I-102 Viral fitness costs and benefits of disrupting the host cell actin cytoskeleton in mucosal HIV-infection

AbstractModern HIV research depends crucially on both viral sequencing and population measurements. To directly link mechanistic biological processes and evolutionary dynamics during HIV infection, we developed multiple within-host phylodynamic (wi-phy) models of HIV primary infection for comparative validation against viral load and evolutionary dynamics data. The most parsimonious and accurate model required no positive selection, suggesting that the host adaptive immune system reduces viral load, but does not drive observed viral evolution. Rather, random genetic drift primarily dictates fitness changes. These results hold during early infection, and even during chronic infection when selection has been observed, viral fitness distributions are not largely different from in vitro distributions that emerge without adaptive immunity. These results highlight how phylogenetic inference must consider complex viral and immune-cell population dynamics to gain accurate mechanistic insights.One sentence summaryThrough the lens of a unified population and phylodynamic model, current data show the first wave of HIV mutations are not driven by selection by the adaptive immune system.

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Actin Cytoskeleton Manipulation by Effector Proteins Secreted by DiarrheagenicEscherichia coliPathotypes

BioMed Research International ◽

10.1155/2013/374395 ◽

2013 ◽

Vol 2013 ◽

pp. 1-22 ◽

Cited By ~ 27

Author(s):

Fernando Navarro-Garcia ◽

Antonio Serapio-Palacios ◽

Paul Ugalde-Silva ◽

Gabriela Tapia-Pastrana ◽

Lucia Chavez-Dueñas

Keyword(s):

Actin Cytoskeleton ◽

Host Cell ◽

Virulence Factors ◽

Cell Biology ◽

Bacterial Species ◽

Effector Proteins ◽

Actin Binding ◽

E Coli ◽

Tissue Organization ◽

Epithelial Barriers

The actin cytoskeleton is a dynamic structure necessary for cell and tissue organization, including the maintenance of epithelial barriers. Disruption of the epithelial barrier coincides with alterations of the actin cytoskeleton in several disease states. These disruptions primarily affect the paracellular space, which is normally regulated by tight junctions. Thereby, the actin cytoskeleton is a common and recurring target of bacterial virulence factors. In order to manipulate the actin cytoskeleton, bacteria secrete and inject toxins and effectors to hijack the host cell machinery, which interferes with host-cell pathways and with a number of actin binding proteins. An interesting model to study actin manipulation by bacterial effectors isEscherichia colisince due to its genome plasticity it has acquired diverse genetic mobile elements, which allow having differentE. colivarieties in one bacterial species. TheseE. colipathotypes, including intracellular and extracellular bacteria, interact with epithelial cells, and their interactions depend on a specific combination of virulence factors. In this paper we focus onE. colieffectors that mimic host cell proteins to manipulate the actin cytoskeleton. The study of bacterial effector-cytoskeleton interaction will contribute not only to the comprehension of the molecular causes of infectious diseases but also to increase our knowledge of cell biology.

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CCR5/CXCR4 Dual Antagonism for the Improvement of HIV Infection Therapy

Molecules ◽

10.3390/molecules24030550 ◽

2019 ◽

Vol 24 (3) ◽

pp. 550 ◽

Cited By ~ 5

Author(s):

Fedora Grande ◽

Maria Occhiuzzi ◽

Bruno Rizzuti ◽

Giuseppina Ioele ◽

Michele De Luca ◽

...

Keyword(s):

Hiv Infection ◽

Host Cell ◽

Membrane Receptor ◽

Next Generation ◽

Receptor Antagonists ◽

Viral Spread ◽

Early Stages ◽

Hiv Entry

HIV entry in the host cell requires the interaction with the CD4 membrane receptor, and depends on the activation of one or both co-receptors CCR5 and CXCR4. Former selective co-receptor antagonists, acting at early stages of infection, are able to impair the receptor functions, preventing the viral spread toward AIDS. Due to the capability of HIV to develop resistance by switching from CCR5 to CXCR4, dual co-receptor antagonists could represent the next generation of AIDS prophylaxis drugs. We herein present a survey on relevant results published in the last few years on compounds acting simultaneously on both co-receptors, potentially useful as preventing agents or in combination with classical anti-retroviral drugs based therapy.

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HLA-Cw*03-Restricted CD8+ T-Cell Responses Targeting the HIV-1 Gag Major Homology Region Drive Virus Immune Escape and Fitness Constraints Compensated for by Intracodon Variation

Journal of Virology ◽

10.1128/jvi.01144-10 ◽

2010 ◽

Vol 84 (21) ◽

pp. 11279-11288 ◽

Cited By ~ 15

Author(s):

Isobella Honeyborne ◽

Francisco M. Codoñer ◽

Alasdair Leslie ◽

Gareth Tudor-Williams ◽

Graz Luzzi ◽

...

