Microbial translocation, immune activation, and HIV disease

doi:10.1016/j.tim.2012.09.001

Trends in Microbiology

Volume 21, Issue 1, January 2013, Pages 6-13

https://doi.org/10.1016/j.tim.2012.09.001 Get rights and content

The advent of combination antiretroviral therapy (cART) has significantly improved the prognosis of human immunodeficiency virus (HIV)-infected individuals. However, individuals treated long-term with cART still manifest increased mortality compared to HIV-uninfected individuals. This increased mortality is closely associated with inflammation, which persists in cART-treated HIV-infected individuals despite levels of plasma viremia below detection limits. Chronic, pathological immune activation is a key factor in progression to acquired immunodeficiency syndrome (AIDS) in untreated HIV-infected individuals. One contributor to immune activation is microbial translocation, which occurs when microbial products traverse the tight epithelial barrier of the gastrointestinal tract. Here we review the mechanisms underlying microbial translocation and its role in contributing to immune activation and disease progression in HIV infection.

Section snippets

Persistent immune activation and microbial translocation during HIV infection

The pathology of disease caused by HIV infection is complex and multifaceted. In addition to high levels of systemic viral replication, HIV infection results in chronic immune activation and overall immunological dysfunction, which are closely associated with progression to AIDS 1, 2, 3. Furthermore, even in HIV-infected individuals who are successfully treated with cART, persistent immune activation is associated with increased morbidity and mortality 4, 5, 6. Several lines of evidence

Immunological abnormalities in progressive infection

One of the earliest insults to the immune system after infection with HIV is direct infection and depletion of CD4 T cells [52]. This depletion first occurs rapidly in mucosal tissues, where high numbers of activated memory CD4 T cells (the preferred target of HIV) reside. A slower, and progressive, depletion of CD4 T cells in peripheral tissues and blood ensues [53]. Given that the majority of CD4 T cells reside within mucosal tissues, early loss of mucosal CD4 T cells represents loss of the

Evidence for microbial translocation

The human GI tract is colonized with approximately 10¹⁴ normal flora bacteria, which live in symbiosis with the host and can enhance immune function [72]. These organisms are essential for efficient metabolic function and digestion, and the human body has coevolved with microbiota leading to a symbiotic relationship that promotes a healthy GI tract [72]. Given the crucial importance for these bacteria to avoid direct contact with the systemic immune system, several structural and immunological

Microbial translocation and immune activation

Although the degree to which microbial translocation, viral replication (e.g., by HIV, CMV, and EBV), and proinflammatory cytokines cause immune activation in progressively HIV or SIV-infected individuals is unclear, several specific effects of microbial product-mediated immune activation can be considered. Indeed, chronic TLR activation in HIV disease, through recognition of translocated bacterial products and/or viral products, can cause dysregulation of immune responses 30, 75 and has been

Causes of microbial translocation

Several key mechanisms underlying microbial translocation have recently been identified (Figure 1). One defense mechanism which protects against microbial translocation is the structural barrier of the GI tract. The tight epithelial barrier is a single layer of cells which serves to protect the body from translocating bacteria and to absorb luminal nutrients [72]. During HIV or SIV infection the integrity of the tight epithelial barrier of the GI tract is compromised, which has been

Microbial translocation despite suppressed viremia

Current cART treatments can suppress viremia to undetectable levels for the life of an individual, and their use vastly improves the life expectancy of HIV-infected individuals. Further, suppressed viremia diminishes the majority of immune activation contributed to direct HIV replication. However, despite this virus suppression, cART-treated individuals still have increased morbidity and mortality compared to HIV-uninfected individuals, and this is associated with ongoing immune activation 4, 5

Therapeutic interventions to decrease microbial translocation

Given the GI tract dysfunctions that lead to microbial translocation and immune activation despite cART, to decrease morbidity and mortality in cART-treated individuals, therapeutic interventions aimed at improving GI tract function should be investigated (Box 1). Indeed, several studies have demonstrated promising results in enhancing mucosal immunity during HIV and SIV infection. For example, PD-1 blockade reduces immune activation and microbial translocation by decreasing type-I IFN

