Long-Term Follow-Up of Asymptomatic HIV-Infected Patients Who Discontinued Antiretroviral Therapy

Guerrero, Manuel L. Fernández; Rivas, Pedro; Molina, Mercedes; Garcı́a, R.; Górgolas, Miguel

doi:10.1086/431487

Cited by 26 publications

(9 citation statements)

References 24 publications

(29 reference statements)

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“…Treatment with ART is life-long as it only suppresses the replication of HIV but does not eradicate or cure the infection 218. Stopping ART results in HIV viral load rebound, progressive CD4 + T-cell count decline, and clinical disease progression 219. One of the primary aims of ART treatment is to maintain health by preventing clinical disease progression at low cost of drug toxicity 220.…”

Section: Treatment and Curabilitymentioning

confidence: 99%

Recent Insights into the HIV/AIDS Pandemic

Becerra

Bildstein²,

Gach

2016

MIC

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Etiology, transmission and protection: Transmission of HIV, the causative agent of AIDS, occurs predominantly through bodily fluids. Factors that significantly alter the risk of HIV transmission include male circumcision, condom use, high viral load, and the presence of other sexually transmitted diseases. Pathology/Symptomatology: HIV infects preferentially CD4+ T lymphocytes, and Monocytes. Because of their central role in regulating the immune response, depletion of CD4+ T cells renders the infected individual incapable of adequately responding to microorganisms otherwise inconsequential. Epidemiology, incidence and prevalence: New HIV infections affect predominantly young heterosexual women and homosexual men. While the mortality rates of AIDS related causes have decreased globally in recent years due to the use of highly active antiretroviral therapy (HAART) treatment, a vaccine remains an elusive goal. Treatment and curability: For those afflicted HIV infection remains a serious illness. Nonetheless, the use of advanced therapeutics have transformed a dire scenario into a chronic condition with near average life spans. When to apply those remedies appears to be as important as the remedies themselves. The high rate of HIV replication and the ability to generate variants are central to the viral survival strategy and major barriers to be overcome. Molecular mechanisms of infection: In this review, we assemble new details on the molecular events from the attachment of the virus, to the assembly and release of the viral progeny. Yet, much remains to be learned as understanding of the molecular mechanisms used in viral replication and the measures engaged in the evasion of immune surveillance will be important to develop effective interventions to address the global HIV pandemic.

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Section: Treatment and Curabilitymentioning

confidence: 99%

Recent Insights into the HIV/AIDS Pandemic

Becerra

Bildstein²,

Gach

2016

MIC

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“…In these cells, integrated proviral genomes undergo transcriptional silencing, can evade the immune system, are not able to be acted upon by traditional therapies, and allow the virus to persist for many years [1,2,4,5]. Upon cessation of therapy, the virus can be reactivated within the patient's body [6]. Recent studies propose a way to eradicate HIV-1 through activation of the silenced virus in resting memory CD4 + cells through a "shock and kill" approach [7,8].…”

