Browsing by Subject "HIV-1"

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  • Saha, Shreya; Hafren, Anders; Makinen, Kristiina (2019)
    One large open reading frame (ORF) encodes 10 potyviral proteins. We compared the accumulation of cylindrical inclusion (CI) protein from the middle, coat protein (CP) from the 3'end, and Renilla luciferase (RLUC) from two distinct locations in potato virus A (PVA) RNA. 5' RLUC was expressed from an rluc gene inserted between the P1 and helper component proteinase (HCPro) cistrons, and 3' RLUC was expressed from the gene inserted between the RNA polymerase and CP cistrons. Viral protein and RNA accumulation were quantitated (i) when expressed from PVA RNA in the presence of ectopically expressed genome-linked viral protein (VPg) and auxiliary proteins and (ii) at different time points during natural infection. The rate and timing of 3' RLUC and CP accumulation were found to be different from those of 5' RLUC and Cl. Ectopic expression of VPg boosted PVA RNA, 3' RLUC, and, together with HCPro, CP accumulation, whereas 5' RLUC and CI accumulation remained unaffected regardless of the increased viral RNA amount. In natural infection, the rate of the noteworthy minute early accumulation of 3' RLUC accelerated toward the end of infection. 5' RLUC accumulation, which was already pronounced at 2 days postinfection, increased moderately and stabilized to a constant level by day 5, whereas PVA RNA and CP levels continued to increase throughout the infection. We propose that these observations connect with the mechanisms by which potyvirus infection limits CP accumulation during early infection and specifically supports its accumulation late in infection, but follow-up studies are required to understand the mechanism of how this occurs. IMPORTANCE The results of this study suggest that the dynamics of potyviral protein accumulation are regulated differentially from the 3' end of viral RNA than from the rest of the genome, the significance of which would be to satisfy the needs of replication early and particle assembly late in infection.
  • Mikkola, Visa (Helsingin yliopisto, 2020)
    Tavoitteet: Itä-Euroopassa ja Keski-Aasiassa HIV-1-infektioiden ilmaantuvuus on noussut 57 % vuosina 2000−2015. Epidemiologista dataa on edelleenkin vähän. Lisäksi se on pääosin venäjänkielistä, eikä ole saatavilla kansainvälisten tietokantojen kautta. Suunnitelma: Keräsimme näytteitä ja epidemiologista dataa 328 HIV-tartunnan saaneelta, joista 91 % asui Venäjän Eteläisen federaatiopiirin alueella ja 9 % Pohjois-Kaukasian federaatiopiirin alueella. Menetelmät: Proteaasi-käänteiskopioijaentsyymi- (PRRT) ja integraasisekvessejä (IN) käytettiin viruksen alatyypin selvittämiseen sekä resistenssimutaatioiden ja lääkeherkkyyksien analysointiin. Fylogeneettisiä analyysejä käytettiin HIV:n ala-alatyyppien A6 ja A1 erottamiseen toisistaan. Tulokset: 303 (92 %) potilaan näytteet pystyttiin analysoimaan, näistä 32 %:lla infektio oli saatu huumeiden pistoskäytön kautta, 27 %:lla heteroseksissä ja 24 % infektioista oli nosokomiaalisia eli hoidon seurauksena tulleita. Miehillä huumeiden pistoskäyttö oli yleisin syy infektioille, naisilla heteroseksi. Tutkimuksessa todettiin eniten A6-viruksia (69 %), joita esiintyi erityisesti huumeita pistämällä käyttävillä sekä heteroseksin kautta saaduissa tartunnoissa. Tätä ja tulevia tutkimuksia varten luotiin A6-pol-referenssisekvenssi. Alatyypin B infektioita esiintyi erityisesti miehillä, joilla oli ollut miesten välistä seksiä. Alatyypin G infektiot olivat yhteydessä nosokomiaaliseen infektioon. Lääkeresistenssimutaatioita havaittiin PI-, NRTI-, NNRTI- ja INI-lääkeaineryhmiä