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1.
Viruses ; 15(4)2023 04 12.
Article in English | MEDLINE | ID: mdl-37112931

ABSTRACT

HIV resistance to the Tat inhibitor didehydro-cortistatin A (dCA) in vitro correlates with higher levels of Tat-independent viral transcription and a seeming inability to enter latency, which rendered resistant isolates more susceptible to CTL-mediated immune clearance. Here, we investigated the ability of dCA-resistant viruses to replicate in vivo using a humanized mouse model of HIV infection. Animals were infected with WT or two dCA-resistant HIV-1 isolates in the absence of dCA and followed for 5 weeks. dCA-resistant viruses exhibited lower replication rates compared to WT. Viral replication was suppressed early after infection, with viral emergence at later time points. Multiplex analysis of cytokine and chemokines from plasma samples early after infection revealed no differences in expression levels between groups, suggesting that dCA-resistance viruses did not elicit potent innate immune responses capable of blocking the establishment of infection. Viral single genome sequencing results from plasma samples collected at euthanasia revealed that at least half of the total number of mutations in the LTR region of the HIV genome considered essential for dCA evasion reverted to WT. These results suggest that dCA-resistant viruses identified in vitro suffer a fitness cost in vivo, with mutations in LTR and Nef pressured to revert to wild type.


Subject(s)
HIV Infections , HIV Seropositivity , HIV-1 , Mice , Animals , tat Gene Products, Human Immunodeficiency Virus/genetics , tat Gene Products, Human Immunodeficiency Virus/metabolism , HIV Infections/drug therapy , HIV-1/physiology , Virus Replication , HIV Long Terminal Repeat
2.
AIDS Res Hum Retroviruses ; 39(5): 222-231, 2023 05.
Article in English | MEDLINE | ID: mdl-36517984

ABSTRACT

The induction of robust circulating antibody titers is a key goal of HIV-1 vaccination. Probiotic supplementation is an established strategy to enhance microbiota and boost antibody responses to vaccines. A recent study tested whether oral probiotics could enhance vaccine-specific mucosal immunity by testing vaccination with and without supplementation in a Rhesus macaque Simian-Human Immunodeficiency Virus challenge model. Although supplementation was not associated with protection, the effects of probiotics on immunity after infection were not examined. To address this question, we measured antibody titers to HIV Env and commensal bacteria in plasma from the vaccination/supplementation time points as well as after Simian-Human Immunodeficiency Virus (SHIV) acquisition. We found that a trend toward lower HIV Env-specific titers in the animals given probiotics plus vaccine became greater after SHIV infection. Significantly lower Immunoglobulin (Ig) A titers were observed in animals vaccinated and supplemented compared with vaccine alone due to a delay in antibody kinetics at week 2 postinfection. We observed no difference, however, in titers to commensal bacteria during probiotic supplementation or after SHIV infection. These results suggest that probiotic supplementation may be a strategy for reducing IgA-specific HIV antibodies in the plasma, a correlate associated with increased HIV infection in the RV144 clinical trial.


Subject(s)
AIDS Vaccines , HIV Infections , HIV-1 , Simian Acquired Immunodeficiency Syndrome , Simian Immunodeficiency Virus , Animals , Humans , HIV Infections/prevention & control , Antibody Formation , Macaca mulatta , Vaccination , Simian Acquired Immunodeficiency Syndrome/prevention & control
3.
Cell ; 184(15): 3899-3914.e16, 2021 07 22.
Article in English | MEDLINE | ID: mdl-34237254

ABSTRACT

The impact of the microbiome on HIV disease is widely acknowledged although the mechanisms downstream of fluctuations in microbial composition remain speculative. We detected rapid, dynamic changes in translocated microbial constituents during two years after cART initiation. An unbiased systems biology approach revealed two distinct pathways driven by changes in the abundance ratio of Serratia to other bacterial genera. Increased CD4 T cell numbers over the first year were associated with high Serratia abundance, pro-inflammatory innate cytokines, and metabolites that drive Th17 gene expression signatures and restoration of mucosal integrity. Subsequently, decreased Serratia abundance and downregulation of innate cytokines allowed re-establishment of systemic T cell homeostasis promoting restoration of Th1 and Th2 gene expression signatures. Analyses of three other geographically distinct cohorts of treated HIV infection established a more generalized principle that changes in diversity and composition of translocated microbial species influence systemic inflammation and consequently CD4 T cell recovery.


Subject(s)
Gastrointestinal Microbiome , HIV Infections/immunology , HIV Infections/microbiology , Antiretroviral Therapy, Highly Active , Biodiversity , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Chemokines/blood , Cohort Studies , Glycolysis , HIV Infections/blood , HIV Infections/drug therapy , Humans , Inflammation/genetics , Inflammation/pathology , Mitochondria/metabolism , Monocytes/metabolism , Nucleic Acids/blood , Principal Component Analysis , Serratia/physiology , Th1 Cells/immunology , Th2 Cells/immunology , Transcription, Genetic , Uganda , Viral Load/immunology
4.
J Vis Exp ; (119)2017 01 31.
Article in English | MEDLINE | ID: mdl-28190068

ABSTRACT

Animal models of central nervous system (CNS) diseases and, consequently, blood-brain barrier disruption diseases, require the delivery of exogenous substances into the brain. These exogenous substances may induce injurious impact or constitute therapeutic strategy. The most common delivery methods of exogenous substances into the brain are based on systemic deliveries, such as subcutaneous or intravenous routes. Although commonly used, these approaches have several limitations, including low delivery efficacy into the brain. In contrast, surgical methods that locally deliver substances into the CNS are more specific and prevent the uptake of the exogenous substances by other organs. Several surgical methods for CNS delivery are available; however, they tend to be very traumatic. Here, we describe a mouse infusion microsurgery technique, which effectively delivers substances into the brain via the internal carotid artery, with minimal trauma and no interference with normal CNS functionality.


Subject(s)
Carotid Artery, Internal/surgery , Pharmaceutical Preparations/administration & dosage , Analgesics/administration & dosage , Animals , Anti-Inflammatory Agents/administration & dosage , Blood-Brain Barrier/metabolism , Brain/metabolism , Brain/pathology , Central Nervous System Diseases/drug therapy , Central Nervous System Diseases/pathology , Central Nervous System Diseases/veterinary , HIV/genetics , Injections, Intravenous , Mice , Microscopy, Fluorescence , Microsurgery , RNA, Viral/administration & dosage
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