Making sense of how HIV kills infected CD4 T cells: implications for HIV cure

Cummins, Nathan W.; Badley, Andrew D.

doi:10.1186/2052-8426-2-20

Cited by 26 publications

(29 citation statements)

References 59 publications

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“…systemic inflammation, potentially reducing future HIVrelated complications (such as cardiovascular events) triggered by BT and inflammation. In this context, several studies have previously demonstrated that starting treatment with INSTIs and/or the intensification or switching to this regimen is associated with a favourable effect on HIVrelated immune activation and also with inhibition of CD4-T cell depletion [28][29][30][31][32] which is in line with our findings. It is also important to note than although an increase in BT and inflammation was observed in HIV-infected patients compared with the controls, such a difference was only significant in HIV-patients using cART.…”

Section: Discussionsupporting

confidence: 92%

Differential effects of antiretrovirals on microbial translocation and gut microbiota composition of HIV‐infected patients

Villanueva-Millán

Pérez-Matute

Recio-Fernández

et al. 2017

Journal of the International AIDS Society

102

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Introduction: Increased bacterial translocation and alterations to gut microbiota composition have been described in HIV infection and contribute to immune activation and inflammation. These effects persist despite combined antiretroviral therapy (cART). However, the contribution of different cART combinations has not yet been investigated. The aim of this study was to analyse the long-term effects of different combinations of cART on bacterial translocation and gut microbiota composition in HIV-infected patients. Methods: We carried out a cross-sectional study of 45 HIV-infected patients on cART, classified as nucleoside reverse transcriptase inhibitors (NRTIs)+ protease inhibitors (PIs) (n = 15), NRTIs+ non-nucleoside reverse transcriptase inhibitors (NNRTIs) (n = 22), and NRTIs+ integrase strand transfer inhibitors (INSTIs) (n = 8). Untreated HIV-infected patients (n = 5) and non-infected volunteers (n = 21) were also included. Soluble markers of bacterial translocation and inflammation were measured and gut microbiota composition was analysed using 16S rDNA pyrosequencing (Illumina MiSeq). Results: The NRTIs+INSTIs regimen was associated with levels of systemic inflammation that were similar to uninfected controls. The reduction in faecal bacterial diversity induced by HIV infection was also restored by this regimen. HIV infection was more closely related to changes in lower taxonomic units and diversity rather than at the phylum level. The NRTIs+PIs regimen showed the highest reduction in bacterial species, whereas NRTIs+INSTIs induced a minor loss of bacterial species and a significant increase in others. Conclusions: Our study demonstrated that INSTI-based ART was associated with levels of systemic inflammation and microbial diversity similar to that of uninfected controls. The role of INSTIs other than raltegravir needs to be further investigated. Patients on the NRTIs+PIs regimen presented the highest reduction in bacterial species compared with other antiretrovirals and naive patients. Thus, different cART regimens are associated with diverse profiles in gut microbiota composition. Longitudinal and functional studies are needed to better understand these findings.

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Section: Discussionsupporting

confidence: 92%

Differential effects of antiretrovirals on microbial translocation and gut microbiota composition of HIV‐infected patients

Villanueva-Millán

Pérez-Matute

Recio-Fernández

et al. 2017

Journal of the International AIDS Society

102

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“…This gene is analogous to the pol gene that encodes reverse transcriptase (RT) and integrase. The integration of the viral genome into the host cell's DNA has a high probability of failing, which is referred to as abortive infection, often leading to apoptosis or pyroptosis of the cell [20]. We model this with a virus-controlled parameter f , representing the fraction of successfully infected cells.…”

Section: The Most Obvious Parameter Under Control Of the Virus Is Thementioning

confidence: 99%

“…Variation in d V can further be caused by differences in antibody affinities and concentrations. Even in the absence of an immune response, an infected cell experiences a virus-induced cytopathic effect [20]. We model this using a viruscontrolled parameter α, which is added to the death rate of virion producing cells.…”

