Immunopathogenic Mechanisms of Human Immunodeficiency Virus (HIV) Disease

National Institute Of Allergy And Infectious Diseases

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Linked publications & trials

Abstract

HIV infection leads to CD4 lymphopenia and immunosuppression, which can be successfully improved with antiretroviral therapy (ART) in the majority of people. Approximately 20 percent of HIV patients starting ART with low CD4 counts, may develop an aberrant immune response known as immune reconstitution syndrome (IRIS). IRIS encompasses the paradoxical worsening of the manifestations of underlying opportunistic diseases (paradoxical IRIS) or the abrupt presentation of previously occult opportunistic disease (unmasking IRIS) in patients who recently started ART. Symptoms of IRIS can range from uncomplicated localized reactions to severe and systemic manifestations and, more rarely, autoimmune phenomena. Clinical studies have identified two main risk factors for IRIS: severe CD4 lymphopenia and the presence of opportunistic infections even if clinically silent (M. tuberculosis, M. avium complex, C. neoformans or other fungi, or viral pathogens) prior to ART initiation. The pathogenesis of IRIS in HIV infection remains unclear. Importantly, IRIS is disproportionally affecting people presenting with late diagnoses of HIV in these populations and frequently higher prevalence of opportunistic infections (for example TB, Cryptococcus, Histoplasma) due to immigration from endemic countries such as Africa or Central America. We have previously found that lower hemoglobin at baseline is associated with IRIS, and high C-reactive protein (CRP) with low BMI with death in advanced disease. With respect to pathogenesis, we previously reported that T cells from IRIS patients are activated CD4 T cells predominantly recognize the underlying opportunistic pathogen and mount polyfunctional cytokine responses. We later showed that monocytes play a prominent role in TB-IRIS with evidence of inflammasome and complement activation on inflammatory monocytes. In a currently ongoing study, we are studying patients with fluorodeoxyglucose (FDG)-PET imaging and found that higher glucose uptake (total glycolytic activity and total glycolytic volume) and higher standardized max uptake pre-ART were associated with IRIS incidence after therapy initiation. PET measurements correlated with plasma inflammatory cytokines and higher Glut-1 expression (main glucose transporter) was observed on CD4 T cells and monocytes of patients who developed IRIS. These observations highlight a seminal role of metabolism in general, and glycolysis more specifically, in IRIS events which may help identify new therapeutic targets. Importantly, we recently described that severe mycobacterial IRIS has features of hemophagocytic lymphohistiocytosis (HLH) and these patients have high ferritin and low hemoglobin when they start ART and also high CXCL9 and sCD25 at time of IRIS along with low to absent regulatory T-cells. People who developed IRIS had a higher prevalence of protein altering variants in genes associated with primary HLH further validating our observations. We most recently reported that IRIS events can lead to changes in viral reservoirs and compartmentalization which may have implications in remission efforts. Finally, we found that clonal hematopoiesis(CH) prevalence -somatic mutations in hematopoietic cells that are linked to heightened inflammation and increased risk of malignancies, cardiovascular disease and mortality- is more common in people with low nadir CD4 cells even at younger than expected age and IRIS was independently associated with CH mutations. Despite the significant improvement of morbidity and mortality in HIV infection in the ART era, mortality in HIV+ patients is still in excess of what is expected based on age and strongly relates to the degree of immunodeficiency as measured by CD4 T cell counts and to the degree of residual inflammation measured by IL-6, CRP, sCD14 and D-dimer. These markers appear to be linked more to activation of the innate system. We have previously evaluated the role of gut microbiome in a HIV+/HIV- carefully matched cohort and found that dysbiosis in HIV is independent of sexual practices and directly associates with prevalence of noncommunicable diseases. Leveraging stool and serum samples collected prior to comorbidity onset, we found that HIV-specific microbiome alterations with reduced microbiome-mediated conversion of lactate to propionate preceded morbidity and mortality in ART-treated PWH. Thus, gut microbial fiber/lactate conversion to SCFAs may modulate HIV-associated comorbidity risk. We are continuing this work to look at both important biomarkers that may be helpful in predicting higher risk for non-infectious complications in PWH and how aging may be impacting this predisposition to higher inflammatory state. In our Idiopathic CD4 lymphopenia (ICL) work, we developed a humanized mouse model and we were able to show that there is heterogeneity in ICL patients with approximately half being able to reconstitute the "empty" mouse host just as healthy controls. The ones who could not, showed evidence of either depressed proliferative capacity of PBMC or increase death. In contrast hematopoietic cells were able to develop normally into T cells. This mouse model provides us with a tool to classify and further study ICL patients evaluating potential defects of T cell development or peripheral expansion and survival. Following up on the observation of impaired T cell survival, we have found that all ICL patients have evidence of autoantibodies compared to healthy controls. Some of these antibodies are able to bind human lymphocytes and at times can cause cytotoxicity either complement or antibody-mediated. These observations suggest a potentially important role of autoantibodies in ICL pathogenesis and open the path for new therapeutic strategies including a pilot trial of belimumab that we are currently conducting. We have evaluated the mucosal associated invariant T cells in people with ICL and found that they are intact in both numbers and function, a factor that may be helpful in important mucosal immune defenses in these patients. Finally we recently reported on the importance of CD4 counts as a biomarker of disease prognosis in ICL with low CD4 count associated with opportunistic infections and cancer but not autoimmunity. CD4 counts also determine response to vaccines with people with higher CD4 counts having vaccine responses to neoantigens that are comparable to controls with normal CD4 counts.