86 research outputs found
HIV-1 envelope, integrins and co-receptor use in mucosal transmission of HIV
It is well established that HIV-1 infection typically involves an interaction between the viral envelope protein gp120/41 and the CD4 molecule followed by a second interaction with a chemokine receptor, usually CCR5 or CXCR4. In the early stages of an HIV-1 infection CCR5 using viruses (R5 viruses) predominate. In some viral subtypes there is a propensity to switch to CXCR4 usage (X4 viruses). The receptor switch occurs in ~ 40% of the infected individuals and is associated with faster disease progression. This holds for subtypes B and D, but occurs less frequently in subtypes A and C. There are several hypotheses to explain the preferential transmission of R5 viruses and the mechanisms that lead to switching of co-receptor usage; however, there is no definitive explanation for either. One important consideration regarding transmission is that signaling by R5 gp120 may facilitate transmission of R5 viruses by inducing a permissive environment for HIV replication. In the case of sexual transmission, infection by HIV requires the virus to breach the mucosal barrier to gain access to the immune cell targets that it infects; however, the immediate events that follow HIV exposure at genital mucosal sites are not well understood. Upon transmission, the HIV quasispecies that is replicating in an infected donor contracts through a âgenetic bottleneckâ, and often infection results from a single infectious event. Many details surrounding this initial infection remain unresolved. In mucosal tissues, CD4+ T cells express high levels of CCR5, and a subset of these CD4+/CCR5high cells express the integrin α4ÎČ7, the gut homing receptor. CD4+/CCR5high/ α4ÎČ7high T cells are highly susceptible to infection by HIV-1 and are ideal targets for an efficient productive infection at the point of transmission. In this context we have demonstrated that the HIV-1 envelope protein gp120 binds to α4ÎČ7 on CD4+ T cells. On CD4+/CCR5high/ α4ÎČ7high T cells, α4ÎČ7 is closely associated with CD4 and CCR5. Furthermore, α4ÎČ7 is ~3 times the size of CD4 on the cell surface, that makes it a prominent receptor for an efficient virus capture. gp120-α4ÎČ7 interactions mediate the activation of the adhesion-associated integrin LFA-1. LFA-1 facilitates the formation of virological synapses and cell-to-cell spread of HIV-1. gp120 binding to α4ÎČ7 is mediated by a tripeptide located in the V1/V2 domain of gp120. Of note, the V1/V2 domain of gp120 has been linked to variations in transmission fitness among viral isolates raising the intriguing possibility that gp120-α4ÎČ7 interactions may be linked to transmission fitness. Although many details remain unresolved, we hypothesize that gp120-α4ÎČ7 interactions play an important role in the very early events following sexual transmission of HIV and may have important implication in the design of vaccine strategies for the prevention of acquisition of HIV infectio
Relaxation of Adaptive Evolution during the HIV-1 Infection Owing to Reduction of CD4+ T Cell Counts
Background: the first stages of HIV-1 infection are essential to establish the diversity of virus population within host. It has been suggested that adaptation to host cells and antibody evasion are the leading forces driving HIV evolution at the initial stages of AIDS infection. in order to gain more insights on adaptive HIV-1 evolution, the genetic diversity was evaluated during the infection time in individuals contaminated by the same viral source in an epidemic cluster. Multiple sequences of V3 loop region of the HIV-1 were serially sampled from four individuals: comprising a single blood donor, two blood recipients, and another sexually infected by one of the blood recipients. the diversity of the viral population within each host was analyzed independently in distinct time points during HIV-1 infection.Results: Phylogenetic analysis identified multiple HIV-1 variants transmitted through blood transfusion but the establishing of new infections was initiated by a limited number of viruses. Positive selection (d(N)/d(S)>1) was detected in the viruses within each host in all time points. in the intra-host viruses of the blood donor and of one blood recipient, X4 variants appeared respectively in 1993 and 1989. in both patients X4 variants never reached high frequencies during infection time. the recipient, who X4 variants appeared, developed AIDS but kept narrow and constant immune response against HIV-1 during the infection time.Conclusion: Slowing rates of adaptive evolution and increasing diversity in HIV-1 are consequences of the CD4+ T cells depletion. the dynamic of R5 to X4 shift is not associated with the initial amplitude of humoral immune response or intensity of positive selection.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Fed Univ Para, Inst Biotechnol, BR-66059 Belem, Para, BrazilUniv São Paulo, Inst Trop Med, São Paulo, SP, BrazilCDC, Ctr Dis Control & Prevent, Branch Lab, Atlanta, GA 30333 USAUniv Calif San Francisco, Dept Lab Med, San Francisco, CA 94143 USABlood Syst Res Inst, San Francisco, CA USABlood Syst Inc, San Francisco, CA USAUniversidade Federal de São Paulo, São Paulo, BrazilUniversidade Federal de São Paulo, São Paulo, BrazilFAPESP: 07/52841-8Web of Scienc
Cervical epidural steroid injections in the management of cervical radiculitis: interlaminar versus transforaminal. A review
There has been recent concern regarding the safety of cervical epidural steroid injections. The decision to proceed with treatment requires balancing the risk and benefits. This article is an in depth review of the efficacy, complications, and technique of both interlaminar and transforaminal cervical epidural steroid injections in the management of cervical radiculitis
The co-receptor signaling model of HIV-1 pathogenesis in peripheral CD4 T cells
HIV-mediated CD4 depletion is the hallmark of AIDS and is the most reliable predictor of disease progression. While HIV replication is associated with CD4 depletion in general, plasma viremia by itself predicts the rate of CD4 loss only minimally in untreated patients. To resolve this paradox, I hypothesize the existence of a subpopulation of R5X4-signaling viruses. I also suggest that the gradual evolution and emergence of this subpopulation are largely responsible for the slow depletion of peripheral CD4 T cells
