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1. Modeling HIV-1 infection in the brain

   https://doi.org/10.1371/journal.pcbi.1008305  

   Barker, Colin T. ; Vaidya, Naveen K. ( November 2020 , PLOS Computational Biology)

   Regoes, Roland R. (Ed.)

   While highly active antiretroviral therapy (HAART) is successful in controlling the replication of Human Immunodeficiency Virus (HIV-1) in many patients, currently there is no cure for HIV-1, presumably due to the presence of reservoirs of the virus. One of the least studied viral reservoirs is the brain, which the virus enters by crossing the blood-brain barrier (BBB) via macrophages, which are considered as conduits between the blood and the brain. The presence of HIV-1 in the brain often leads to HIV associated neurocognitive disorders (HAND), such as encephalitis and early-onset dementia. In this study we develop a novel mathematical model that describes HIV-1 infection in the brain and in the plasma coupled via the BBB. The model predictions are consistent with data from macaques infected with a mixture of simian immunodeficiency virus (SIV) and simian-human immunodeficiency virus (SHIV). Using our model, we estimate the rate of virus transport across the BBB as well as viral replication inside the brain, and we compute the basic reproduction number. We also carry out thorough sensitivity analysis to define the robustness of the model predictions on virus dynamics inside the brain. Our model provides useful insight into virus replication within the brain and suggests that the brain can be an important reservoir causing long-term viral persistence. 

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2. Modeling the Effects of Morphine-Altered Virus Specific Antibody Responses on HIV/SIV Dynamics

   https://doi.org/10.1038/s41598-019-41751-8  

   Mutua, Jones_M ; Perelson, Alan_S ; Kumar, Anil ; Vaidya, Naveen_K ( April 2019 , Scientific Reports)

   Drugs of abuse, such as opiates, have been widely associated with enhancing HIV replication, accelerating disease progression and diminishing host-immune responses, thereby making it harder to effectively manage HIV infection. It is thus important to study the effects of drugs of abuse on HIV-infection and immune responses. Here, we develop mathematical models that incorporate the effects of morphine-altered antibody responses on HIV/SIV dynamics. Based on fitting the model to experimental data from simian immunodeficiency virus (SIV) infections in control and morphine-addicted macaques, we found that two of the most significant effects of virus specific antibodies are neutralizing viral particles and enhancing viral clearance. Using our model, we quantified how morphine alters virus-specific antibody responses, and how this alteration affects the key components of virus dynamics such as infection rate, virus clearance, viral load, CD4⁺T cell count, and CD4⁺T cell loss in SIV-infected macaques under conditioning with morphine. We found that in a subpopulation of SIV-infected morphine addicted macaques, the presence of drugs of abuse may cause significantly diminished antibody responses, resulting in more severe infection with increased SIV infectivity, a decreased viral clearance rate, increased viral load, and higher CD4⁺T cell loss.

    

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3. Multi-arm RNA junctions encoding molecular logic unconstrained by input sequence for versatile cell-free diagnostics

   https://doi.org/10.1038/s41551-022-00857-7  

   Ma, Duo ; Li, Yuexin ; Wu, Kaiyue ; Yan, Zhaoqing ; Tang, Anli A. ; Chaudhary, Soma ; Ticktin, Zachary M. ; Alcantar-Fernandez, Jonathan ; Moreno-Camacho, José L. ; Campos-Romero, Abraham ; et al ( March 2022 , Nature Biomedical Engineering)

   Abstract Applications of RNA-based molecular logic have been hampered by sequence constraints imposed on the input and output of the circuits. Here we show that the sequence constraints can be substantially reduced by appropriately encoded multi-arm junctions of single-stranded RNA structures. To conditionally activate RNA translation, we integrated multi-arm junctions, self-assembled upstream of a regulated gene and designed to unfold sequentially in response to different RNA inputs, with motifs of loop-initiated RNA activators that function independently of the sequence of the input RNAs and that reduce interference with the output gene. We used the integrated RNA system and sequence-independent input RNAs to execute two-input and three-input OR and AND logic in Escherichia coli , and designed paper-based cell-free colourimetric assays that accurately identified two human immunodeficiency virus (HIV) subtypes (by executing OR logic) in amplified synthetic HIV RNA as well as severe acute respiratory syndrome coronavirus-2 (via two-input AND logic) in amplified RNA from saliva samples. The sequence-independent molecular logic enabled by the integration of multi-arm junction RNAs with motifs for loop-initiated RNA activators may be broadly applicable in biotechnology. 

