Distinct biomarker signatures in HIV acute infection associate with viral dynamics and reservoir size

Teigler, Jeffrey E.; Leyre, Louise; Chomont, Nicolas; Slike, Bonnie M.; Jian, Ningbo; Eller, Michael A.; Phanuphak, Nittaya; Kroon, Eugène; Pinyakorn, Suteeraporn; Eller, Leigh Anne; Robb, Merlin L.; Ananworanich, Jintanat; Michael, Nelson L.; Streeck, Hendrik; Krebs, Shelly J.

doi:10.1172/jci.insight.98420

Cited by 32 publications

(33 citation statements)

References 66 publications

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“…Similar observations of the cytokine storm have been reported in acute pathogenic SIV infections in rhesus macaques [8][9][10][11]. Even though the initiation of ART significantly reduces the plasma levels of inflammatory cytokines, some residual immune activation has been reported to persist even after the early initiation of ART [7,12,13].…”

Section: Introductionsupporting

confidence: 73%

“…HIV infection is associated with immune activation which manifests in the elevation of numerous plasma cytokines and chemokines [1][2][3][4][5][6][7]. Notably, the elevation of some plasma cytokines occurs very early after infection, with acute HIV infection (AHI) being characterized by the onset of a cytokine storm in the period leading up to peak viremia [1,2,4,6].…”

Section: Introductionmentioning

confidence: 99%

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Association between the cytokine storm, immune cell dynamics, and viral replicative capacity in hyperacute HIV infection

Muema

Akilimali

Ndumnego

et al. 2020

BMC Med

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Introduction: Immunological damage in acute HIV infection (AHI) may predispose to detrimental clinical sequela. However, studies on the earliest HIV-induced immunological changes are limited, particularly in sub-Saharan Africa. We assessed the plasma cytokines kinetics, and their associations with virological and immunological parameters, in a well-characterized AHI cohort where participants were diagnosed before peak viremia. Methods: Blood cytokine levels were measured using Luminex and ELISA assays pre-infection, during the hyperacute infection phase (before or at peak viremia, 1-11 days after the first detection of viremia), after peak viremia (24-32 days), and during the early chronic phase (77-263 days). Gag-protease-driven replicative capacities of the transmitted/founder viruses were determined using a green fluorescent reporter T cell assay. Complete blood counts were determined before and immediately following AHI detection before ART initiation. Results: Untreated AHI was associated with a cytokine storm of 12 out of the 33 cytokines analyzed. Initiation of ART during Fiebig stages I-II abrogated the cytokine storm. In untreated AHI, virus replicative capacity correlated positively with IP-10 (rho = 0.84, P < 0.001) and IFN-alpha (rho = 0.59, P = 0.045) and inversely with nadir CD4 + T cell counts (rho = − 0.58, P = 0.048). Hyperacute HIV infection before the initiation of ART was associated with a transient increase in monocytes (P < 0.001), decreased lymphocytes (P = 0.011) and eosinophils (P = 0.003) at Fiebig stages I-II, and decreased eosinophils (P < 0.001) and basophils (P = 0.007) at Fiebig stages III-V. Levels of CXCL13 during the untreated hyperacute phase correlated inversely with blood eosinophils (rho = − 0.89, P < 0.001), basophils (rho = − 0.87, P = 0.001) and lymphocytes (rho = − 0.81, P = 0.005), suggesting their trafficking into tissues. In early treated individuals, time to viral load suppression correlated positively with plasma CXCL13 at the early chronic phase (rho = 0.83, P = 0.042). Conclusion: While commencement of ART during Fiebig stages I-II of AHI abrogated the HIV-induced cytokine storm, significant depletions of eosinophils, basophils, and lymphocytes, as well as transient expansions of monocytes, were still observed in these individuals in the hyperacute phase before the initiation of ART, suggesting that even ART initiated during the onset of viremia does not abrogate all HIV-induced immune changes.

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Section: Introductionsupporting

confidence: 73%

Section: Introductionmentioning

confidence: 99%

Association between the cytokine storm, immune cell dynamics, and viral replicative capacity in hyperacute HIV infection

Muema

Akilimali

Ndumnego

et al. 2020

BMC Med

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“…Several studies have shown that the plasma cytokine profiles of HIV-infected individuals differ from the profiles of uninfected individuals. [64,65] Higher levels of IL-1, IL-6, IL-7, G-CSF and tumour necrosis factor α (TNFα) were detected in the plasma of HIV-infected patients. Pro-inflammatory cytokines TNFα, IL-1 and IL-6 and chemokines macrophage inflammatory protein (MIP)-1α, MIP-1β and RANTES were also found to be up-regulated in the bone marrow of HIV-infected individuals.…”

