifiable parameter called bone material strength (BMSi). Thirty patients were included: ten LTNPs, ten HIV+ progressors, and ten HIV-negative individuals. LTNPs showed an abnormal pattern of immune activation that was represented by significantly lower levels of anti-inflammatory cytokine IL-10 (p = 0.03), pro-inflammatory cytokine IL-8 (p = 0.01), and TNF-α (p < 0.001) with respect to the other groups. Regarding bone health, LTNPs presented lower BMSi, and thus, worse bone tissue quality than HIV-negative individuals (83 (78–85) vs. 90 (89–93), respectively; p = 0.003), and also lower BMSi than HIV+ progressors (83 (78–85) vs. 86 (85–89), respectively; p = 0.022). A trend was found of lower BMSi in HIV+ progressors with respect to the HIV-negative individuals (86 (85–89) vs. 90 (89–93), respectively; p = 0.083). No differences were detected in bone mineral density between groups. In conclusion, LTNPs showed a different inflammatory profile, along with worse bone tissue quality, when compared to HIV+ progressors and HIV-negative individuals. This may contribute to increasing evidence that HIV infection itself has a deleterious effect on bone tissue, likely through a persistent altered inflammation status.

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“…Among people living with HIV-1, rare individuals naturally control viral replication, a control driven by a potent immune response that kill cells exposing viral proteins [ 7 ] in combination with a majority of proviruses integrated in repressive chromatin [ 8 ]. This combined approach of eliminating the reservoir of activatable proviruses while tolerating permanently silenced proviruses, produces a sustained, drug-free HIV-1 remission–a de facto HIV-1 cure [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

T cell stimulation remodels the latently HIV-1 infected cell population by differential activation of proviral chromatin

et al. 2022

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The reservoir of latently HIV-1 infected cells is heterogeneous. To achieve an HIV-1 cure, the reservoir of activatable proviruses must be eliminated while permanently silenced proviruses may be tolerated. We have developed a method to assess the proviral nuclear microenvironment in single cells. In latently HIV-1 infected cells, a zinc finger protein tethered to the HIV-1 promoter produced a fluorescent signal as a protein of interest came in its proximity, such as the viral transactivator Tat when recruited to the nascent RNA. Tat is essential for viral replication. In these cells we assessed the proviral activation and chromatin composition. By linking Tat recruitment to proviral activity, we dissected the mechanisms of HIV-1 latency reversal and the consequences of HIV-1 production. A pulse of promoter-associated Tat was identified that contrasted to the continuous production of viral proteins. As expected, promoter H3K4me3 led to substantial expression of the provirus following T cell stimulation. However, the activation-induced cell cycle arrest and death led to a surviving cell fraction with proviruses encapsulated in repressive chromatin. Further, this cellular model was used to reveal mechanisms of action of small molecules. In a proof-of-concept study we determined the effect of modifying enhancer chromatin on HIV-1 latency reversal. Only proviruses resembling active enhancers, associated with H3K4me1 and H3K27ac and subsequentially recognized by BRD4, efficiently recruited Tat upon cell stimulation. Tat-independent HIV-1 latency reversal of unknown significance still occurred. We present a method for single cell assessment of the microenvironment of the latent HIV-1 proviruses, used here to reveal how T cell stimulation modulates the proviral activity and how the subsequent fate of the infected cell depends on the chromatin context.

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A Possible Sterilizing Cure of HIV-1 Infection Without Stem Cell Transplantation

Cited by 42 publications

References 17 publications

Elevated α-Ketoglutaric Acid Concentrations and a Lipid-Balanced Signature Are the Key Factors in Long-Term HIV Control

Elevated α-Ketoglutaric Acid Concentrations and a Lipid-Balanced Signature Are the Key Factors in Long-Term HIV Control

An Abnormal Inflammatory Pattern Associated with Long-Term Non-Progression of HIV Infection Impacts Negatively on Bone Quality

T cell stimulation remodels the latently HIV-1 infected cell population by differential activation of proviral chromatin

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