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4. Human immunodeficiency virus (HIV) dynamics in secondary lymphoid tissues and the evolution of cytotoxic T lymphocyte (CTL) escape mutants

   https://doi.org/10.1093/ve/vead084  

   Chung, Wen-Jian ; Connick, Elizabeth ; Wodarz, Dominik ( January 2024 , Virus Evolution)

   In the secondary lymphoid tissues, human immunodeficiency virus (HIV) can replicate both in the follicular and the extrafollicular compartments. Yet, virus is concentrated in the follicular compartment in the absence of antiretroviral therapy, in part due to the lack of cytotoxic T lymphocyte (CTL)-mediated activity there. CTL home to the extrafollicular compartment, where they can suppress virus load to relatively low levels. We use mathematical models to show that this compartmentalization can explain seemingly counterintuitive observations. First, it can explain the observed constancy of the viral decline slope during antiviral therapy in the peripheral blood, irrespective of the presence of CTL in SIV-infected macaques, under the assumption that CTL-mediated lysis significantly contributes to virus suppression. Second, it can account for the relatively long times it takes for CTL escape mutants to emerge during chronic infection even if CTL-mediated lysis is responsible for virus suppression. The reason is the heterogeneity in CTL activity, and the consequent heterogeneity in selection pressure between the follicular and extrafollicular compartments. Hence, to understand HIV dynamics more thoroughly, this analysis highlights the importance of measuring virus populations separately in the extrafollicular and follicular compartments rather than using virus load in peripheral blood as an observable; this hides the heterogeneity between compartments that might be responsible for the particular patterns seen in the dynamics and evolution of the HIV in vivo.

    

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5. Occurrence and genetic evaluation of potentially pathogenic Acanthamoeba genotypes in nasal mucosa of immunocompromised patients: a case–control study in Iran

   https://doi.org/10.1093/trstmh/trac026  

   Moslemzadeh, Hamid Reza ; Mahami-Oskouei, Mahmoud ; Ahmadpour, Ehsan ; Niyyati, Maryam ; Rostami, Ali ; Memari, Fatemeh ; Spotin, Adel ( April 2022 , Transactions of The Royal Society of Tropical Medicine and Hygiene)

   The occurrence of granulomatous amoebic encephalitis (GAE) was investigated due to the exposure of a large number of immunocompromised patients to opportunistic Acanthamoeba infections, which in most cases are fatal.

   In this case–control study, 160 samples from the nasal mucosa of immunocompromised patients were collected between February 2019 to February 2020 in Isfahan, central Iran, using sterile cotton swabs; 150 ethnically matched controls were included. The pathogenic potential of the identified isolates was evaluated using temperature and osmotolerance assays. The identification of Acanthamoeba infection was confirmed by both morphological and phylomolecular tools.

   Of 310 collected samples, 32 strains, including 25 (15.6%) and 7 (4.6%) isolates, were positive for the Acanthamoeba genus in the patient and control groups, respectively. The topology of the phylogenetic tree indicated that all the Acanthamoeba strains belonged to the T4 genotype. Only five of the isolates genotyped as T4 were positive for potential pathogenic assays. The heterogeneity analysis of 18S ribosomal RNA sequences of Acanthamoeba in human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) and hepatitis B and C patients revealed significant genetic diversity (haplotype diversity [Hd] 0.511) compared with that of healthy individuals (Hd 0.210).

   The circulation of pathogenic isolates of Acanthamoeba, particularly in HIV/AIDS patients, along with their genetic traits, indicates that clinicians should be more aware of fatal cases of GAE, especially in suspected encephalitis, in Iran and worldwide.

    

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