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HIV infection and immune activation: the role of coinfections.

ABSTRACT: PURPOSE OF REVIEW:This article explores new data from recent studies addressing the role of coinfections in immune activation in HIV-1-infected patients, with a focus on immune reconstitution inflammatory syndrome (IRIS), an aberrant inflammatory response occurring shortly after antiretroviral therapy (ART) initiation. RECENT FINDINGS:Chronic HIV infection is associated with several coinfections that contribute to immune activation in various settings including early after ART initiation in the most noticeable form of IRIS and also in chronic-treated infection, with chronic viral infections like cytomegalovirus and hepatitis C or hepatitis B virus contributing to immune activation and also morbidity and mortality. Expanding on older studies, the role of T cells in IRIS has been further elucidated with evidence of more pronounced effector activity in patients with IRIS that may be leading to excessive tissue disorder. Newer studies are also continuing to shed light on the role of myeloid cells as well as the contribution of antigen load in IRIS. In addition, preliminary data are beginning to suggest a possible role of inflammasome formation in IRIS. In cryptococcal IRIS, the role of activated immune cells (T cell and myeloid) and biomarkers were evaluated in more detail at the site of infection (cerebrospinal fluid). Finally, important differences of patients developing IRIS versus those who die from tuberculosis despite ART initiation were reported, a distinction that may have important implications for participant selection in studies aiming to prevent IRIS with immunosuppressive agents. SUMMARY:Better understanding of the role of opportunistic infections at ART initiation and IRIS pathogenesis will assist in improved strategies for prevention and treatment. The long-term consequences of IRIS remain unclear. Chronic viral coinfections with herpesviruses and hepatitis C virus are important factors in persistent immune activation in chronic-treated HIV.

SUBMITTER: Boulougoura A

PROVIDER: S-EPMC4831133 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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HIV infection and immune activation: the role of coinfections.

Boulougoura Afroditi A Sereti Irini I

Current opinion in HIV and AIDS 20160301 2

<h4>Purpose of review</h4>This article explores new data from recent studies addressing the role of coinfections in immune activation in HIV-1-infected patients, with a focus on immune reconstitution inflammatory syndrome (IRIS), an aberrant inflammatory response occurring shortly after antiretroviral therapy (ART) initiation.<h4>Recent findings</h4>Chronic HIV infection is associated with several coinfections that contribute to immune activation in various settings including early after ART ini ...[more]

PMID: 26720550

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Project description:BackgroundAlthough immune activation is associated with HIV acquisition, the nature of inflammatory profiles that increase HIV risk, which may include responses to M. tuberculosis (Mtb) infection, are not well characterized.MethodsWe conducted a nested case-control study using cryopreserved samples from persons who did and did not acquire HIV during the multinational Step clinical trial of the MRKAd5 HIV-1 vaccine. PBMCs from the last HIV-negative sample from incident HIV cases and controls were stimulated with Mtb-specific antigens (ESAT-6/CFP-10) and analyzed by flow cytometry with intracellular cytokine staining and scored with COMPASS. We measured inflammatory profiles with five Correlates of TB Risk (CoR) transcriptomic signatures. Our primary analysis examined the association of latent Mtb infection (LTBI; IFNγ+CD4+ T cell frequency) or RISK6 CoR signature with HIV acquisition. Conditional logistic regression analyses, adjusted for known predictors of HIV acquisition, were employed to assess whether TB-associated immune markers were associated with HIV acquisition.ResultsAmong 465 participants, LTBI prevalence (21.5% controls vs 19.1% cases, p = 0.51) and the RISK6 signature were not higher in those who acquired HIV. In exploratory analyses, Mtb antigen-specific polyfunctional CD4+ T cell COMPASS scores (aOR 0.96, 95% CI 0.77, 1.20) were not higher in those who acquired HIV. Two CoR signatures, Sweeney3 (aOR 1.38 (1.07, 1.78) per SD change) and RESPONSE5 (0.78 (0.61, 0.98)), were associated with HIV acquisition. The transcriptomic pattern used to differentiate active vs latent TB (Sweeney3) was most strongly associated with acquiring HIV.ConclusionsLTBI, Mtb polyfunctional antigen-specific CD4+ T cell activation, and RISK6 were not identified as risks for HIV acquisition. In exploratory transcriptomic analyses, two CoR signatures were associated with HIV risk after adjustment for known behavioral and clinical risk factors. We identified host gene expression signatures associated with HIV acquisition, but the observed effects are likely not mediated through Mtb infection.

Project description:Although conventional regulatory T cells (Tregs) are sufficient in controlling low residual T-cell activation in ART-treated patients, they are not efficient in controlling exaggerated immune activation associated with high levels of HIV replication in primary HIV infection (PHI). Our previous data suggested that double negative (DN) T cells including mainly γδ DN T cells play a role in the control of immune activation in PHI. Since γδ T cells are capable of exerting regulatory functions, we investigated their implication as Tregs in PHI as well as chronic HIV infection (CHI). In a cross-sectional study of 58 HIV-infected patients, in the primary and the chronic phase either ART-treated or untreated (UT), we analyzed phenotype and cytokine production of γδ T cells using flow cytometry. Cytokine production was assessed following in vitro stimulation with isopentenyl pyrophosphate or plate-bound anti-CD3/anti-CD28 monoclonal antibodies. We found that the proportion of γδ T cells negatively correlated with CD8 T-cell activation in PHI patients. Furthermore, we found that in these patients, the Vδ2 receptor bearing (Vδ2+) γδ T cells were strongly activated, exhibited low terminal differentiation, and produced the anti-inflammatory cytokine, TGF-β. In contrast, in UT-CHI, we observed a remarkable expansion of γδ T cells, where the Vδ2+ γδ T cells comprised of an elevated proportion of terminally differentiated cells producing high levels of IFN-γ but very low levels of TGF-β. We also found that this loss of regulatory feature of γδ T cells in CHI was a lasting impairment as we did not find recovery of TGF-β production even in ART-CHI patients successfully treated for more than 5 years. Our data therefore suggest that during the primary HIV infection, Vδ2+ γδ T cells may act as Tregs controlling immune activation through production of TGF-β. However, in CHI, γδ T cells transform from an anti-inflammatory into pro-inflammatory cytokine profile and participate in sustenance of immune activation.