kohtaan. Spesifisten mutaatioiden esiintyvyys korreloi tiettyjen HIV:n alatyyppien kanssa. Esimerkiksi ala-alatyyppi A6 yhteydessä esiintyi merkittävästi enemmän mutaatioita NRTI A62V sekä NNRTI G190S, kun taas alatyyppiin G korreloivat NRTI-lääkeaineryhmään liittyvät mutaatiot D67N ja M41L. Näytteissä havaittiin lääkeherkkyyden alentuma: 14,5 % PI-, 29,6 % NNRTI-, 27,1 % NNRTI- ja 8,2 % INI-ryhmän lääkkeitä kohtaan. Yhteenveto: Tutkimuksessa havaittu HIV-1 alatyyppijakauma Venäjällä on merkittävästi erilainen kuin Saksassa. A6 oli yleisin tutkimuksen näytteissä havaittu alatyyppi samoin kuin muissakin Venäjälle sijoittuvissa tutkimuksissa on kuvattu. Alatyyppiä G esiintyi poikkeuksellisen paljon tämän tutkimuksen näytteissä verrattuna muihin Venäjältä julkaistuihin tutkimuksiin, mikä viittaa paikalliseen epidemiaan. HIV-1:n resistenssitestauksen yleistyminen parantaisi HIV-lääkehoidon tehokkuutta sekä toisi lisätietoa Venäjän HIV-epidemiasta. (271 sanaa)
  • Mokkala, Kati (University of Helsinki, 1994)
  • Frentz, Dineke; Van de Vijver, David A. M. C.; Abecasis, Ana B.; Albert, Jan; Hamouda, Osamah; Jorgensen, Louise B.; Kucherer, Claudia; Struck, Daniel; Schmit, Jean-Claude; Vercauteren, Jurgen; Asjo, Birgitta; Balotta, Claudia; Beshkov, Danail; Camacho, Ricardo J.; Clotet, Bonaventura; Coughlan, Suzie; Griskevicius, Algirdas; Grossman, Zehava; Horban, Andrzej; Kolupajeva, Tatjana; Korn, Klaus; Kostrikis, Leondios G.; Liitsola, Kirsi; Linka, Marek; Nielsen, Claus; Otelea, Dan; Paraskevis, Dimitrios; Paredes, Roger; Poljak, Mario; Puchhammer-Stockl, Elisabeth; Sonnerborg, Anders; Stanekova, Danica; Stanojevic, Maja; Van Wijngaerden, Eric; Wensing, Annemarie M. J.; Boucher, Charles A. B.; SPREAD Programme; Ristola, Matti A (2014)
  • Llibre, Josep M.; Cozzi-Lepri, Alessandro; Pedersen, Court; Ristola, Matti; Losso, Marcelo; Mocroft, Amanda; Mitsura, Viktar; Falconer, Karolin; Maltez, Fernando; Beniowski, Marek; Vullo, Vincenzo; Hassoun, Gamal; Kuzovatova, Elena; Szlavik, Janos; Kuznetsova, Anastasiia; Stellbrink, Hans-Juergen; Duvivier, Claudine; Edwards, Simon; Laut, Kamilla; Paredes, Roger (2016)
    Effectiveness data of an unboosted atazanavir (ATV) with abacavir/lamivudine (ABC/3TC) switch strategy in clinical routine are scant.We evaluated treatment outcomes of ATV + ABC/3TC in pretreated subjects in the EuroSIDA cohort when started with undetectable plasma HIV-1 viral load (pVL), performing a time to loss of virological response (TLOVR 50copies/mL.We included 285 subjects, 67% male, with median baseline CD4 530 cells, and 44 months with pVL 50copies/mL. The third drug in the previous regimen was ritonavir-boosted atazanavir (ATV/r) in 79 (28%), and another ritonavir-boosted protease inhibitor (PI/r) in 29 (10%). Ninety (32%) had previously failed with a PI. Proportions of people with virological success at 48/96/144 weeks were 90%/87%/88% (TLOVR) and 74%/67%/59% (snapshot analysis), respectively. The rates of VF were 8%/8%/6%. Rates of adverse events leading to study discontinuation were 0.4%/1%/2%. The multivariable adjusted analysis showed an association between VF and nadir CD4+ (hazard ratio [HR] 0.63 [95% confidence interval [CI]: 0.42-0.93] per 100 cells higher), time with pVL 50copies/mL (HR 0.87 [95% CI: 0.79-0.96] per 6 months longer), and previous failure with a PI (HR 2.78 [95% CI: 1.28-6.04]). Resistance selection at failure was uncommon.A switch to ATV + ABC/3TC in selected subjects with suppressed viremia was associated with low rates of VF and discontinuation due to adverse events, even in subjects not receiving ATV/r. The strategy might be considered in those with long-term suppression and no prior PI failure.
