Mehandru, S. et al. Lack of Mucosal Immune Reconstitution during Prolonged Treatment of Acute and Early HIV-1 Infection. PLoS. Med. 3, e484

Aaron Diamond AIDS Research Center, Rockefeller University, New York, New York, United States of America.
PLoS Medicine (Impact Factor: 14.43). 01/2007; 3(12):e484. DOI: 10.1371/journal.pmed.0030484
Source: PubMed


During acute and early HIV-1 infection (AEI), up to 60% of CD4(+) T cells in the lamina propria of the lower gastrointestinal (GI) tract are lost as early as 2-4 wk after infection. Reconstitution in the peripheral blood during therapy with highly active antiretroviral therapy (HAART) is well established. However, the extent of immune reconstitution in the GI tract is unknown.
Fifty-four AEI patients and 18 uninfected control participants underwent colonic biopsy. Forty of the 54 AEI patients were followed after initiation of antiretroviral therapy (18 were studied longitudinally with sequential biopsies over a 3-y period after beginning HAART, and 22 were studied cross sectionally after 1-7 y of uninterrupted therapy). Lymphocyte subsets, markers of immune activation and memory in the peripheral blood and GI tract were determined by flow cytometry and immunohistochemistry. In situ hybridization was performed in order to identify persistent HIV-1 RNA expression. Of the patients studied, 70% maintained, on average, a 50%-60% depletion of lamina propria lymphocytes despite 1-7 y of HAART. Lymphocytes expressing CCR5 and both CCR5 and CXCR4 were persistently and preferentially depleted. Levels of immune activation in the memory cell population, CD45RO+ HLA-DR+, returned to levels seen in the uninfected control participants in the peripheral blood, but were elevated in the GI tract of patients with persistent CD4+ T cell depletion despite therapy. Rare HIV-1 RNA-expressing cells were detected by in situ hybridization.
Apparently suppressive treatment with HAART during acute and early infection does not lead to complete immune reconstitution in the GI mucosa in the majority of patients studied, despite immune reconstitution in the peripheral blood. Though the mechanism remains obscure, the data suggest that there is either viral or immune-mediated accelerated T cell destruction or, possibly, alterations in T cell homing to the GI tract. Although clinically silent over the short term, the long-term consequences of the persistence of this lesion may emerge as the HIV-1-infected population survives longer owing to the benefits of HAART.

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    • "Abdominal pain Anxiety X Changes in body weight/fat X X X Cognitive decline X lymph nodes, and effector tissues leading to AIDS ( Klatt & Brenchley , 2010 ) , and the continuous loss of CD41 T memory cells inhibits reconstitution in spite of treatment ( Mehandru et al., 2006 ). Addition - ally , cART fails to restore CD41 T memory cells back to preinfection levels and persistent immune activation continues in response to low levels of viremia in GALT , leading to chronic mucosal inflam - mation and microbial translocation ( Estes et al . "
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    ABSTRACT: Microbial translocation within the context of HIV disease has been described as one of the contributing causes of inflammation and disease progression in HIV infection. HIV-associated symptoms have been related to inflammatory markers and sCD14, a surrogate marker for microbial translocation, suggesting a plausible link between microbial translocation and symptom burden in HIV disease. Similar pathophysiological responses and symptoms have been reported in inflammatory bowel disease (IBD). We provide a comprehensive review of microbial translocation, HIV-associated symptoms, and symptoms connected with inflammation. We identify studies showing a relationship among inflammatory markers, sCD14, and symptoms reported in HIV disease. A conceptual framework and rationale to investigate the link between microbial translocation and symptoms is presented. The impact of inflammation on symptoms supports recommendations to reduce inflammation as part of HIV symptom management. Research in reducing microbial translocation-induced inflammation is limited, but needed, to further promote positive health outcomes among HIV-infected patients.
    Full-text · Article · Nov 2014 · Journal of the Association of Nurses in AIDS Care
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    • "With acute disease progression, microbial product translocation and its inflammatory effects becomes systemic (Brenchley et al., 2006; Burdo et al., 2011a; Hunt et al., 2012; Mehandru et al., 2004). Effective antiretroviral therapy might temper this process, particularly if initiated early, but the effect is incomplete (Jiang et al., 2009; Mavigner et al., 2012; Mehandru et al., 2006). "
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    ABSTRACT: Combination antiretroviral therapy for HIV infection improves immune function and eliminates the risk of AIDS-related complications but does not restore full health. HIV-infected adults have excess risk of cardiovascular, liver, kidney, bone, and neurologic diseases. Many markers of inflammation are elevated in HIV disease and strongly predictive of the risk of morbidity and mortality. A conceptual model has emerged to explain this syndrome of diseases where HIV-mediated destruction of gut mucosa leads to local and systemic inflammation. Translocated microbial products then pass through the liver, contributing to hepatic damage, impaired microbial clearance, and impaired protein synthesis. Chronic activation of monocytes and altered liver protein synthesis subsequently contribute to a hypercoagulable state. The combined effect of systemic inflammation and excess clotting on tissue function leads to end-organ disease. Multiple therapeutic interventions designed to reverse these pathways are now being tested in the clinic. It is likely that knowledge gained on how inflammation affects health in HIV disease could have implications for our understanding of other chronic inflammatory diseases and the biology of aging.
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    • "Even after sustained suppression of viremia during ART, mechanisms that are thought to drive immune activation in HIV-1 infection may persist [24]. Damage to intestinal mucosa, plasma levels of CD14, and chronic T cell activation (as measured by CD38 expression) are all reduced following ART-mediated viral suppression, but often fail to return to levels seen in uninfected individuals [24], [25], [26], [27]. Therefore, we sought to determine if HIV-1-infected subjects receiving ART have concentrations of plasma IFNαthat are different to those we observed in untreated HIV-1-infected subjects. "
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    ABSTRACT: Type-I interferon (IFN-I) has been increasingly implicated in HIV-1 pathogenesis. Various studies have shown elevated IFN-I and an IFN-I-induced gene and protein expression signature in HIV-1 infection, yet the elevated IFN-I species has not been conclusively identified, its source remains obscure and its role in driving HIV-1 pathogenesis is controversial. We assessed IFN-I species in plasma by ELISAs and bioassay, and we investigated potential sources of IFN-I in blood and lymph node tissue by qRT-PCR. Furthermore, we measured the effect of therapeutic administration of IFNα in HCV-infected subjects to model the effect of IFNα on chronic immune activation. IFN-I bioactivity was significantly increased in plasma of untreated HIV-1-infected subjects relative to uninfected subjects (p = 0.012), and IFNα was the predominant IFN-I subtype correlating with IFN-I bioactivity (r = 0.658, p<0.001). IFNα was not detectable in plasma of subjects receiving anti-retroviral therapy. Elevated expression of IFNα mRNA was limited to lymph node tissue cells, suggesting that peripheral blood leukocytes are not a major source of IFNα in untreated chronic HIV-1 infection. Plasma IFN-I levels correlated inversely with CD4 T cell count (p = 0.003) and positively with levels of plasma HIV-1 RNA and CD38 expression on CD8 T cells (p = 0.009). In hepatitis C virus-infected subjects, treatment with IFN-I and ribavirin increased expression of CD38 on CD8 T cells (p = 0.003). These studies identify IFNα derived from lymph nodes, rather than blood leukocytes, as a possible source of the IFN-I signature that contributes to immune activation in HIV-1 infection.
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