Concluding remarks

During HIV infection, the strongest predictor of disease progression is immune activation, which persists despite cART and is associated with morbidity and mortality. One cause of immune activation is microbial translocation, which occurs during HIV infection and is associated with driving immune activation and mortality even during cART treatment. Altered mucosal immunity and a damaged tight epithelial barrier of the GI tract probably underlie microbial translocation during HIV infection, and

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From 2020–2022, 75 SMM in Miami, Florida with and without HIV completed an online survey and provided biospecimens to assess HIV status and viral load (VL), recent stimulant use, and soluble markers of immune activation and inflammation in plasma, including soluble CD14 (sCD14) and elevated high-sensitivity C-reactive protein (hs-CRP > 1.0 mg/L). Sociodemographics and prior SARS-CoV-2 infection were compared across HIV status/stimulant use groups. Moderation models examined the independent and interactive associations of stimulant use and HIV status with sCD14 and elevated hs-CRP.
Thirty participants were persons living with HIV (PWH) (50% with stimulant use), and 45 were HIV-negative (44% with stimulant use). SARS-CoV-2 infection was not associated with stimulant use/HIV groups or immune outcomes. HIV-negative SMM without stimulant use had lower sCD14 compared to other SMM, as well as lower odds of elevated hs-CRP compared to PWH who used stimulants. Stimulant use showed independent associations with immune dysregulation that persisted after controlling for HIV status and VL, whereas HIV status was only independently associated with elevated hs-CRP in one model not controlling for VL.
Among SMM, stimulant use was independently associated with elevated immune activation and inflammation.
Immune recovery among Romanian HIV/AIDS patients receiving darunavir/ritonavir or darunavir/cobicistat regimens in cART management: A three-year study
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Approximately two-thirds of Romanian HIV patients were parenterally infected with the F subtype of HIV in early childhood. They are now in the context of immunological aging, with immunosuppression posing an additional challenge in developing the most effective and well-tolerated regimens. The risk of an improper immune recovery is higher in these patients than in newly diagnosed patients. The primary goal of this retrospective study was to conduct a comparative analysis of the immune recovery, measured at three time points, on 462 HIV-infected patients who were registered at the “Matei Balş National Institute of Infectious Diseases”, Bucharest, Romania, between 2018 and 2021, as follows: darunavir (DRV) 600 mg plus ritonavir (RTV) 100 mg (twice daily) was given to 384 patients, while DRV 800 mg plus cobicistat (COBI) 150 mg was given to 78 patients (once daily). The immune response was assessed by counting T lymphocytes, CD4 count cells/mm³, and the CD4/CD8 lymphocyte count ratio. Additionally, the study assessed the relationship between the immune and virological responses to therapy. Using various statistical tests, the results revealed that the immune response is normal in both groups, but with a statistically significant difference (p < 0.05) for the DRV/c group. Statistical associations between RNA viral plasma load and immune response (CD4 count and CD4/CD8 ratio) were assessed at all three visits and showed an insignificant association for the first two time points; however, at the final visit, the outcomes changed and reached statistical significance for both groups.
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Trends in Microbiology

ReviewMicrobial translocation, immune activation, and HIV disease

Section snippets

Persistent immune activation and microbial translocation during HIV infection

Immunological abnormalities in progressive infection

Evidence for microbial translocation

Microbial translocation and immune activation

Causes of microbial translocation

Microbial translocation despite suppressed viremia

Therapeutic interventions to decrease microbial translocation

Concluding remarks

Gastroenterology

J. Clin. Virol.

Mucosal Immunol.

Blood

Mucosal Immunol.

Blood

Mucosal Immunol.

Blood

Mucosal Immunol.

Blood

Blood

Semin. Immunol.

Trends Immunol.

Blood

Blood

Immunity

Shorter survival in advanced human immunodeficiency virus type 1 infection is more closely associated with T lymphocyte activation than with plasma virus burden or virus chemokine coreceptor usage

J. Infect. Dis.

Increased immune activation precedes the inflection point of CD4 T cells and the increased serum virus load in human immunodeficiency virus infection

J. Infect. Dis.

Relationship between T cell activation and CD4+ T cell count in HIV-seropositive individuals with undetectable plasma HIV RNA levels in the absence of therapy

J. Infect. Dis.

Inflammatory and coagulation biomarkers and mortality in patients with HIV infection

PLoS Med.