  • BEEHIVE Collaboration; Zhao, Lele; Wymant, Chris; Blanquart, Francois; Kivelä, Pia; Ferretti, Luca (2022)
    Set-point viral load (SPVL), a common measure of human immunodeficiency virus (HIV)-1 virulence, is partially determined by viral genotype. Epidemiological evidence suggests that this viral property has been under stabilising selection, with a typical optimum for the virus between 10(4) and 10(5) copies of viral RNA per ml. Here we aimed to detect transmission fitness differences between viruses from individuals with different SPVLs directly from phylogenetic trees inferred from whole-genome sequences. We used the local branching index (LBI) as a proxy for transmission fitness. We found that LBI is more sensitive to differences in infectiousness than to differences in the duration of the infectious state. By analysing subtype-B samples from the Bridging the Evolution and Epidemiology of HIV in Europe project, we inferred a significant positive relationship between SPVL and LBI up to approximately 10(5) copies/ml, with some evidence for a peak around this value of SPVL. This is evidence of selection against low values of SPVL in HIV-1 subtype-B strains, likely related to lower infectiousness, and perhaps a peak in the transmission fitness in the expected range of SPVL. The less prominent signatures of selection against higher SPVL could be explained by an inherent limit of the method or the deployment of antiretroviral therapy.
  • Tossavainen, Helena; Ugurlu, Hasan; Karjalainen, Mikael; Hellman, Maarit; Antenucci, Lina; Fagerlund, Riku; Saksela, Kalle; Permi, Perttu (2022)
    Class I SH3 domain-binding motifs generally comply with the consensus sequence [R/K]x0PxxP, the hydrophobic residue 0 being proline or leucine. We have studied the unusual 0 = Ala-specificity of SNX9 SH3 by determining its complex structure with a peptide present in eastern equine encephalitis virus (EEEV) nsP3. The structure revealed the length and composition of the n-Src loop as important factors determining specificity. We also compared the affinities of EEEV nsP3 peptide, its mutants, and cellular ligands to SNX9 SH3. These data suggest that nsP3 has evolved to minimize reduction of conformational entropy upon binding, hence acquiring stronger affinity, enabling takeover of SNX9. The RxAPxxP motif was also found in human T cell leukemia virus-1 (HTLV-1) Gag polyprotein. We found that this motif was required for efficient HTLV-1 infection, and that the specificity of SNX9 SH3 for the RxAPxxP core binding motif was importantly involved in this process.