Project description:BackgroundTegumentary leishmaniasis (TL) is a disease of skin and/or mucosal tissues caused by Leishmania parasites. TL patients may concurrently carry other pathogens, which may influence the clinical outcome of TL.Methodology and principal findingsThis review focuses on the frequency of TL coinfections in human populations, interactions between Leishmania and other pathogens in animal models and human subjects, and implications of TL coinfections for clinical practice. For the purpose of this review, TL is defined as all forms of cutaneous (localised, disseminated, or diffuse) and mucocutaneous leishmaniasis. Human immunodeficiency virus (HIV) coinfection, superinfection with skin bacteria, and skin manifestations of visceral leishmaniasis are not included. We searched MEDLINE and other databases and included 73 records: 21 experimental studies in animals and 52 studies about human subjects (mainly cross-sectional and case studies). Several reports describe the frequency of Trypanosoma cruzi coinfection in TL patients in Argentina (about 41%) and the frequency of helminthiasis in TL patients in Brazil (15% to 88%). Different hypotheses have been explored about mechanisms of interaction between different microorganisms, but no clear answers emerge. Such interactions may involve innate immunity coupled with regulatory networks that affect quality and quantity of acquired immune responses. Diagnostic problems may occur when concurrent infections cause similar lesions (e.g., TL and leprosy), when different pathogens are present in the same lesions (e.g., Leishmania and Sporothrix schenckii), or when similarities between phylogenetically close pathogens affect accuracy of diagnostic tests (e.g., serology for leishmaniasis and Chagas disease). Some coinfections (e.g., helminthiasis) appear to reduce the effectiveness of antileishmanial treatment, and drug combinations may cause cumulative adverse effects.Conclusions and significanceIn patients with TL, coinfection is frequent, it can lead to diagnostic errors and delays, and it can influence the effectiveness and safety of treatment. More research is needed to unravel how coinfections interfere with the pathogenesis of TL.

Project description:BackgroundPeople with HIV infection in the United States are often affected by chronic viral hepatitis. These coinfected people with either HBV or HCV are at increased risk for serious, life-threatening complications. Coinfections with viral hepatitis may also complicate the delivery of anti-retroviral therapy (ART) by escalating the risk of drug-related hepatoxicity. According to the Centers for Disease Control and Prevention (CDC), approximately 10 percent of people with HIV in the United States also have HBV, and 25 percent also have HCV coinfection. With the advent of highly active antiretroviral therapy (HAART) and the increased life-expectancy of HIV patients, clinicians are more likely to be confronted with issues related to co-infection and the management challenges that they present, especially in resource-limited settings. The purpose of this analysis was to identify geographical clusters of HIV- (HBV/HCV) co-infection and compared to the geographical clusters of not co-infected using DC, Department of Health surveillance data. The results of the analysis will be used to target resources to areas at risk.MethodsHIV and Hepatitis surveillance data were matched among cases diagnosed between 1980 and 2016. HIV-hepatitis co-infected and the not co-infected spatial clusters were detected using discrete Poisson model. Kulldorff's spatial scan statistic method was implemented in the free software tool called SaTScan which has been widely adopted for detecting disease cluster. The analysis was conducted by tracts, but for visualization, ease of interpretation and assist in policy making the tract map was overlaid with the ward map using ArcGIS 10.5.1.ResultsBetween 1980 and 2016, there were 12,965 diagnosed cases of HIV, of which 2,316 HIV/Hepatitis matches were identified. Of the 2316 co-infected people living in DC, 25 percent (N = 590) of people had HBV, and 75 percent (N = 1,726) had HCV. Out of 12,965 diagnosed cases, remaining 10,649 did not have any co-infections (not co-infected). IDU (27.16 percent) and MSM (32.86 percent) were the highest mode of transmission for co-infected population. African-American were reported 83.64 percent (N = 1,937) among co-infection population. Three clusters were identified for both co-infected population in DC. The largest cluster radius for co-infected analysis covers wards 6, 7 and 8 as well as large parts of 2 and 5 (p < 0.001). Multiple clusters were identified for not co-infected population (p < 0.001). IDU (n = 450) was the highest mode of transmission for the co-infected clusters. For all clusters combined of not co-infected population highest mode of transmission were MSM (n = 2,534). This analysis also showed racial disparity, economic deprivation and lack of education were prominent in the co-infected clusters.ConclusionWe identified locations of high risk clusters where enhanced hepatitis and HIV prevention, treatment, and care can help combat the epidemic. The clusters radius expands into the neighboring state of Maryland as well. The findings from this analysis will be used to target area based public health policy and healthcare interventions for HIV-hepatitis. It is recommended based on the analysis that needle exchange programs can successfully control new HIV infections as well as hepatitis co-infections.

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HIV infection and immune activation: the role of coinfections.

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HIV infection and immune activation: the role of coinfections.

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