Specific amino acids in HIV-1 Vpr are significantly associated with differences in patient neurocognitive status

Dampier, Will; Antell, Gregory C.; Aiamkitsumrit, Benjamas; Nonnemacher, Michael R.; Jacobson, Jeffrey M.; Pirrone, Vanessa; Zhong, Wenyi; Kercher, Katherine; Passic, Shendra; Williams, Jennifer L.; James, Tony; Devlin, Kathryn N.; Giovannetti, Tania; Libon, David J.; Szep, Zsofia; Ehrlich, Garth D.; Wigdahl, Brian; Krebs, Fred C.

doi:10.1007/s13365-016-0462-3

Cited by 19 publications

(23 citation statements)

References 71 publications

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“…As such, Vpr derived from patient HIV-1 sequences have also been studied for genetic heterogeneity that affects its functionality. Specific genetic determinants in blood-and brain-derived Vpr, such as Ile37 and Ser41, have been correlated with more severe neurocognitive deficits in patient populations [257], which emphasizes the detrimental impact of certain genetic variants throughout the HIV-1 genome on CNS function. Vpr has been determined to be a cis-acting element produced by HIV-1 [258] and its likeness to Tat in pathogenic function suggest that variation within either protein may enhance or deplete neuropathogenesis in an additive manner.…”

Section: Discussionmentioning

confidence: 99%

Genetic variation and function of the HIV-1 Tat protein

Spector

Mele

Wigdahl

et al. 2019

Med Microbiol Immunol

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Human immunodeficiency virus type 1 (HIV-1) encodes a transactivator of transcription (Tat) protein, which has several functions that promote viral replication, pathogenesis, and disease. Amino acid variation within Tat has been observed to alter the functional properties of Tat and, depending on the HIV-1 subtype, may produce Tat phenotypes differing from viruses representative of each subtype and commonly used in in vivo and in vitro experimentation. The molecular properties of Tat allow for distinctive functional activities to be determined such as the subcellular localization and other intra-and extracellular functional aspects of this important viral protein influenced by variation within the Tat sequence. Once Tat has been transported into the nucleus and becomes engaged in transactivation of the long terminal repeat (LTR), various Tat variants may differ in their capacity to activate viral transcription. Post-translational modification patterns based on these amino acid variations may alter interactions between Tat and host factors, which may positively or negatively affect this process. Additionally, the ability of HIV-1 to utilize or not utilize the transactivation response (TAR) element within the LTR, based on genetic variation and cellular phenotype, adds a layer of complexity to the processes that govern Tatmediated proviral DNA-driven transcription and replication. In contrast, cytoplasmic or extracellular localization of Tat may cause pathogenic effects in the form of altered cell activation, apoptosis, or neurotoxicity. Tat variants have been shown to differentially induce these processes, which may have implications for long-term HIV-1-infected patient care in the antiretroviral therapy era. Future studies concerning genetic variation of Tat with respect to function should focus on variants derived from HIV-1-infected individuals to efficiently guide Tat-targeted therapies and elucidate mechanisms of pathogenesis within the global patient population.

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Section: Discussionmentioning

confidence: 99%

Genetic variation and function of the HIV-1 Tat protein

Spector

Mele

Wigdahl

et al. 2019

Med Microbiol Immunol

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“…hetero- and homozygous individuals were grouped. We classified AAs according to their effects on cognition, as reported by Dampier et al [11], with higher scores indicative of greater risk. Accordingly, the AAs were scored as follows: AA37 I (neuroprotective) variant = 0, other (neutral) variants = 1; AA41 S (neuroprotective) variant = 0, N (risk) variant = 2, other (neutral) variants = 1; and AA55 A (risk) variant = 1, other (neutral) variants = 0.…”

Section: Methodsmentioning

confidence: 99%

“…This genetic variation, specifically the ε4 isoform, may affect HIV infection [8] and replication in the brain [9], as well as susceptibility to HIV-related neurotoxic proteins [10]. Viral genetic variation may also contribute to HAND, with a study by Dampier et al [11] identifying three amino acids (AAs) in viral protein R (Vpr) that affect neurocognitive performance. This 96-AA accessory protein plays a role in HIV infection and viral transcription, and may contribute to neuronal apoptosis, synaptic loss, proinflammatory signalling, oxidative stress and blood–brain barrier permeability [12–17].…”

Section: Introductionmentioning

confidence: 99%

The effect of childhood trauma, ApoE genotype and HIV-1 viral protein R variants on change in cognitive performance

et al. 2019

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ObjectiveGene–environment interactions contribute to the development of HIV-associated neurocognitive disorders. We examined whether childhood trauma, apolipoprotein E isoforms and viral protein R (Vpr) variants were associated with change in cognitive performance. Seventy-three seropositive women completed neuropsychological assessments at baseline and 1-year follow-up. We conducted genetic analyses using DNA obtained from blood and calculated risk scores based on Vpr amino acid 37, 41 and 55 variants that were previously associated with cognitive performance.ResultsGlobal cognitive scores declined significantly over the 1-year study period (p = 0.029). A reduction in global cognitive scores was associated with childhood trauma experience (p = 0.039).

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“…3 Journal of Immunology Research makes immunotherapy more challenging by altering the targets of therapy but also alters the spectrum of HIV-1associated pathogenesis. Studies have uncovered mutations in genes encoding HIV-1 proteins, such as Tat and Vpr, that can be considered determinants and/or markers for altered HIV-1 pathogenic outcomes [63][64][65][66][67][68]. Minimizing the emergence of HIV-1 quasispecies during the course of infection has been recognized as an important objective of an effective dendritic cell immunotherapy.…”

Section: Variables and Therapeutic Outcomes Of Clinical Trialsmentioning

confidence: 99%

The Evolution of Dendritic Cell Immunotherapy against HIV-1 Infection: Improvements and Outlook

Mohamed

Miller

Jennings

et al. 2020

Journal of Immunology Research

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Dendritic cells (DC) are key phagocytic cells that play crucial roles in both the innate and adaptive immune responses against the human immunodeficiency virus type 1 (HIV-1). By processing and presenting pathogen-derived antigens, dendritic cells initiate a directed response against infected cells. They activate the adaptive immune system upon recognition of pathogen-associated molecular patterns (PAMPs) on infected cells. During the course of HIV-1 infection, a successful adaptive (cytotoxic CD8+ T-cell) response is necessary for preventing the progression and spread of infection in a variety of cells. Dendritic cells have thus been recognized as a valuable tool in the development of immunotherapeutic approaches and vaccines effective against HIV-1. The advancements in dendritic cell vaccines in cancers have paved the way for applications of this form of immunotherapy to HIV-1 infection. Clinical trials with patients infected with HIV-1 who are well-suppressed by antiretroviral therapy (ART) were recently performed to assess the efficacy of DC vaccines, with the goal of mounting an HIV-1 antigen-specific T-cell response, ideally to clear infection and eliminate the need for long-term ART. This review summarizes and compares methods and efficacies of a number of DC vaccine trials utilizing autologous dendritic cells loaded with HIV-1 antigens. The potential for advancement and novel strategies of improving efficacy of this type of immunotherapy is also discussed.

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Specific amino acids in HIV-1 Vpr are significantly associated with differences in patient neurocognitive status

Cited by 19 publications

References 71 publications

Genetic variation and function of the HIV-1 Tat protein

Genetic variation and function of the HIV-1 Tat protein

The effect of childhood trauma, ApoE genotype and HIV-1 viral protein R variants on change in cognitive performance

The Evolution of Dendritic Cell Immunotherapy against HIV-1 Infection: Improvements and Outlook

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