HIV infection leads to CD4 lymphopenia and immunosuppression, which can be successfully improved with antiretroviral therapy (ART) in the majority of cases. Approximately 20 percent of HIV patients initiated on ART 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. 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. In order to study the clinical predictors, biomarkers and pathogenesis of IRIS we are conducting a large prospective observational clinical trial of ART-naive HIV+ patients with severe CD4 lymphopenia (<100 cells/L) who are followed longitudinally after initiation of ART. The study is being conducted both in the US and in Kenya. Our collaborators in Dr Sher's laboratory in LPD are also developing a murine model of mycobacterial IRIS. Preliminary findings from a pilot human study of HIV+ patients who were ART-naive and developed IRIS and were compared with HIV+ patients who did not develop IRIS despite having similar opportunistic infections, suggest that two easily accessible tests from clinical laboratories (CRP and D-dimer) may be useful to predict or diagnose IRIS. Further evaluation of these biomarkers in larger prospective studies is warranted. In the same cohort we evaluated the phenotype of T cells at baseline (pre-ART) and around the IRIS events. T cells from IRIS patients bore a highly activated phenotype (effector cells with high PD-1 expression) both pre-ART and at the time of IRIS, showing evidence of profound antigenic stimulation. IRIS patients also had a slower recovery of naive CD4 T cells following the IRIS events. These findings suggest a significant antigenic drive of T cell activation and expansion that becomes dysregulated as severe immunosuppression reverses. 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 immunodeficieny as measured by CD4 T cell counts. Immune-based therapies are thus still being pursued with the objective to improve immune restoration in CD4 lymphopenic states. IL-7 is a cytokine that plays an essential role in thymopoiesis and in post-thymic maturation, differentiation, proliferation and survival of T cells, making it an attractive candidate for immunotherapy of lymphopenias. Preliminary studies have shown that IL-7 is well tolerated in HIV infection at doses that show promising biologic activity (T cell cycling and T cell count increases). IL-7 immunotherapy is currently being studied in phase II studies in HIV and in idiopathic CD4 lymphopenia.

Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2010
Total Cost
$234,593
Indirect Cost
City
State
Country
Zip Code
Wang, Chao; Edilova, Maria I; Wagar, Lisa E et al. (2018) Effect of IL-7 Therapy on Phospho-Ribosomal Protein S6 and TRAF1 Expression in HIV-Specific CD8 T Cells in Patients Receiving Antiretroviral Therapy. J Immunol 200:558-564
Hsu, Denise C; Breglio, Kimberly F; Pei, Luxin et al. (2018) Emergence of Polyfunctional Cytotoxic CD4+ T Cells in Mycobacterium avium Immune Reconstitution Inflammatory Syndrome in Human Immunodeficiency Virus-Infected Patients. Clin Infect Dis 67:437-446
Crowell, Trevor A; Colby, Donn J; Pinyakorn, Suteeraporn et al. (2018) Acute Retroviral Syndrome Is Associated With High Viral Burden, CD4 Depletion, and Immune Activation in Systemic and Tissue Compartments. Clin Infect Dis 66:1540-1549
Bruzzesi, Elena; Sereti, Irini (2018) Residual Immune Activation and Latency. Curr Top Microbiol Immunol :
Sortino, Ornella; Richards, Elizabeth; Dias, Joana et al. (2018) IL-7 treatment supports CD8+ mucosa-associated invariant T-cell restoration in HIV-1-infected patients on antiretroviral therapy. AIDS 32:825-828
Coleman, Benjamin W; Sereti, Irini; Bishop, Rachel et al. (2018) Upbeat nystagmus in an HIV-positive patient with a tuberculoma in the medulla. Lancet Infect Dis 18:225
Tawakol, Ahmed; Ishai, Amorina; Li, Danny et al. (2017) Association of Arterial and Lymph Node Inflammation With Distinct Inflammatory Pathways in Human Immunodeficiency Virus Infection. JAMA Cardiol 2:163-171
Panackal, Anil A; Rosen, Lindsey B; Uzel, Gulbu et al. (2017) Susceptibility to Cryptococcal Meningoencephalitis Associated With Idiopathic CD4+ Lymphopenia and Secondary Germline or Acquired Defects. Open Forum Infect Dis 4:ofx082
Manion, Maura; Hullsiek, Katherine Huppler; Wilson, Eleanor M P et al. (2017) Vitamin D deficiency is associated with IL-6 levels and monocyte activation in HIV-infected persons. PLoS One 12:e0175517
Wong, C-S; Richards, E S; Pei, L et al. (2017) Immune reconstitution inflammatory syndrome in HIV infection: taking the bad with the good. Oral Dis 23:822-827

Showing the most recent 10 out of 89 publications