The Colocalization Potential of HIV-Specific CD8+ and CD4+ T-Cells is Mediated by Integrin ÎČ7 but Not CCR6 and Regulated by Retinoic Acid
CD4+ T-cells from gut-associated lymphoid tissues (GALT) are major targets for HIV-1 infection. Recruitment of excess effector CD8+ T-cells in the proximity of target cells is critical for the control of viral replication. Here, we investigated the colocalization potential of HIV-specific CD8+ and CD4+ T-cells into the GALT and explored the role of retinoic acid (RA) in regulating this process in a cohort of HIV-infected subjects with slow disease progression. The expression of the gut-homing molecules integrin ÎČ7, CCR6, and CXCR3 was identified as a âsignatureâ for HIV-specific but not CMV-specific CD4+ T-cells thus providing a new explanation for their enhanced permissiveness to infection in vivo. HIV-specific CD8+ T-cells also expressed high levels of integrin ÎČ7 and CXCR3; however CCR6 was detected at superior levels on HIV-specific CD4+
versus CD8+ T-cells. All trans RA (ATRA) upregulated the expression of integrin ÎČ7 but not CCR6 on HIV-specific T-cells. Together, these results suggest that HIV-specific CD8+ T-cells may colocalize in excess with CD4+ T-cells into the GALT via integrin ÎČ7 and CXCR3, but not via CCR6. Considering our previous findings that CCR6+CD4+ T-cells are major cellular targets for HIV-DNA integration in vivo, a limited ability of CD8+ T-cells to migrate in the vicinity of CCR6+CD4+ T-cells may facilitate HIV replication and dissemination at mucosal sites
Observation of Two New Excited Îb0 States Decaying to Îb0 K-Ï+
Two narrow resonant states are observed in the Îb0K-Ï+ mass spectrum using a data sample of proton-proton collisions at a center-of-mass energy of 13 TeV, collected by the LHCb experiment and corresponding to an integrated luminosity of 6 fb-1. The minimal quark content of the Îb0K-Ï+ system indicates that these are excited Îb0 baryons. The masses of the Îb(6327)0 and Îb(6333)0 states are m[Îb(6327)0]=6327.28-0.21+0.23±0.12±0.24 and m[Îb(6333)0]=6332.69-0.18+0.17±0.03±0.22 MeV, respectively, with a mass splitting of Îm=5.41-0.27+0.26±0.12 MeV, where the uncertainties are statistical, systematic, and due to the Îb0 mass measurement. The measured natural widths of these states are consistent with zero, with upper limits of Î[Îb(6327)0]<2.20(2.56) and Î[Îb(6333)0]<1.60(1.92) MeV at a 90% (95%) credibility level. The significance of the two-peak hypothesis is larger than nine (five) Gaussian standard deviations compared to the no-peak (one-peak) hypothesis. The masses, widths, and resonant structure of the new states are in good agreement with the expectations for a doublet of 1D Îb0 resonances
The HIV-1 transmission bottleneck
It is well established that most new systemic infections of HIV-1 can be traced back to one or a limited number of founder viruses. Usually, these founders are more closely related to minor HIV-1 populations in the blood of the presumed donor than to more abundant lineages. This has led to the widely accepted idea that transmission selects for viral characteristics that facilitate crossing the mucosal barrier of the recipientâs genital tract, although the specific selective forces or advantages are not completely defined. However, there are other steps along the way to becoming a founder virus at which selection may occur. These steps include the transition from the donorâs general circulation to the genital tract compartment, survival within the transmission fluid, and establishment of a nascent stable local infection in the recipientâs genital tract. Finally, there is the possibility that important narrowing events may also occur during establishment of systemic infection. This is suggested by the surprising observation that the number of founder viruses detected after transmission in intravenous drug users is also limited. Although some of these steps may be heavily selective, others may result mostly in a stochastic narrowing of the available founder pool. Collectively, they shape the initial infection in each recipient
Measurement of the electron reconstruction efficiency at LHCb
The single electron track-reconstruction efficiency is calibrated using a sample corresponding to 1.3 fbâ1 of pp collision data recorded with the LHCb detector in 2017. This measurement exploits B+â J/Ï(e+eâ)K+ decays, where one of the electrons is fully reconstructed and paired with the kaon, while the other electron is reconstructed using only the information of the vertex detector. Despite this partial reconstruction, kinematic and geometric constraints allow the B meson mass to be reconstructed and the signal to be well separated from backgrounds. This in turn allows the electron reconstruction efficiency to be measured by matching the partial track segment found in the vertex detector to tracks found by LHCb's regular reconstruction algorithms. The agreement between data and simulation is evaluated, and corrections are derived for simulated electrons in bins of kinematics. These correction factors allow LHCb to measure branching fractions involving single electrons with a systematic uncertainty below 1%
Measurement of antiproton production from antihyperon decays in p He collisions at âsNN = 110 GeV
The interpretation of cosmic antiproton flux measurements from space-borne experiments is currently limited by the knowledge of the antiproton production cross-section in collisions between primary cosmic rays and the interstellar medium. Using collisions of protons with an energy of 6.5TeV incident on helium nuclei at rest in the proximity of the interaction region of the LHCb experiment, the ratio of antiprotons originating from antihyperon decays to prompt production is measured for antiproton momenta between 12 and 110GeV. The dominant antihyperon contribution, namely ÎÂŻâpÂŻÏ+ decays from promptly produced ÎÂŻ particles, is also exclusively measured. The results complement the measurement of prompt antiproton production obtained from the same data sample. At the energy scale of this measurement, the antihyperon contributions to antiproton production are observed to be significantly larger than predictions of commonly used hadronic production models
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