Section: The Most Obvious Parameter Under Control Of the Virus Is Thementioning

confidence: 99%

Modeling the immunological pre-adaptation of HIV-1

Dorp

Boven

Boer³

2020

Preprint

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It is becoming increasingly evident that the evolution of HIV-1 is to a large extent determined by the immunological background of the host. On the population-level this results in associations between specific human leukocyte antigen (HLA) alleles and polymorphic loci of the virus. Furthermore, some HLA alleles that were previously associated with slow progression to AIDS have been shown to lose their protective effect, because HLA-specific immunological escape variants have spread through the population. This phenomenon is known as immunological preadaptation. Apart from adapting to human immune responses, the set-point virus load (SPVL) of HIV-1 is thought to have evolved to values that optimize the population-level fitness of the virus. This suggestion is supported by considerable heritability of the SPVL. Previous modeling studies show that whether or not SPVL optimization is expected to occur depends sensitively on the underlying assumptions with respect to the extent of within-versus between-host selection. Here we use a detailed and semi-realistic multi-level HIV-1 model in which immunological preadaptation and SPVL evolution can emerge from the underlying interactions of the virus with the immune system of the host. This enables us to study the effect of immunological escape on disease progression, and how disease progression may be molded by SPVL evolution. We find that the time to AIDS could decrease significantly (0.5-1.0 years) in a HLA-dependent manner by immunological pre-adaptation over the long-term course of the epidemic (> 100 years). We find that SPVL is not expected to evolve to optimize the population-level fitness of HIV-1, even though high heritability of the SPVL emerges from continual selection of immune-escape mutations.

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“…While many strategies promote the elimination of virus-expressing cells via the immune system (8)(9)(10)(11), another approach is to directly target and kill latent HIV-infected T cells (12). There is evidence that HIV infection affects both pro-apoptotic and anti-apoptotic signaling pathways (13)(14)(15) and targeting these pathways in combination with LRAs has the potential to reduce reservoir size (16). However, due to the interconnected, multivariate nature of signaling pathways that regulate apoptosis (17)(18)(19) and the heterogeneous nature of latent HIV activation (20,21), successful identification of novel therapeutic targets requires systems-level single-cell analysis.…”

Section: Introductionmentioning

confidence: 99%

Systems analysis by mass cytometry identifies susceptibility of latent HIV-infected T cells to targeting of p38 and mTOR pathways

Spudich

et al. 2018

Preprint

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Efforts to cure HIV are hindered by viral persistence in latently infected memory CD4+ T cells.Targeting T cell death pathways dysregulated by HIV infection offers a novel approach for eradication of the latent reservoir. To identify potential therapeutic targets, we compared signaling and apoptosis in uninfected and latently infected primary cultured CD4+ central memory T cells by mass cytometry following T cell receptor stimulation. We found that HIV-infected cells were sensitized to activation of pro-apoptotic p38 kinase signaling via p53, and to inhibition of antiapoptotic mTOR kinase signaling, even without HIV protein expression. Simultaneous targeting of p38 and mTOR kinases in resting CD4+ T cells from virally-suppressed HIV+ patients ex vivo reduced cell-associated HIV RNA and DNA. Our results demonstrate how systems biology approaches are useful for identifying novel therapeutic approaches to treat HIV latency, and further suggest that it may be possible to deplete latent HIV-infected T cells without viral reactivation.

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Making sense of how HIV kills infected CD4 T cells: implications for HIV cure

Cited by 26 publications

References 59 publications

Differential effects of antiretrovirals on microbial translocation and gut microbiota composition of HIV‐infected patients

Differential effects of antiretrovirals on microbial translocation and gut microbiota composition of HIV‐infected patients

Modeling the immunological pre-adaptation of HIV-1

Systems analysis by mass cytometry identifies susceptibility of latent HIV-infected T cells to targeting of p38 and mTOR pathways

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