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Principal Investigator: Frank Maldarelli
Organization: DIVISION OF BASIC SCIENCES - NCI
Fiscal Year: 2021
Award: $634,967
Funding agency: National Cancer Institute
Fundamental gaps in our understanding of HIV reservoirs preclude a precisely targeted approach to eradication. HIV is neither eliminated nor often controlled by the human immune system, and the immunologic defect(s) responsible for this lack of control are unknown. We are conducting several studies to investigate the effects of clinical events on HIV reservoirs. We have established useful collaborations to investigate the effects of clinical interventions on HIV reservoirs. We are collaborating with R. Yarchoan (HIV and AIDS Malignancy Branch, NCI) to study individuals with HIV infection and comorbid cancer treated at the NIH Clinical Center. These study patients receive antineoplastic cytotoxic and immune modulator therapy to treat cancers, treatment modalities that may also have significant effects on HIV-infected cells, and we are studying the effects of these therapies on HIV reservoirs. In collaboration with I. Sereti (NIAID), we are studying patients with advanced HIV/AIDS who initiate antiretroviral therapy (ART) and experience immune reconstitution inflammatory syndrome (IRIS) in response to coinfections such as tuberculosis. IRIS results in a vigorous immune response to the comorbid infection with significant increases in CD4 T cells; as such, IRIS may have profound effects on HIV reservoirs. We have been studying individuals with IRIS and TB and found that HIV-infected cells are part of the robust immune response that occurs during IRIS. In fact, HIV-infected cells can specifically respond to TB antigens. We have also found that IRIS has long-term effects on the structure of HIV populations during therapy, suggesting IRIS may alter HIV reservoirs. These studies indicate that specific events may have profound effects on HIV reservoirs and our ability to eradicate HIV. We are now developing a new protocol to investigate the effects of the SARS-CoV-2 virus infection on HIV reservoirs. We are especially interested in the effects of COVID-19 on HIV infection for a number of reasons. COVID-19 may have particularly devastating effects on individuals with immunosuppression, and it is not known what the clinical effects of COVID-19 are in HIV-infected individuals. Participants in the new study will have detailed clinical evaluations and sample acquisition. We are collaborating closely with colleagues in NINDS (A. Nath) in the development of this protocol, so that we can evaluate the specific and long-term effects of COVID-19 on the central nervous system. We are also conducting clinical trials of targeted interventions to characterize HIV reservoirs in individuals suppressed on ART. We are also initiating new analytic treatment interruption studies to determine the sources of rebound viremia when HIV therapy is interrupted. We are completing a clinical study (NIH protocol 13-I-0062) investigating generalized immune activation in the gastrointestinal-associated lymphoid tissue (GALT) on persistent HIV in individuals undergoing ART. We have been studying the effects of the nonabsorbable antibiotic rifaximin to specifically alter the gut microbiome and affect translocation of bacterial cell products, and the consequent levels of generalized immune activation and low-level HIV viremia. Although we identified changes in the gut microbiome, these changes did not result in downstream effects on levels of HIV viremia or levels of immune activation. These studies will further our understanding of the role of modifying the microbiome in immune activation. We are also investigating the role of innate immunity in HIV persistence by studying the effects of the innate immune modulator interferon alpha 2b. We have characterized the effects of exogenous interferon therapy in a series of HIV-infected individuals undergoing ART (NIH protocol 11-I-0057). We found no effect of interferon on levels of HIV in plasma or in peripheral blood lymphocytes, and are now characterizing interferon effects on the phylogenetic structure of the HIV populations. Our studies of HIV reservoirs indicate a critical role of anatomic locations, particularly lymphoid tissues, in HIV persistence. We are developing a new protocol to evaluate the role of tissue sanctuaries of HIV reservoirs using detailed PET/CT imaging combined with targeted biopsy to obtain tissue samples prior to and following analytic treatment interruption. We will analyze virologic and immunologic characteristics prior to and following interruption of HIV therapy to determine the forces that contribute to the emergence of rebound viremia.
