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Restricted SIV replication in rhesus macaque lung tissues during the acute phase of infection.

ABSTRACT: The extent to which simian immunodeficiency virus (SIV) replication in lung tissues contributes to the pool of viruses replicating during acute infection is incompletely understood. To address this issue, in situ hybridization was used to examine SIV replication in multiple lobes of lung from rhesus macaques infected with pathogenic SIV. Despite widespread viral replication in lymphoid and intestinal tissues, the lungs during acute infection harbored rare productively infected cells. Simultaneous immunohistochemical staining for the monocytic marker, CD68, revealed that SIV RNA(+) cells in lung tissues during acute infection were CD68(-), whereas during AIDS they were predominantly CD68(+) and localized in large foci in caudal lobes. SIV RNA(+) cells in spleen remained CD68(-) throughout disease. Since CD68 is also expressed by subpopulations of dendritic cells (DC), we also examined pulmonary CD68(+) cells for expression of additional DC markers. DC-LAMP mRNA was abundant in lung tissues and expressed predominantly by CD68(-) cells, whereas DC-SIGN mRNA was expressed in only very rare cells, indicating that SIV RNA(+) cells late in disease were most likely macrophages. These studies of SIV/host interactions demonstrate that macaque lung tissues are minimally infected during acute infection, exhibit changes in predominant target cells for infection, and express very little DC-SIGN.

SUBMITTER: Fuller CL

PROVIDER: S-EPMC1867265 | biostudies-literature | 2002 Sep

REPOSITORIES: biostudies-literature

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Restricted SIV replication in rhesus macaque lung tissues during the acute phase of infection.

Fuller Craig L CL Choi Yang K YK Fallert Beth A BA Capuano Saverio S Rajakumar Premeela P Murphey-Corb Michael M Reinhart Todd A TA

The American journal of pathology 20020901 3

The extent to which simian immunodeficiency virus (SIV) replication in lung tissues contributes to the pool of viruses replicating during acute infection is incompletely understood. To address this issue, in situ hybridization was used to examine SIV replication in multiple lobes of lung from rhesus macaques infected with pathogenic SIV. Despite widespread viral replication in lymphoid and intestinal tissues, the lungs during acute infection harbored rare productively infected cells. Simultaneou ...[more]

PMID: 12213725

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Project description:Persons living with HIV experience significant metabolic dysregulation, frequently resulting in immune and other cellular dysfunction. However, our understanding of metabolism and its relationship to immunity in the context of HIV remains incompletely understood, especially as it relates to the acute and early chronic phases of HIV infection. Herein, we employed mass spectrometry and a simian immunodeficiency virus (SIV)-infected rhesus macaque model to characterize changes in over 500 plasma metabolites throughout SIV infection. This broad metabolomic approach recapitulated known pathogenic signatures of HIV, such as a perturbed tryptophan/kynurenine ratio, but also identified novel metabolic changes. We observed a general decrease in plasma amino acid concentrations, with the notable exceptions of elevated aspartate and glutamate. Acute infection was marked by a transient increase in lactate dehydrogenase activity, indicating a shift toward anaerobic metabolism. Indoleamine 2,3-dioxygenase activity, defined by the kynurenine/tryptophan ratio, was significantly increased in both acute and chronic phases and strongly correlated with viral load. These results provide a comprehensive characterization of metabolic fluctuations during early lentiviral infection, furthering our understanding of the crucial interplay between metabolism and immune response. Our findings highlight systemic metabolic consequences of infection and provide potential targets for therapeutic intervention or biomarkers of disease progression.ImportanceDespite significant advances in antiretroviral therapy and pre-exposure prophylaxis, HIV remains a global challenge. Understanding the underlying immune mechanisms is critical for improving HIV control and therapeutic development. Cellular metabolism represents a crucial yet underappreciated area of immune system function. Metabolite availability and metabolic pathway preferences directly influence the functional response capacity of immune cells and are highly dysregulated during HIV infection. To further the understanding of metabolic impacts of HIV infection, we utilized cutting-edge mass spectrometry-based metabolome interrogation to measure over 500 metabolites using an acute simian immunodeficiency virus infection model in rhesus macaques. Our comprehensive analysis provides insights into the dynamic metabolic landscape throughout early infection, revealing both known and novel metabolic signatures. These findings enhance our understanding of the complex interplay between metabolism and immunity in lentiviral infections, potentially informing new strategies for early detection, prevention, and treatment of HIV.

Project description:Viruses that persist despite seemingly effective antiretroviral treatment (ART) and can reinitiate infection if treatment is stopped preclude definitive treatment of HIV-1 infected individuals, requiring lifelong ART. Among strategies proposed for targeting these viral reservoirs, the premise of the "shock and kill" strategy is to induce expression of latent proviruses [for example with histone deacetylase inhibitors (HDACis)] resulting in elimination of the affected cells through viral cytolysis or immune clearance mechanisms. Yet, ex vivo studies reported that HDACis have variable efficacy for reactivating latent proviruses, and hinder immune functions. We developed a nonhuman primate model of post-treatment control of SIV through early and prolonged administration of ART and performed in vivo reactivation experiments in controller RMs, evaluating the ability of the HDACi romidepsin (RMD) to reactivate SIV and the impact of RMD treatment on SIV-specific T cell responses. Ten RMs were IV-infected with a SIVsmmFTq transmitted-founder infectious molecular clone. Four RMs received conventional ART for >9 months, starting from 65 days post-infection. SIVsmmFTq plasma viremia was robustly controlled to <10 SIV RNA copies/mL with ART, without viral blips. At ART cessation, initial rebound viremia to ~106 copies/mL was followed by a decline to < 10 copies/mL, suggesting effective immune control. Three post-treatment controller RMs received three doses of RMD every 35-50 days, followed by in vivo experimental depletion of CD8+ cells using monoclonal antibody M-T807R1. RMD was well-tolerated and resulted in a rapid and massive surge in T cell activation, as well as significant virus rebounds (~104 copies/ml) peaking at 5-12 days post-treatment. CD8+ cell depletion resulted in a more robust viral rebound (107 copies/ml) that was controlled upon CD8+ T cell recovery. Our results show that RMD can reactivate SIV in vivo in the setting of post-ART viral control. Comparison of the patterns of virus rebound after RMD administration and CD8+ cell depletion suggested that RMD impact on T cells is only transient and does not irreversibly alter the ability of SIV-specific T cells to control the reactivated virus.

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Restricted SIV replication in rhesus macaque lung tissues during the acute phase of infection.

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Restricted SIV replication in rhesus macaque lung tissues during the acute phase of infection.

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