Section: Hiv-associated Auto-immune Reactionsmentioning

confidence: 99%

HIV and haematopoiesis

et al. 2019

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Human immunodeficiency virus (HIV) infection not only leads to a compromised immune system, but also disrupts normal haematopoiesis, resulting in the frequent manifestation of cytopenias (anaemia, thrombocytopenia and neutropenia). Although there is a definite association between the severity of cytopenia and HIV disease stage, this relationship is not always linear. For example, cytopenias such as thrombocytopenia may occur during early stages of infection. The aetiology of these haematological abnormalities is complex and multifactorial, including druginduced impaired haematopoiesis, bone marrow suppression due to infiltration of infectious agents or malignant cells, HIV-induced impaired haematopoiesis, and several other factors. In this review, we describe the frequencies of anaemia, thrombocytopenia and neutropenia reported for HIV-infected, treatment-naïve cohorts studied in eastern and southern sub-Saharan African countries. We present a rational approach for the use of diagnostic tests during the workup of HIV-infected patients presenting with cytopenia, and discuss how HIV impacts on haematopoietic stem/progenitor cells (HSPCs) resulting in impaired haematopoiesis. Finally, we describe the direct and indirect effects of HIV on HSPCs which result in defective haematopoiesis leading to cytopenias. S Afr Med J 2019;109(8 Suppl 1):S41-S46. https://doi.org/10.7196/SAMJ.2019.v109i8b.13829 Fig. 1. Schematic illustration of the differentiation of haematopoietic stem/progenitor cells (HSPCs) into mature blood cell types. (MPP = multipotent progenitor; CMP = common myeloid progenitor; CLP = common lymphoid progenitor; MEP = megakaryocyte-erythroid progenitor; GMP = granulocytemacrophage progenitor; NK = natural killer cell.)

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“…Immunological factors also play a role. The homeostatic proliferation (22) and clonal expansion (23)(24)(25)(26)(27)(28) of latently HIV-infected CD4 ϩ T cells directly influence the latent HIV reservoir size and dynamics, and evidence indicates that initial antiviral immune responses may also modulate reservoir establishment and persistence (29,30). A recent longitudinal study of an acute infection cohort reported that the pretherapy levels of key cytokines correlated with HIV DNA levels after 96 weeks of cART (29).…”

mentioning

confidence: 99%

“…The homeostatic proliferation (22) and clonal expansion (23)(24)(25)(26)(27)(28) of latently HIV-infected CD4 ϩ T cells directly influence the latent HIV reservoir size and dynamics, and evidence indicates that initial antiviral immune responses may also modulate reservoir establishment and persistence (29,30). A recent longitudinal study of an acute infection cohort reported that the pretherapy levels of key cytokines correlated with HIV DNA levels after 96 weeks of cART (29). Moreover, a previous analysis of the cohort evaluated in the present study identified baseline HIV-specific granzyme B responses, contributed mainly by human leukocyte antigen class I (HLA-I)-restricted CD8 ϩ T cells, to be significant negative correlates of the reservoir size at 48 weeks post-cART, as measured in terms of HIV proviral loads as well as the levels of replication-competent viral infectious units per million CD4 ϩ T cells (IUPM) (30).…”

mentioning

confidence: 99%

HIV Subtype and Nef-Mediated Immune Evasion Function Correlate with Viral Reservoir Size in Early-Treated Individuals

Omondi

Chandrarathna

Mujib

et al. 2019

J Virol

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The HIV accessory protein Nef modulates key immune evasion and pathogenic functions, and its encoding gene region exhibits high sequence diversity. Given the recent identification of early HIV-specific adaptive immune responses as novel correlates of HIV reservoir size, we hypothesized that viral factors that facilitate the evasion of such responses—namely, Nef genetic and functional diversity—might also influence reservoir establishment and/or persistence. We isolated baseline plasma HIV RNA-derivednefclones from 30 acute/early-infected individuals who participated in a clinical trial of early combination antiretroviral therapy (cART) (<6 months following infection) and assessed each Nef clone's ability to downregulate CD4 and human leukocyte antigen (HLA) class Iin vitro. We then explored the relationships between baseline clinical, immunological, and virological characteristics and the HIV reservoir size measured 48 weeks following initiation of suppressive cART (where the reservoir size was quantified in terms of the proviral DNA loads as well as the levels of replication-competent HIV in CD4+T cells). Maximal within-host Nef-mediated downregulation of HLA, but not CD4, correlated positively with post-cART proviral DNA levels (Spearman'sR = 0.61,P = 0.0004) and replication-competent reservoir sizes (Spearman'sR = 0.36,P = 0.056) in univariable analyses. Furthermore, the Nef-mediated HLA downregulation function was retained in final multivariable models adjusting for established clinical and immunological correlates of reservoir size. Finally, HIV subtype B-infected persons (n = 25) harbored significantly larger viral reservoirs than non-subtype B-infected persons (2 infected with subtype CRF01_AE and 3 infected with subtype G). Our results highlight a potentially important role of viral factors—in particular, HIV subtype and accessory protein function—in modulating viral reservoir establishment and persistence.IMPORTANCEWhile combination antiretroviral therapies (cART) have transformed HIV infection into a chronic manageable condition, they do not act upon the latent HIV reservoir and are therefore not curative. As HIV cure or remission should be more readily achievable in individuals with smaller HIV reservoirs, achieving a deeper understanding of the clinical, immunological, and virological determinants of reservoir size is critical to eradication efforts. We performed apost hocanalysis of 30 participants of a clinical trial of early cART who had previously been assessed in detail for their clinical, immunological, and reservoir size characteristics. We observed that the HIV subtype and autologous Nef-mediated HLA downregulation function correlated with the viral reservoir size measured approximately 1 year post-cART initiation. Our findings highlight virological characteristics—both genetic and functional—as possible novel determinants of HIV reservoir establishment and persistence.

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Distinct biomarker signatures in HIV acute infection associate with viral dynamics and reservoir size

Cited by 32 publications

References 66 publications

Association between the cytokine storm, immune cell dynamics, and viral replicative capacity in hyperacute HIV infection

Association between the cytokine storm, immune cell dynamics, and viral replicative capacity in hyperacute HIV infection

HIV and haematopoiesis

HIV Subtype and Nef-Mediated Immune Evasion Function Correlate with Viral Reservoir Size in Early-Treated Individuals

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