Hospitalization Rates and Reasons Among HIV Elite Controllers and Persons With Medically Controlled HIV Infection

Crowell, Trevor A; Gebo, Kelly A.; Blankson, Joel N.; Korthuis, P. Todd; Yehia, Baligh R.; Rutstein, Richard M.; Moore, Richard D.; Sharp, Victoria L.; Nijhawan, Ank E.; Mathews, W. Christopher; Hanau, Lawrence H.; Corales, Roberto; Beil, Robert; Somboonwit, Charurut; Edelstein, Howard; Allen, S; Berry, Stephen

doi:10.1093/infdis/jiu809

Cited by 108 publications

(119 citation statements)

References 43 publications

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“…This response, in turn, readily controls the infection, maintaining a steady state between infected cells and the immune system (Fig. 5A), which may result in residual systemic activation and mild progression in the absence of therapy (45)(46)(47). The virtuous circle between the virus and the host response would be interrupted when the frequency of latently infected CD4 ϩ T cells falls to a very low level, hindering the stochastic reactivation of fit viruses (18) and leading to fewer viral amplification events.…”

Section: Discussionmentioning

confidence: 99%

Long-Term Spontaneous Control of HIV-1 Is Related to Low Frequency of Infected Cells and Inefficient Viral Reactivation

Noël

Peña

David

et al. 2016

J Virol

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HIV establishes reservoirs of infected cells that persist despite effective antiretroviral therapy (ART). In most patients, the virus begins to replicate soon after treatment interruption. However, a low frequency of infected cells at the time of treatment interruption has been associated with delayed viral rebound. Likewise, individuals who control the infection spontaneously, so-called HIV-1 controllers (HICs), carry particularly low levels of infected cells. It is unclear, however, whether and how this small number of infected cells contributes to durable viral control. Here we compared 38 HICs with 12 patients on effective combined antiretroviral therapy (cART) and found that the low frequency of infected cells in the former subjects was associated both with less efficient viral reactivation in resting CD4؉ T cells and with less efficient virion production ex vivo. We also found that a potent HIV-specific CD8 ؉ T cell response was present only in those HICs whose CD4 ؉ T cells produced virus ex vivo. Long-term spontaneous control of HIV infection in HICs thus appears to be sustained on the basis of the inefficient reactivation of viruses from a limited number of infected cells and the capacity of HICs to activate a potent HIV-specific CD8؉ T cell response to counteract efficient viral reactivation events. IMPORTANCEThere is a strong scientific interest in developing strategies to eradicate the HIV-1 reservoir. Very rare HIV-1-infected patients are able to spontaneously control viremia for long periods of time (HIV-1 controllers [HICs]) and are put forward as a model of HIV-1 remission. Here, we show that the low viral reservoirs found in HICs are a critical part of the mechanisms underlying viral control and result in a lower probability of HIV-1 reactivation events, resulting in limited HIV-1 release and spread. We found that those HICs in whom viral reactivation and spread from CD4 ؉ T cells in vitro were the most difficult were those with diminished CD8 ؉ T cell responses. These results suggest that, in some settings, low HIV-1 reservoirs decisively contribute to at least the temporary control of infection without antiretroviral therapy. We believe that this work provides information of relevance in the context of the search for HIV-1 remission.

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Section: Discussionmentioning

confidence: 99%

Long-Term Spontaneous Control of HIV-1 Is Related to Low Frequency of Infected Cells and Inefficient Viral Reactivation

Noël

Peña

David

et al. 2016

J Virol

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“…Alterations in innate immune function have also been reported in EC with increased inflammatory monocytes compared to HIV uninfected controls [22]. Recently, EC have also been shown to have elevated levels of key soluble inflammatory markers [23] and higher hospitalization rates than ART treated individuals [24]. …”