Terms: <(IFN) α><(IFN)-α><(IFN)α><2019 novel corona virus><2019 novel coronavirus><2019-nCoV><AIDS><AIDS Virus><AIDS/HIV><AIDS/HIV problem><Acquired Immune Deficiency><Acquired Immune Deficiency Syndrome><Acquired Immune Deficiency Syndrome Virus><Acquired Immuno-Deficiency Syndrome><Acquired Immunodeficiency Syndrome><Acquired Immunodeficiency Syndrome Virus><Acquired Immunologic Deficiency Syndrome><Adverse effects><Affect><Alferon><Anatomic><Anatomic Sites><Anatomic structures><Anatomical Sciences><Anatomy><Anti-Cancer Agents><Antibiotic Agents><Antibiotic Drugs><Antibiotics><Antigens><Antineoplastic Agents><Antineoplastic Drugs><Antineoplastics><Bacterial Translocation><Biopsy><Blood Plasma><Body Tissues><CAT scan><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><CNS Nervous System><COVID-19><COVID-19 virus><COVID19><COVID19 virus><CT X Ray><CT Xray><CT imaging><CT scan><CV-19><CV19><Cancer Drug><Cancer Treatment><Cancers><Cell Body><Cells><Central Nervous System><Characteristics><Clinical><Clinical Evaluation><Clinical Protocols><Clinical Research><Clinical Study><Clinical Testing><Clonal Expansion><CoV-2><CoV2><Collaborations><Computed Tomography><Conduct Clinical Trials><Defect><Disease><Disorder><Event><GI microbiome><Goals><HIV><HIV Infections><HIV therapy><HIV/AIDS><HIV/AIDS problem><HTLV-III Infections><HTLV-III-LAV Infections><Host Factor><Host Factor Protein><Human><Human Immunodeficiency Viruses><Human T-Lymphotropic Virus Type III Infections><IFN><IFN Alpha><IFN α><IFN-α><IFNa><IFNα><IMiD><Immune Cell Activation><Immune modulatory therapeutic><Immune response><Immune system><Immunochemical Immunologic><Immunologic><Immunological><Immunological response><Immunologically><Immunologics><Immunomodulators><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Individual><Infection><Inflammatory><Innate Immunity><Integration Host Factors><Interferon Alfa-n3><Interferon-alpha><Interferon-α><Interferons><Interruption><Intervention><Intervention Strategies><Intervention Studies><LAV-HTLV-III><Leukocyte Interferon><Location><Long-Term Effects><Longterm Effects><Lymphadenopathy-Associated Virus><Lymphatic Tissue><Lymphoblast Interferon><Lymphoblastoid Interferon><Lymphoid Tissue><M tuberculosis infection><M. tb infection><M. tuberculosis infection><M.tb infection><M.tuberculosis infection><MTB infection><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Miscellaneous Antibiotic><Modality><Modern Man><Mycobacterium tuberculosis (MTB) infection><Mycobacterium tuberculosis infection><NIAID><NIH><NINDS><National Institute of Allergy and Infectious Disease><National Institute of Neurological Diseases and Stroke><National Institute of Neurological Disorders and Stroke><National Institutes of Health><Native Immunity><Natural Immunity><Neoplastic Disease Chemotherapeutic Agents><Neuraxis><Non-Specific Immunity><Nonspecific Immunity><PET/CT><PET/CT scan><Participant><Patients><Peripheral Blood Lymphocyte><Phylogenetic Analysis><Phylogenetics><Plasma><Plasma Serum><Population><Protocol><Protocols documentation><Resistance><Reticuloendothelial System, Serum, Plasma><Retrovirology><Role><SARS corona virus 2><SARS-CoV-2><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Sampling><Series><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome related corona virus 2><Source><Structure><Syndrome><T4 Cells><T4 Lymphocytes><TB infection><Tissue Sample><Tissues><Tomodensitometry><Tuberculosis><Tumor-Specific Treatment Agents><United States National Institutes of Health><Viral><Viral Diseases><Viremia><Virus Diseases><Virus-HIV><Wuhan coronavirus><X-Ray CAT Scan><X-Ray Computed Tomography><X-Ray Computerized Tomography><Xray CAT scan><Xray Computed Tomography><Xray computerized tomography><allergic/immunologic body system><allergic/immunologic organ system><anti-cancer drug><anti-cancer therapy><anti-retroviral therapy><anti-retroviral treatment><anticancer agent><anticancer drug><anticancer therapy><antiretroviral therapy><antiretroviral treatment><cancer therapy><cancer-directed therapy><catscan><clinical center><clinical effect><clinical test><co-infection><co-morbid><co-morbidity><coinfection><comorbidity><computed axial tomography><computer tomography><computerized axial tomography><computerized tomography><corona virus disease 2019><coronavirus disease 2019><coronavirus disease 2019 virus><cytotoxic><design><designing><digestive tract microbiome><disseminated TB><disseminated tuberculosis><driving force><enteric microbiome><experience><gastrointestinal><gastrointestinal microbiome><gut microbiome><gut-associated microbiome><hCoV19><host response><immune activation><immune modulating agents><immune modulating drug><immune modulating therapeutics><immune modulators><immune modulatory agents><immune modulatory drugs><immune reconstitution><immune suppression><immune system response><immunogen><immunomodulating agents><immunomodulatory agents><immunomodulatory drugs><immunomodulatory therapeutics><immunoresponse><in vivo><infection due to Mycobacterium tuberculosis><interest><interferon therapy><intervention research><interventional research><interventional strategy><interventional study><interventions research><intestinal biome><intestinal microbiome><malignancy><microbiome><nCoV2><neoplasm/cancer><neoplastic><protocol development><research clinical testing><resistant><response><rifaximin><social role><tuberculosis infection><tuberculous spondyloarthropathy><viraemia><viral infection><viral sepsis><virology><virus infection><virus-induced disease><virusemia>