  • Carlson, Colin J.; Farrell, Maxwell J.; Grange, Zoe; Han, Barbara A.; Mollentze, Nardus; Phelan, Alexandra L.; Rasmussen, Angela L.; Albery, Gregory F.; Bett, Bernard; Brett-Major, David M.; Cohen, Lily E.; Dallas, Tad; Eskew, Evan A.; Fagre, Anna C.; Forbes, Kristian M.; Gibb, Rory; Halabi, Sam; Hammer, Charlotte C.; Katz, Rebecca; Kindrachuk, Jason; Muylaert, Renata L.; Nutter, Felicia B.; Ogola, Joseph; Olival, Kevin J.; Rourke, Michelle; Ryan, Sadie J.; Ross, Noam; Seifert, Stephanie N.; Sironen, Tarja; Standley, Claire J.; Taylor, Kishana; Venter, Marietjie; Webala, Paul W. (2021)
    In the light of the urgency raised by the COVID-19 pandemic, global investment in wildlife virology is likely to increase, and new surveillance programmes will identify hundreds of novel viruses that might someday pose a threat to humans. To support the extensive task of laboratory characterization, scientists may increasingly rely on data-driven rubrics or machine learning models that learn from known zoonoses to identify which animal pathogens could someday pose a threat to global health. We synthesize the findings of an interdisciplinary workshop on zoonotic risk technologies to answer the following questions. What are the prerequisites, in terms of open data, equity and interdisciplinary collaboration, to the development and application of those tools? What effect could the technology have on global health? Who would control that technology, who would have access to it and who would benefit from it? Would it improve pandemic prevention? Could it create new challenges? This article is part of the theme issue 'Infectious disease macroecology: parasite diversity and dynamics across the globe'.
  • Barboric, Matjaz; Fujinaga, Koh (2016)
  • Hofstra, L. Marije; Sauvageot, Nicolas; Albert, Jan; Alexiev, Ivailo; Garcia, Federico; Struck, Daniel; Van de Vijver, David A. M. C.; Asjo, Birgitta; Beshkov, Danail; Coughlan, Suzie; Descamps, Diane; Griskevicius, Algirdas; Hamouda, Osamah; Horban, Andrzej; Van Kasteren, Marjo; Kolupajeva, Tatjana; Kostrikis, Leondios G.; Liitsola, Kirsi; Linka, Marek; Mor, Orna; Nielsen, Claus; Otelea, Dan; Paraskevis, Dimitrios; Paredes, Roger; Poljak, Mario; Puchhammer-Stoeckl, Elisabeth; Sonnerborg, Anders; Stanekova, Danica; Stanojevic, Maja; Van Laethem, Kristel; Zazzi, Maurizio; Lepej, Snjezana Zidovec; Boucher, Charles A. B.; Schmit, Jean-Claude; Wensing, Annemarie M. J.; SPREAD Program; Ristola, M. (2016)
    Background. Numerous studies have shown that baseline drug resistance patterns may influence the outcome of antiretroviral therapy. Therefore, guidelines recommend drug resistance testing to guide the choice of initial regimen. In addition to optimizing individual patient management, these baseline resistance data enable transmitted drug resistance (TDR) to be surveyed for public health purposes. The SPREAD program systematically collects data to gain insight into TDR occurring in Europe since 2001. Methods. Demographic, clinical, and virological data from 4140 antiretroviral-naive human immunodeficiency virus (HIV)-infected individuals from 26 countries who were newly diagnosed between 2008 and 2010 were analyzed. Evidence of TDR was defined using the WHO list for surveillance of drug resistance mutations. Prevalence of TDR was assessed over time by comparing the results to SPREAD data from 2002 to 2007. Baseline susceptibility to antiretroviral drugs was predicted using the Stanford HIVdb program version 7.0. Results. The overall prevalence of TDR did not change significantly over time and was 8.3% (95% confidence interval, 7.2%-9.5%) in 2008-2010. The most frequent indicators of TDR were nucleoside reverse transcriptase inhibitor (NRTI) mutations (4.5%), followed by nonnucleoside reverse transcriptase inhibitor (NNRTI) mutations (2.9%) and protease inhibitor mutations (2.0%). Baseline mutations were most predictive of reduced susceptibility to initial NNRTI-based regimens: 4.5% and 6.5% of patient isolates were predicted to have resistance to regimens containing efavirenz or rilpivirine, respectively, independent of current NRTI backbones. Conclusions. Although TDR was highest for NRTIs, the impact of baseline drug resistance patterns on susceptibility was largest for NNRTIs. The prevalence of TDR assessed by epidemiological surveys does not clearly indicate to what degree susceptibility to different drug classes is affected.