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Synaptic transmission may provide an evolutionary benefit to HIV through modulation of latency.

ABSTRACT: Transmission of HIV is known to occur by two mechanisms in vivo: the free virus pathway, where viral particles bud off an infected cell before attaching to an uninfected cell, and the cell-cell pathway, where infected cells form virological synapses through close contact with an uninfected cell. It has also been shown that HIV replication includes a positive feedback loop controlled by the viral protein Tat, which may act as a stochastic switch in determining whether an infected cell enters latency. In this paper, we introduce a simple mathematical model of HIV replication containing both the free virus and cell-cell pathways. Using this model, we demonstrate that the high multiplicity of infection in cell-cell transmission results in a suppression of latent infection, and that this modulation of latency through balancing the two transmission mechanisms can provide an evolutionary benefit to the virus. This benefit increases with decreasing overall viral fitness, which may provide a within-host evolutionary pressure toward more cell-cell transmission in late-stage HIV infection.

SUBMITTER: Vargas-Garcia C

PROVIDER: S-EPMC7187919 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Synaptic transmission may provide an evolutionary benefit to HIV through modulation of latency.

Vargas-Garcia Cesar C Zurakowski Ryan R Singh Abhyudai A

Journal of theoretical biology 20180723

Transmission of HIV is known to occur by two mechanisms in vivo: the free virus pathway, where viral particles bud off an infected cell before attaching to an uninfected cell, and the cell-cell pathway, where infected cells form virological synapses through close contact with an uninfected cell. It has also been shown that HIV replication includes a positive feedback loop controlled by the viral protein Tat, which may act as a stochastic switch in determining whether an infected cell enters late ...[more]

PMID: 30048721

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Project description:Functional diversification along the longitudinal axis of the hippocampus is a rapidly growing concept. Modulation of synaptic transmission by neurotransmitter receptors may importantly contribute to specialization of local intrinsic network function along the hippocampus. In the present study, using transverse slices from the dorsal and the ventral hippocampus of adult rats and recordings of evoked field postsynaptic excitatory potentials (fEPSPs) from the CA1 stratum radiatum, we aimed to compare modulation of synaptic transmission between the dorsal and the ventral hippocampus. We found that transient heterosynaptic depression (tHSD, <2 s), a physiologically relevant phenomenon of regulation of excitatory synaptic transmission induced by paired stimulation of two independent inputs to stratum radiatum of CA1 field, has an increased magnitude and duration in the ventral hippocampus, presumably contributing to increased input segregation in this segment of the hippocampus. GABAB receptors, GABAA receptors, adenosine A1 receptors and L-type voltage-gated calcium channels appear to contribute differently to tHSD in the two hippocampal segments; GABABRs play a predominant role in the ventral hippocampus while both GABABRs and A1Rs play important roles in the dorsal hippocampus. Activation of GABAB receptors by an exogenous agonist, baclofen, robustly and reversibly modulated both the initial fast and the late slow components of excitatory synaptic transmission, expressed by the fEPSPslope and fEPSP decay time constant (fEPSP?), respectively. Specifically, baclofen suppressed fEPSP slope more in the ventral than in the dorsal hippocampus and enhanced fEPSP? more in the dorsal than in the ventral hippocampus. Also, baclofen enhanced paired-pulse facilitation in the two hippocampal segments similarly. Blockade of GABAB receptors did not affect basal paired-pulse facilitation in either hippocampal segment. We propose that the revealed dorsal-ventral differences in modulation of synaptic transmission may provide a means for specialization of information processing in the local neuronal circuits, thereby significantly contributing to diversifying neuronal network functioning along the dorsal-ventral axis of hippocampus.

Project description:BackgroundHIV-1 can persist for the duration of a patient's life due in part to its ability to hide from the immune system, and from antiretroviral drugs, in long-lived latent reservoirs. Latent forms of HIV-1 may also be disproportionally involved in transmission. Thus, it is important to detect and quantify latency in the HIV-1 life cycle.ResultsWe developed a novel molecular clock-based phylogenetic tool to investigate the prevalence of HIV-1 lineages that have experienced latency. The method removes alternative sources that may affect evolutionary rates, such as hypermutation, recombination, and selection, to reveal the contribution of generation-time effects caused by latency. Our method was able to recover latent lineages with high specificity and sensitivity, and low false discovery rates, even on relatively short branches on simulated phylogenies. Applying the tool to HIV-1 sequences from 26 patients, we show that the majority of phylogenetic lineages have been affected by generation-time effects in every patient type, whether untreated, elite controller, or under effective or failing treatment. Furthermore, we discovered extensive effects of latency in sequence data (gag, pol, and env) from reservoirs as well as in the replicating plasma population. To better understand our phylogenetic findings, we developed a dynamic model of virus-host interactions to investigate the proportion of lineages in the actively replicating population that have ever been latent. Assuming neutral evolution, our dynamic modeling showed that under most parameter conditions, it is possible for a few activated latent viruses to propagate so that in time, most HIV-1 lineages will have been latent at some time in their past.ConclusionsThese results suggest that cycling in and out of latency plays a major role in the evolution of HIV-1. Thus, no aspect of HIV-1 evolution can be fully understood without considering latency - including treatment, drug resistance, immune evasion, transmission, and pathogenesis.

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Synaptic transmission may provide an evolutionary benefit to HIV through modulation of latency.

Publications

Synaptic transmission may provide an evolutionary benefit to HIV through modulation of latency.

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