Inflammation and Intervention: How Does HIV Cause AIDS and How Does It Cause Disease Despite ART
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HIV infection was first thought to lead to AIDS by the uncontrolled replication of the highly cytopathic virus, killing CD4 cells and laying waste to the immune system. Some studies, however, suggest that the direct killing of lymphocytes by HIV is insufficient to account for immunodeficiency. A state of chronic, generalised immune activation has been suggested, in combination with viral replication, to be required to ignite progression to AIDS.
A recent paper in Cell by Warner Greene's group has revived the claim that HIV replication is central to CD4 depletion and immune collapse via the triggering of pyroptosis, a form of programmed cell death that engulfs surrounding, uninfected cells in the doom triggered by the viral death of the few.1 However, this view was not represented at CROI.
The current majority view, reinforced by many related presentations at CROI, emphasised the role in HIV immunopathogenesis played by the mucosal immune dysfunction and its partner in guilt-by-association, bacterial translocation. It has been long observed that antiretroviral therapy (ART) suppression of viraemia usually does not fully resolve immune activation, although for most patients the proportion of cells bearing markers of activation are far below that of untreated patients. Two general types of studies at CROI focused on the issue of immune activation in HIV infection: 1) those outlining phenomena that were associated with immune inflammation, and that perhaps drive the process, and 2) those that used therapeutic interventions in an attempt to perturb the system and perhaps ameliorate pathology.
Various soluble markers such as LPS and bacterial rDNA have been reported to be the result of microbial translocation, and associated with immune activation. Abdurahman and colleagues introduced bacterial flagellin-specific antibodies and an assay of soluble flagellin protein as new surrogate markers for immune activation.2
Flagellin is a potent inducer of the toll-like receptor, a human receptor designed to sense foreign proteins and respond by the induction of inflammation. The group showed higher levels of flagellin and flagellin antibodies in untreated patients than in treated patients, both groups being higher than uninfected controls. As with other such markers, flagellin markers were reduced but not completely by the use of ART. The investigators also noted that levels were higher in patients from Ethiopia and Vietnam than from Sweden, but given the diversity of these populations and the small sample size, it is difficult to make much of this difference. It remains to be seen if this biomarker is cheaper, more reproducible, or simpler to use in research setting than others that have been described.
Kamat and colleagues discussed a small but interesting study of the application of serological markers used to diagnose inflammatory bowel disease (IBD) to HIV-infected patients.3 Antibodies to ASCA, pANCA, anti-OmpC, and anti-CBir1 were measured by ELISA in plasma from AIDS patients (n = 26) with low CD4 counts (<300 cells/mm3) and high plasma LPS (>80 pg/mL), and results correlated with clinical data. A weakness of this study was the fact that only 6 of the 26 patients were virologically suppressed, and in this report suppression was considered to be < 400 copies HIV RNA/ml. Further this was an advanced cohort with a mean CD4 count of 80 cells/Ál. However antibodies linked to IBD was detected in 46%, and of these 75% had a Crohn's-like pattern. Analysis showed a positive correlation between the flagellin antibody anti-CBir1 and IL-6 levels (r = 0.447, p = 0.048). The authors suggested that, like in IBD, these biomarkers might serve to monitor HIV-related gut inflammation. Should specific therapies to downmodulate inflammation be developed, such monitoring strategies might be useful, either in trials or in practice.
Nagy and colleagues showed that antigen-presenting cells, capable of phagocytising foreign antigens and microbes, differed in their behavior in uninfected, HIV-infected, and HIV-infected but ART-suppressed patients.4 Antigen-presenting cells from untreated HIV-positive patients on average produced more of the pro-inflammatory cytokines TNF, IL-6, and IL-12 when exposed to several microbes, or when stimulated through Toll-like receptors, the innate receptors that detect the presence of such pathogens. In most cases, the dysregulation or hyper-reponsiveness of antigen-presenting cells was ameliorated by suppressive ART. Assays of global cellular gene expression in APCs, illustrated that this dysregulation was correlated with global alterations in cellular gene expression. This observation added to the catalog of cellular immune dysfunction that has been observed in viraemic patients, partially ameliorated by effective ART. It remains to be seen if the duration of ART or the timing of it initiation after infection allows fuller normalisation of this immune response.
In thematic agreement with this observation, Funderburg and the ACTG 5248 investigators examined immune parameters in patients initiating a raltegravir/Truvada regimen.5 The 37 patients included in this immunological substudy had moderately advanced disease, with a median CD4 count of 259 cells/mm3. In patients in whom viraemia was successfully suppressed, over the 72-week study markers of T cell activation such as the presence of the activation markers CD38 or HLA-DR, the marker of cell turnover Ki67, the levels of TNF receptor and the soluble receptor for lipopolysaccharide (sCD14) all fell precipitously in the first few days of therapy. However, in general, most markers were still measurably elevated after 8 weeks of therapy, and in most patients did not return completely after 2 years of therapy (week 72) to levels typically seen in uninfected patients. Similarly, bacterial lipopolysaccharide declined but did not normalise. The authors speculated that the association observed between continuing microbial translocation (higher LPS levels) and increased turnover (Ki67+) of central memory CD4 cells might mean that microbial translocation was the cause of CD4 cell depletion.
Similarly, Shive and colleagues from Case Western Reserve University studied a cohort of 61 patients who failed to enjoy immune reconstitution despite durable, successful ART (CD4 <350/ÁL after at least 2 years of HIV RNA below the limit of detection), and compared these immune failure (IF) patients to 21 HIV-negative controls, and 20 HIV-positive treated patients with immune reconstitution (immune success, IS).6
A panoply of soluble markers and mediators of inflammation were measured: the pro-inflammatory cytokine IL-6, the D-dimer coagulation marker, and markers of microbial translocation -- the soluble CD14 LPS receptor and LPS itself. Overall, the mean levels of these markers were statistically different in ways that would be largely expected, given the prior work of this group and others. IL-6 and sCD14 levels were higher in IF than IS, and both higher than in uninfected patients. D-dimer levels were similar in IF and IS, but higher than healthy controls. LPS tended to be higher in IF and IS than in controls, but not significantly. In IF patients, but not IS patients, statistical correlations were seen between duration of untreated HIV infection and IL-6 and to D-dimer levels. What is unsatisfying is that there is considerable overlap in the individual data points, despite the statistically significant difference that can be demonstrated in mean or median values. If these parameters are critical drivers of immunopathogenesis, it is dissonant that these parameters are well within the normal range in a large number of patients with profound immune abnormalities.
A study of 9 patients from UCSF, who initiated therapy with advanced disease (mean nadir CD4 count 87 cells/mm3) and had maintained ART suppression for a median of 40 months, visually quantitated the density of collagen seen on staining of rectal biopsies.7 Hunt and colleagues speculated that fibrosis in the lymphoid tissue of the GALT might impair functional T cell responses. In particular, it was hypothesised that the maintenance of CD8 cell responses might be impaired by fibrosis. As is generally the case in many such studies, a hyperactivated CD4 cell population was observed. Why abnormalities of lymphoid architecture would specifically lead to a dichotomised phenotype of CD38+ CD4+ cells but not CD38+ CD8+ cells was not addressed. Why the maintenance of an HIV-specific CD8+ T cell response would be expected in patients in whom viraemia had been suppressed for a median of almost 3.5 years was also unclear.
This article was provided by HIV i-Base. It is a part of the publication HIV Treatment Bulletin. Visit HIV i-Base's website to find out more about their activities, publications and services.
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