Publications by authors named "Ramesh Akkina"

HIV-1 emerged from SIVcpz evolving in humans. Humanized mice are an effective tool for assessing viral evolution via measuring viral loads, CD4 T cell decline, and analyzing genetic changes. Four serial passages showed many non-synonymous mutations important for the adaptation and evolution of SIVcpz to human immune cells.

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HIV-2 Group F virus with an origin in NHPs was isolated from only two individuals. Two serial passages in hu-mice showed increased viral loads, CD4 T cell decline and nonsynonymous genetic changes showing its capacity for further evolution, and spread in the human.

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Introduction: Immunocompetent and immunocompromised murine models have been instrumental in answering important questions regarding ZIKV pathogenesis and vertical transmission. However, mimicking human congenital zika syndrome (CZS) characteristics in these murine models has been less than optimal and does not address the potential viral effects on the human immune system.

Methods: Here, we utilized neonatal humanized Rag2γc mice to model CZS and evaluate the potential viral effects on the differentiation of human hematopoietic stem cells .

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Article Synopsis
  • Serial passage of the SIVmac239 virus helps scientists learn about the genetic changes that enable it to jump from monkeys to humans.
  • Research using humanized mice demonstrates that SIVmac239 continues to evolve with adaptive mutations through four cycles of passage.
  • This study observes a consistent decline in CD4 T cells and an increase in viral loads as SIVmac239 is passed serially, indicating the virus's adaptation process.
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Critical genetic adaptations needed for SIV chimpanzee to evolve into HIV-1 are not well understood. Using humanized mice, we mimicked the evolution of SIVcpzLB715 into HIV-1 Group M over the course of four generations. Higher initial viral load, increased CD4 T-cell decline, and nonsynonymous substitutions arose suggesting viral evolution.

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HIV-1 evolved from SIV during cross-species transmission events, though viral genetic changes are not well understood. Here, we studied the evolution of SIVcpzLB715 into HIV-1 Group M using humanized mice. High viral loads, rapid CD4 T-cell decline, and non-synonymous substitutions were identified throughout the viral genome suggesting viral adaptation.

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Simian immunodeficiency virus native to sooty mangabeys (SIVsm) is believed to have given rise to HIV-2 through cross-species transmission and evolution in the human. SIVmac239 and SIV, pathogenic to macaques, and SIVhu, isolated from an accidental human infection, also have origins in SIVsm. With their common ancestral lineage as that of HIV-2 from the progenitor SIVsm, but with different passage history in different hosts, they provide a unique opportunity to evaluate cross-species transmission to a new host and their adaptation/evolution both in terms of potential genetic and phenotypic changes.

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The genetic evolution of HIV-1 from its progenitor virus SIV following cross-species transmission is not well understood. Here we simulated the SIVcpz initial transmission to humans using humanized mice and followed the viral evolution during serial passages lasting more than a year. All three SIVcpz progenitor viruses used, namely LB715 and MB897 (group M) as well as EK505 (group N) readily infected hu-mice resulting in chronic viremia.

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Through the accumulation of adaptive mutations, HIV-2 originated from SIVsm. To identify these evolutionary changes, a humanized mouse model recapitulated the process that likely enabled this cross-species transmission event. Various adaptive mutations arose, as well as increased virulence and CD4 T-cell decline as the virus was passaged in humanized mice.

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Adequate antiretroviral (ARV) concentrations in lymphoid tissues are critical for optimal antiretroviral therapy (ART). While the spleen contains 25% of the body's lymphocytes, there are minimal data on ARV penetration in this organ. This study quantified total and protein-unbound splenic ARV concentrations and determined whether drug transporters, sex, or infection status were modifiers of these concentrations in animal models and humans.

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The main advantage of animal models of infectious diseases over in vitro studies is the gain in the understanding of the complex dynamics between the immune system and the pathogen. While small animal models have practical advantages over large animal models, it is crucial to be aware of their limitations. Although the small animal model at least needs to be susceptible to the pathogen under study to obtain meaningful data, key elements of pathogenesis should also be reflected when compared to humans.