Keyword(s):

Hiv Infection ◽

Immune Escape ◽

Viral Fitness ◽

Gag Protein ◽

Major Homology Region ◽

Cell Responses ◽

Homology Region ◽

Escape Mutants

ABSTRACT The potential importance of HLA-C-restricted CD8+ cytotoxic T lymphocytes (CTL) in HIV infection remains undetermined. We studied the dominant HLA-Cw*03-restricted CTL response to YVDRFFKTL296-304 (YL9), within the conserved major homology region (MHR) of the Gag protein, in 80 HLA-Cw*03-positive individuals with chronic HIV infection to better define the efficacy of the YL9 HLA-C-restricted response. The HLA-Cw*03 allele is strongly associated with HIV sequence changes from Thr-303 to Val, Ile, or Ala at position 8 within the YL9 epitope (P = 1.62 × 10−10). In vitro studies revealed that introduction of the changes T303I and T303A into the YL9 epitope both significantly reduced CTL recognition and substantially reduced the viral replicative capacity. However, subsequent selection of the Val-303 variant, via intracodon variation from Ile-303 (I303V) or Ala-303 (A303V), restored both viral fitness and CTL recognition, as supported by our in vivo data. These results illustrate that HLA-C-restricted CTL responses are capable of driving viral immune escape within Gag, but in contrast to what was previously described for HLA-B-restricted Gag escape mutants, the common Cw*03-Gag-303V variant selected resulted in no detectable benefit to the host.

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Fitness Costs and Benefits Associated with Dispersal in Northern Bobwhites (Colinus virginianus)

The American Midland Naturalist ◽

10.1674/0003-0031(2003)150[0073:fcabaw]2.0.co;2 ◽

2003 ◽

Vol 150 (1) ◽

pp. 73-82 ◽

Cited By ~ 23

Author(s):

DARRELL E. TOWNSEND ◽

DAVID M. LESLIE ◽

ROBERT L. LOCHMILLER ◽

STEPHEN J. DeMASO ◽

SCOTT A. COX ◽

...

Keyword(s):

Colinus Virginianus ◽

Costs And Benefits ◽

Fitness Costs ◽

Northern Bobwhites

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Differential Incorporation of CD45, CD80 (B7-1), CD86 (B7-2), and Major Histocompatibility Complex Class I and II Molecules into Human Immunodeficiency Virus Type 1 Virions and Microvesicles: Implications for Viral Pathogenesis and Immune Regulation

Journal of Virology ◽

10.1128/jvi.75.13.6173-6182.2001 ◽

2001 ◽

Vol 75 (13) ◽

pp. 6173-6182 ◽

Cited By ~ 117

Author(s):

Mark T. Esser ◽

David R. Graham ◽

Lori V. Coren ◽

Charles M. Trubey ◽

Julian W. Bess ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

T Cells ◽

Hiv Infection ◽

Host Cell ◽

Mhc Ii ◽

Host Cell Proteins ◽

Histocompatibility Complex ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT Human immunodeficiency virus (HIV) infection results in a functional impairment of CD4+ T cells long before a quantitative decline in circulating CD4+ T cells is evident. The mechanism(s) responsible for this functional unresponsiveness and eventual depletion of CD4+ T cells remains unclear. Both direct effects of cytopathic infection of CD4+ cells and indirect effects in which uninfected “bystander” cells are functionally compromised or killed have been implicated as contributing to the immunopathogenesis of HIV infection. Because T-cell receptor engagement of major histocompatibility complex (MHC) molecules in the absence of costimulation mediated via CD28 binding to CD80 (B7-1) or CD86 (B7-2) can lead to anergy or apoptosis, we determined whether HIV type 1 (HIV-1) virions incorporated MHC class I (MHC-I), MHC-II, CD80, or CD86. Microvesicles produced from matched uninfected cells were also evaluated. HIV infection increased MHC-II expression on T- and B-cell lines, macrophages, and peripheral blood mononclear cells (PBMC) but did not significantly alter the expression of CD80 or CD86. HIV virions derived from all MHC-II-positive cell types incorporated high levels of MHC-II, and both virions and microvesicles preferentially incorporated CD86 compared to CD80. CD45, expressed at high levels on cells, was identified as a protein present at high levels on microvesicles but was not detected on HIV-1 virions. Virion-associated, host cell-derived molecules impacted the ability of noninfectious HIV virions to trigger death in freshly isolated PBMC. These results demonstrate the preferential incorporation or exclusion of host cell proteins by budding HIV-1 virions and suggest that host cell proteins present on HIV-1 virions may contribute to the overall pathogenesis of HIV-1 infection.

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