Abstract
Human immunodeficiency virus type one (HIV-1) tissue compartments are established soon after viral infection. However, the timing in which virus gains a permanent foothold in tissue and the cellular factors that control early viral-immune events are incompletely understood. These are critical events in studies of HIV-1 pathogenesis and in the development of viral reservoirs after antiretroviral therapy. Moreover, factors affecting the permanence of viral-tissue interactions underlie barriers designed to eliminate HIV-1 infection. To this end we investigated the temporal and spatial viral and host factors during HIV-1 seeding of tissue compartments. Two humanized NOD.Cg-Prkdcscid IL2rgtm1Wjl/SzJ mouse models were employed. In the first, immune deficient mice were reconstituted with human CD34+ cord blood hematopoietic stem cells (HSC) (hu-HSC) and in the second mice were transplanted with adult mature human peripheral lymphocytes (hu-PBL). Both, in measure, reflect relationships between immune activation and viral infection as seen in an infected human host. Following humanization both mice models were infected with HIV-1ADA at 104 50% tissue culture infective doses. Viral nucleic acids and protein and immune cell profiles were assayed in brain, lung, spleen, liver, kidney, lymph nodes, bone marrow, and gut from 3 to 42 days. Peripheral CD4+ T cell loss began at 3 days together with detection of HIV-1 RNA in both mouse models after initiation of HIV-1 infection. HIV-1 was observed in all tested tissues at days 3 and 14 in hu- PBL and HSC mice, respectively. Immune impairment was most prominent in hu-PBL mice. T cell maturation and inflammation factors were linked directly to viral tissue seeding in both mouse models. We conclude that early viral tissue compartmentalization provides a roadmap for investigations into HIV-1 elimination.
Highlights
Following the introduction of antiretroviral therapy (ART) in the mid-1990s, remarkable progress was made toward reducing disease morbidities and mortality during a life-long human immunodeficiency virus type one (HIV-1) infection [1,2,3]
NOD.CgPrkdcscid Il2rgtm1Wjl/SzJ (NSG) mice were irradiated at birth were transplanted by intrahepatic injection with human CD34+ cord blood hematopoietic stem cells [12]
Following HIV-1ADA infection at 104 50% tissue culture infection dose (TCID50)/animal, assays for viral, and immune profiles were performed in blood and tissues at days 0, 3, 5, 7, 14, 28, and 42
Summary
Following the introduction of antiretroviral therapy (ART) in the mid-1990s, remarkable progress was made toward reducing disease morbidities and mortality during a life-long human immunodeficiency virus type one (HIV-1) infection [1,2,3]. An HIV-1 susceptible animal model would be preferable for studies that reflect human infection. To such ends, humanized mouse models were developed. These models received engraftment of human cells into immunodeficient rodents resulting in the establishment of a functional human immune systems and tissue microenvironment that support long-term HIV-1 replication in target cells and tissues [11]. To date, limited studies were performed to dissect when and to what extent HIV-1 establishes persistent infection in tissue compartments. If this information is gleamed they could prove instrumental in developing improved antiretroviral therapies
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