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The Global Virus Network (GVN) was established in 2011 to strengthen research and responses to emerging viral causes of human disease and to prepare against new viral pandemics. There are now 52 GVN Centers of Excellence and 9 Affiliate laboratories in 32 countries. The 11th International GVN meeting was held from June 9-11, 2019 in Barcelona, Spain and was jointly organized with the Spanish Society of Virology.

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For HIV cure strategies like "kick and kill" to succeed, antiretroviral (ARV) drugs must reach effective concentrations in putative viral reservoirs. We characterize penetration of six ARVs in three preclinical animal models and humans. We found that standard dosing strategies in preclinical species closely mimicked tissue concentrations in humans for some, but not all, ARVs.

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HIV-1 evolved from its progenitor SIV strains, but details are lacking on its adaptation to the human host. We followed the evolution of SIVcpz in humanized mice to mimic cross-species transmission. Increasing viral loads, CD4 T-cell decline, and non-synonymous mutations were seen in the entire genome reflecting viral adaptation.

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HIV replication within tissues may increase in response to a reduced exposure to antiretroviral drugs. Traditional approaches to measuring drug concentrations in tissues are unable to characterize a heterogeneous drug distribution. Here, we used mass spectrometry imaging (MSI) to visualize the distribution of six HIV antiretroviral drugs in gut tissue sections from three species (two strains of humanized mice, macaques, and humans).

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In a "kick and kill" strategy for human immunodeficiency virus (HIV) eradication, protective concentrations of antiretrovirals (ARVs) in the lymph node are important to prevent vulnerable cells from further HIV infection. However, the factors responsible for drug distribution and concentration into these tissues are largely unknown. Although humanized mice and nonhuman primates (NHPs) are crucial to HIV research, ARV tissue pharmacology has not been well characterized across species.

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Lentiviral vectors (LVs) are widely used in gene transfer protocols due to many advantages that include stable gene expression, higher transgene payloads, and, importantly, the ability to pseudotype the vectors with a diverse number of heterologous viral envelopes with broad or restricted cell tropism depending on the need. The pseudotyping process also allows for incorporation of specific antibodies/ligands to engineer LVs. These features greatly facilitate customization of lentiviral vectors for cell/tissue specific gene delivery.

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1. Antiretroviral concentrations in cerebrospinal fluid (CSF) are used as surrogate for brain tissue, although sparse data support this. We quantified antiretrovirals in brain tissue across preclinical models, compared them to CSF, and calculated 90% inhibitory quotients (IQ) for nonhuman primate (NHP) brain tissue.

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How SIV progenitors evolved into deadly HIV-1 and HIV-2 following initial cross-species transmission still remains a mystery. Here, we used humanized mice as a human surrogate system to evaluate SIVsm evolution into HIV-2. Increased viral virulence to human CD4 T cells and adaptive genetic changes were observed during serial passages.

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Gene-based therapies represent a promising treatment for HIV-1 infection, as they offer the potential for sustained viral inhibition and reduced treatment interventions. One approach developed here involves using conditionally replicating vectors (CR-vectors). CR-vectors utilize HIV-expressed proteins to replicate and disseminate along with HIV into the budding viral particles, thereby co-infecting target cellular reservoirs.

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Gene-based therapies represent a promising therapeutic paradigm for the treatment of HIV-1, as they have the potential to maintain sustained viral inhibition with reduced treatment interventions. Such an option may represent a long-term treatment alternative to highly active antiretroviral therapy. We previously described a therapeutic approach, referred to as transcriptional gene silencing (TGS), whereby small noncoding RNAs directly inhibit the transcriptional activity of HIV-1 by targeting sites within the viral promoter, specifically the 5' long terminal repeat (LTR).

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In the current quest for a complete cure for HIV/AIDS, highly sensitive HIV-1 latency detection methods are critical to verify full viral eradication. Until now, the quantitative viral outgrowth assays (qVOA) have been the gold standard for assessing latent HIV-1 viral burden. However, these assays have been inadequate in detecting the presence of ultralow levels of latent virus in a number of patients who were initially thought to have been cured, but eventually showed viral rebound.

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