Section: Introductionmentioning

confidence: 99%

Benzodiazepines Drive Alteration of Chromatin at the Integrated HIV-1 LTR

Elbezanti

Lin

Schirling

et al. 2020

Viruses

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Antiretroviral therapy (ART) lowers human immunodeficiency virus type 1 (HIV-1) viral load to undetectable levels, but does not eliminate the latent reservoir. One of the factors controlling the latent reservoir is transcriptional silencing of the integrated HIV-1 long terminal repeat (LTR). The molecular mechanisms that control HIV-1 transcription are not completely understood. We have previously shown that RUNX1, a host transcription factor, may play a role in the establishment and maintenance of HIV-1 latency. Prior work has demonstrated that inhibition of RUNX1 by the benzodiazepine (BDZ) Ro5-3335 synergizes with suberanilohydroxamic acid (SAHA) to activate HIV-1 transcription. In this current work, we examine the effect of RUNX1 inhibition on the chromatin state of the integrated HIV-1 LTR. Using chromatin immunoprecipitation (ChIP), we found that Ro5-3335 significantly increased the occupancy of STAT5 at the HIV-1 LTR. We also screened other BDZs for their ability to regulate HIV-1 transcription and demonstrate their ability to increase transcription and alter chromatin at the LTR without negatively affecting Tat activity. These findings shed further light on the mechanism by which RUNX proteins control HIV-1 transcription and suggest that BDZ compounds might be useful in activating HIV-1 transcription through STAT5 recruitment to the HIV-1 LTR.Viruses 2020, 12, 191 2 of 16 viral cytopathic effects, the host immune response or a second therapeutic intervention. At the same time, new infection of other cells would be controlled using antiretroviral therapy (ART) [9]. Proposed LRAs work through interfering with cellular mechanisms known to be involved in maintaining HIV-1 in a transcriptionally silent state [10]. The current commonly targeted mechanisms include (i) histone deacetylase inhibitors (HDACi) such as panobinostat, suberanilohydroxamic acid (SAHA; Vorinostat) and Trichostatin-A (TSA); (ii) bromodomain-containing protein inhibitors such as JQ1, and (iii) protein kinase C (PKC) agonists [11], which work through activation of NF-κB such as prostratin, bryostatin and ingenol. SAHA and other treatments have been unsuccessful in decreasing the size of the latent pool in vivo [9,[12][13][14][15]. Therefore, there is a need to further characterize the mechanisms that control HIV-1 transcription.The HIV-1 long terminal repeat (LTR) promoter is regulated by numerous transcription factors and chromatin-associated proteins. We have previously shown that the U3 region of HIV-1 contains a potential binding site for RUNX1 protein and that overexpression of RUNX1 and/or core binding factor-β (CBF-β) inhibits HIV-1 transcription. Conversely, suppression of endogenous RUNX1 or CBF-β with siRNA significantly increases HIV-1 transcription [16]. The benzodiazepine (BDZ) inhibitor of RUNX1/ CBF-β function, , synergizes with the HDAC inhibitor SAHA in activating HIV-1 transcription [16]. RUNX1 is one of three RUNX proteins found in humans, all of which possess a highly conserved 128 amino acid Runt DNA-binding domain at t...

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“…There are also other cellular reservoirs that are sources for re-emergence of virus including monocytes, macrophages, astrocytes, dendritic cells, hematopoietic progenitor cells, natural killer cells, mast cells and neurons [6]. HAART can decrease the plasma viral load to undetectable levels [7], but upon interruption of treatment viremia rebounds as a result of replication from this minimal population of latent cells [8]. Consequently a major limitation of HAART is that it does not represent a cure for the disease since it does not target the latent population.…”

Section: Introductionmentioning

confidence: 99%

An Upstream YY1 Binding Site on the HIV-1 LTR Contributes to Latent Infection

et al. 2013

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During HIV-1 infection a population of latently infected cells is established. This population is the major obstacle preventing total eradication of the virus from AIDS patients. HIV-1 latency is thought to arise by various mechanisms including repressive chromatin modifications. Transcription factors such as YY1 have been shown to facilitate repressive chromatin modifications by the recruitment of histone deacetylases. In this study, we identified a novel binding site for YY1 on the HIV-1 LTR, 120 nucleotides upstream of the transcription start site. We show that YY1 can bind to this site in vitro and in vivo and that binding to the LTR is dissociated upon T cell activation. Overexpression of YY1 causes an increase in the proportion of cells that produce latent infections. These observations, in combination with previous results, demonstrate that YY1 plays a prominent role in controlling the establishment and maintenance of latent HIV-1 provirus in unstimulated cells.

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Long-Term Follow-Up of Asymptomatic HIV-Infected Patients Who Discontinued Antiretroviral Therapy

Abstract: Selected asymptomatic HIV-infected patients can safely discontinue therapy for prolonged periods of time.

Cited by 26 publications

References 24 publications

Recent Insights into the HIV/AIDS Pandemic

Recent Insights into the HIV/AIDS Pandemic

Benzodiazepines Drive Alteration of Chromatin at the Integrated HIV-1 LTR

An Upstream YY1 Binding Site on the HIV-1 LTR Contributes to Latent Infection

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