Activation and coagulation biomarkers are independent predictors of the development of opportunistic disease in patients with HIV infection

J. Infect. Dis.

Biomarkers of immune dysfunction following combination antiretroviral therapy for HIV infection

Biomark. Med.

Microbial translocation is a cause of systemic immune activation in chronic HIV infection

Nat. Med.

Microbial translocation is associated with increased monocyte activation and dementia in AIDS patients

PLoS ONE

Microbial translocation is associated with sustained failure in CD4+ T-cell reconstitution in HIV-infected patients on long-term highly active antiretroviral therapy

AIDS

Plasma levels of bacterial DNA correlate with immune activation and the magnitude of immune restoration in persons with antiretroviral-treated HIV infection

J. Infect. Dis.

High systemic levels of interleukin-10, interleukin-22 and C-reactive protein in Indian patients are associated with low in vitro replication of HIV-1 subtype C viruses

Retrovirology

Persistent microbial translocation and immune activation in HIV-1-infected South Africans receiving combination antiretroviral therapy

J. Infect. Dis.

Damaged intestinal epithelial integrity linked to microbial translocation in pathogenic simian immunodeficiency virus infections

PLoS Pathog.

Tryptophan catabolism by indoleamine 2,3-dioxygenase 1 alters the balance of TH17 to regulatory T cells in HIV disease

Sci. Transl. Med.

Disruption of intestinal CD4+ T cell homeostasis is a key marker of systemic CD4+ T cell activation in HIV-infected individuals

J. Immunol.

Serological markers for inflammatory bowel disease in AIDS patients with evidence of microbial translocation

PLoS ONE

Microbial translocation in simian immunodeficiency virus (SIV)-infected rhesus monkeys (Macaca mulatta)

J. Med. Primatol.

CD4 T-cell hyperactivation and susceptibility to cell death determine poor CD4 T-cell recovery during suppressive HAART

AIDS

Exposure to HIV-1 directly impairs mucosal epithelial barrier integrity allowing microbial translocation

PLoS Pathog.

Microbial translocation correlates with the severity of both HIV-1 and HIV-2 infections

J. Infect. Dis.

Biological determinants of immune reconstitution in HIV-infected patients receiving antiretroviral therapy: the role of interleukin 7 and interleukin 7 receptor alpha and microbial translocation

J. Infect. Dis.

Programmed death-1-induced interleukin-10 production by monocytes impairs CD4+ T cell activation during HIV infection

Nat. Med.

A role for syndecan-1 and claudin-2 in microbial translocation during HIV-1 infection

J. Acquir. Immune Defic. Syndr.

Microbial translocation induces persistent macrophage activation unrelated to HIV-1 levels or T-cell activation following therapy

AIDS

Endotoxemia is associated with altered innate and adaptive immune responses in untreated HIV-1 infected individuals

PLoS ONE

Sigmoid Th17 populations, the HIV latent reservoir, and microbial translocation in men on long-term antiretroviral therapy

AIDS

HIV persistence in the gut mucosa of HIV-infected subjects undergoing antiretroviral therapy correlates with immune activation and increased levels of LPS

Review
Microbial translocation, immune activation, and HIV disease

Relationship between T cell activation and CD4⁺ T cell count in HIV-seropositive individuals with undetectable plasma HIV RNA levels in the absence of therapy

Microbial translocation is associated with sustained failure in CD4⁺ T-cell reconstitution in HIV-infected patients on long-term highly active antiretroviral therapy

Disruption of intestinal CD4⁺ T cell homeostasis is a key marker of systemic CD4⁺ T cell activation in HIV-infected individuals

Programmed death-1-induced interleukin-10 production by monocytes impairs CD4⁺ T cell activation during HIV infection

Microbial translocation predicts disease progression of HIV-infected antiretroviral-naive patients with high CD4⁺ cell count

Altered CD4⁺ T cell homing to the gut impairs mucosal immune reconstitution in treated HIV-infected individuals