Immunopathogenic Mechanisms of Human Immunodeficiency Virus (HIV) Disease

National Institute Of Allergy And Infectious Diseases

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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, especially with lower 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 and there is no animal model that adequately mimics the clinical observations. Importantly, IRIS is disproportionally affecting minorities because of the more common 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. In order to study the clinical predictors, biomarkers and pathogenesis of IRIS we conducted a large prospective international multi-site study of 506 ART-naive HIV+ patients with low CD4 (<100 cells/L) who were followed after initiation of ART in US, Kenya and Thailand. Participants with lower hemoglobin at baseline were at higher IRIS risk and IRIS were independently associated with increased risk of death after adjustment for known risk factors. Lower levels of hemoglobin was found predictive of IRIS, and high C-reactive protein (CRP) >106 g/mL with low BMI was predictive of death. Adding other inflammatory mediators such as cytokines led to an inflammatory score that was highly predictive of mycobacterial (but not viral) IRIS. With respect to pathogenesis, we previously reported that T cells from IRIS patients bore a highly activated phenotype (high PD-1 expression) showing evidence of profound antigenic stimulation. These 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. Finally, comparing HIV persons and HIV-seronegative with the same pathogen (MAC) we found that the CD4 responses against MAC during IRIS are far greater than those of HIV-seronegative patients with MAC with unique features suggesting cytotoxic potential. In a currently ongoing study, we also studied 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. Finally our most recent work clearly delineated the role of inflammasome and complement activation in monocytes in people with TB-IRIS. More recently we showed the spectrum of lack of immune response with overwhelming infection to intense IRIS in a case series of M. genavense in HIV patients and similar phenomena in people with Histoplasmosis IRIS. Importantly, we also described that paradoxical reactions can occur in people without HIV infection, specifically some marrow recipients with primary immunodeficiencies who had disseminated mycobacterial infections and recovered their pathogen-specific immune responses. With respect to therapeutics, in a small case series we showed that TNF blockade may be a useful means to treat refractory to corticosteroids IRIS. Our current work focuses on identifying biomarkers of severe IRIS that may be refractory to corticosteroids and studying possible genetic predisposition to these hyperinflammatory syndromes. 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. More recently, we also 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. 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 appear 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 recently 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 also identified important genetic defects manifesting with CD4 lymphopenia either due to CD4 gene mutation with absence of CD4 translation and also a novel gamma c mutation with reversion in T-cells manifesting with HPV diseases that regressed after hematopoietic transplant.