Section: Introductionmentioning

confidence: 99%

Normal T-cell activation in elite controllers with preserved CD4+ T-cell counts

Bansal

Erdmann

Westfall

et al. 2015

Aids

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Background HIV Elite controllers (EC) suppress HIV viremia without ART, yet previous studies demonstrated that EC maintain an activated T cell phenotype. Chronic immune activation has detrimental consequences and thus ART has been advocated for all EC. However, EC is not a clinically homogenous group. Since CD4% is among the best predictors of AIDS related events, in the current study, we assessed whether this marker can be used to stratify EC needing ART. Methods Sixteen EC were divided into 2 groups based on CD4% (EChi>40% and EClo ≤40%), and T cell subsets were analyzed for markers of memory/differentiation (CD45RA, CCR7, CD28), activation (CD38/HLA-DR), immunosenescence (CD57), co-stimulation (CD73, CD28) and exhaustion (PD-1, CD160, Tim-3). Monocyte subsets (CD14, CD16) were also analyzed and sCD14 levels were quantified using ELISA. Results In the EChi group, expression of activation, exhaustion, and immunosensescence markers on T cells were significantly reduced compared to the EClo group and similar to the seronegative controls. The EChi group expressed higher levels of co-stimulatory molecules CD28 and CD73 and had lower levels of monocyte activation (HLA-DR expression) with a reduced frequency of inflammatory monocyte (CD14++CD16+) subset. Furthermore, the EChi group maintained a stable CD4% during a median follow up of six years. Conclusions Elite controllers with preserved CD4 T cells (EChi) have normal T cell and monocyte phenotypes and therefore may have limited benefit from antiretroviral therapy (ART). CD4% can be an important marker for evaluating future studies aimed at determining the need for ART in this group of individuals.

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“…And despite the success of ART, and our ability to achieve viral suppression, there will be the growing future burden of treating an aging population of HIV-infected individuals suffering additional HIV-related illness. Recent reports indicate that elite controllers who maintain viral levels below detectable limits in the absence of ART, have a 2-fold increased level of hospitalization 66 and add a further confounder to our understanding of the long term effects of HIV infection. Gene therapy using CRISPR/Cas9 presents new opportunities to address some of the fundamental barriers to progress.…”

Section: Expert Opinionmentioning

confidence: 99%

The therapeutic application of CRISPR/Cas9 technologies for HIV

Saayman

Ali

Morris

et al. 2015

Expert Opinion on Biological Therapy

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Introduction The use of antiretroviral therapy (ART) has led to a significant decrease in morbidity and mortality in HIV-infected individuals. Nevertheless gene-based therapies represent a promising therapeutic paradigm for HIV-1, as they have the potential for sustained viral inhibition and reduced treatment interventions. One new method amendable to a gene-based therapy is the clustered regularly interspaced palindromic repeats (CRISPR)/Cas9 gene editing system. Areas covered CRISPR/Cas9 can be engineered to successfully modulate an array of disease-causing genetic elements. We discuss the diverse roles that CRISPR/Cas9 may play in targeting HIV and eradicating infection. The Cas9 nuclease coupled with one or more small guide RNAs (sgRNAs) can target the provirus to mediate excision of the integrated viral genome. Moreover, a modified nuclease deficient Cas9 fused to transcription activating domains may induce targeted activation of proviral gene expression allowing for the purging of the latent reservoirs. These technologies can also be exploited to target host dependency factors such as the co-receptor CCR5, thus preventing cellular entry of the virus. Expert opinion The diversity of the CRISPR/Cas9 technologies hold great promise for targeting different stages of the viral life cycle, and have the capacity for mediating an effective and sustained genetic therapy against HIV.

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Hospitalization Rates and Reasons Among HIV Elite Controllers and Persons With Medically Controlled HIV Infection

Abstract: Elite controllers are hospitalized more frequently than persons with medically controlled HIV and cardiovascular hospitalizations are an important contributor.

Cited by 108 publications

References 43 publications

Long-Term Spontaneous Control of HIV-1 Is Related to Low Frequency of Infected Cells and Inefficient Viral Reactivation

Long-Term Spontaneous Control of HIV-1 Is Related to Low Frequency of Infected Cells and Inefficient Viral Reactivation

Normal T-cell activation in elite controllers with preserved CD4+ T-cell counts

The therapeutic application of CRISPR/Cas9 technologies for HIV

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