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  • Therapeutic immunization of highly active antiretroviral therapy-treated HIV-1-infected patients: safety and immunogenicity of an HIV-1 gag/poly-epitope DNA vaccine.

    20 December 2017

    In view of the global emergency posed by lack of access to highly active antiretroviral therapy (HAART) and the limitations of current drug regimens, alternative therapeutic strategies are urgently needed. Cellular immune responses elicited by HIV-1 exert some control over virus replication, therefore the enhancement of HIV-1-specific responses by therapeutic vaccination might lead to viral containment without HAART. We evaluated the safety and immunogenicity, in HIV-1-infected individuals under HAART suppression, of a DNA vaccine, pTHr.HIVA.

  • Coalescent estimates of HIV-1 generation time in vivo.

    8 December 2017

    The generation time of HIV Type 1 (HIV-1) in vivo has previously been estimated using a mathematical model of viral dynamics and was found to be on the order of one to two days per generation. Here, we describe a new method based on coalescence theory that allows the estimate of generation times to be derived by using nucleotide sequence data and a reconstructed genealogy of sequences obtained over time. The method is applied to sequences obtained from a long-term nonprogressing individual at five sampling occasions. The estimate of viral generation time using the coalescent method is 1.2 days per generation and is close to that obtained by mathematical modeling (1.8 days per generation), thus strengthening confidence in estimates of a short viral generation time. Apart from the estimation of relevant parameters relating to viral dynamics, coalescent modeling also allows us to simulate the evolutionary behavior of samples of sequences obtained over time.

  • Longitudinal and cross-sectional studies of HIV-1 RNA and DNA loads in blood and the female genital tract.

    25 December 2017

    OBJECTIVE: To examine if correlates of HIV-1 genital shedding in cross-sectional studies can be used to determine the risk of shedding in individual HIV-1-positive women. STUDY DESIGN: Longitudinal samples from blood and cervix were obtained from 18 HIV-1 infected women, and HIV-1 RNA and cell-associated DNA virus, and beta-chemokine levels, were measured. Associations between variables were analyzed at both individual and group level. RESULTS: The variation over time was 2.9-, 2.1-, and 2.3-fold in plasma RNA, PBMC DNA and cervical RNA load, respectively, and reached 6.2-fold in cervical DNA load. Differences were observed between associations in individual- and group-level comparisons, suggesting that a separate reservoir of HIV replication may exist in the genital tract of some women, which is influenced by local environmental factors. CONCLUSIONS: Our study underscores the importance of caution during contact with genital fluids at all stages of infection and disease regardless of treatment and HIV-1 blood loads.

  • Presence of multiple HIV subtypes and a high frequency of subtype chimeric viruses in heterosexually infected women.

    16 February 2018

    The HIV-1 subtype distribution was determined in 41 HIV-positive women (-8% of all HIV-infected women in Denmark) belonging to different risk groups. HIV p17 gag and env gene subtypes were determined by DNA sequence analysis. Five different HIV subtypes were detected across all patients. Most HIV-1-positive women of Danish origin carried subtype B viruses, and a minority had virus belonging to subtypes A or C. All injecting drug users (IDUs) were infected with HIV subtype B viruses, whereas all non-B subtypes were present in cases linked to heterosexual transmission. In contrast, all women of African origin carried non-B HIV subtypes (subtypes A, C, D, or G) regardless of transmission mode. Of these women, 21% infected with non-B HIV subtypes appeared to be infected by subtype chimeric viruses and 7% were jointly infected with viruses belonging to two different subtypes (A and C). Data demonstrate a preferential representation of non-B HIV subtypes in women infected through heterosexual contact, as well as a high degree of recombination between viruses derived from endemic areas in which several HIV subtypes predominate. Combined with the increased incidence of heterosexual transmission of HIV, the results imply that an increased subtype diversity can be anticipated in newly infected individuals.

  • HIV-infected individuals with the CCR delta32/CCR5 genotype have lower HIV RNA levels and higher CD4 cell counts in the early years of the infection than do patients with the wild type. Copenhagen AIDS Cohort Study Group.

    12 December 2017

    The relations among serum HIV RNA levels, CD4 cell counts, presence of the mutant CCR5-allele in heterozygous form, and clinical outcome was analyzed in 96 patients from the Copenhagen AIDS Cohort. In the early years of the infection, patients with the CCR5 delta32/CCR5 genotype had significantly lower HIV RNA levels (p = 0.005) and higher CD4 cell counts (p < 0.005) than did patients homozygous for the normal allele. The long-term clinical benefit of being heterozygous is small and cannot solely explain the large interpatient variation in progression rates. The beneficial effect of being heterozygous seems to be mediated by events in the early stages of the HIV infection.

  • Functional characteristics of HIV-1 subtype C compatible with increased heterosexual transmissibility.

    9 January 2018

    BACKGROUND: Despite the existence of over 50 subtypes and circulating recombinant forms of HIV-1, subtype C dominates the heterosexual pandemic causing approximately 56% of all infections. OBJECTIVE: To evaluate whether viral genetic factors may contribute to the observed subtype-C predominance. METHODS: Chimeric viruses were generated using V1-V3 envelope fragments from a subtype-A/C dually infected woman with preferential genital replication of subtype C. Viral adaptation, spread and cell fusion ability were evaluated in vitro using peripheral blood mononuclear cells and HeLa-CD4-CCR5 cell lines, sequencing and cloning. Structural modeling was performed using a crystal structure of gp120-CD4-X5. Phylogenetic analysis was done using subtype-A, subtype-B and subtype-C sequences from blood and cervix of 37 infected women and database sequences. RESULTS: We identified two envelope motifs, compact V1-V2 loops and V3-316T, which are found at high frequency throughout subtype-C evolution and affect gp120 interactions with CD4 and CCR5, respectively. When a V1-Delta5 deletion or V3-A316T was incorporated into subtype A, each increased viral fusion and spread several fold in peripheral blood mononuclear cell and cell lines with low CCR5 expression. Structural modeling suggested the formation of an additional hydrogen bond between V3 and CCR5. Moreover, we found preferential selection of HIV with 316T and/or extremely short V1-V2 loops in cervices of three women infected with subtypes A/C, B or C. CONCLUSION: As CD4-CCR5-T cells are key targets for genital HIV infection and cervical selection can favor compact V1-V2 loops and 316T, which increase viral infectivity, we propose that these conserved subtype-C motifs may contribute to transmission and spread of this subtype.

  • Chemokine receptor CCR2b 64I polymorphism and its relation to CD4 T-cell counts and disease progression in a Danish cohort of HIV-infected individuals. Copenhagen AIDS cohort.

    28 January 2018

    We have investigated the role of the recently described mutation in CCR2b named 64I in relation to HIV resistance, CD4 T-cell counts, and disease progression in Danish individuals by polymerase chain reaction (PCR)-based methods as well as sequenced full-length CXCR4 and CCR5 genes from HIV-infected long-term nonprogressors for possible mutations. In total, 215 Danish individuals were analyzed for 64I allele frequency; disease progression was followed in 105 HIV-1-positive homosexual Danish men from their first known positive HIV-1 test result and up to 11 years. In 87 individuals, the CD4 T-cell count was monitored closely. We found no significant difference in 64I allele frequency between HIV-1-seropositive persons (0.08), high-risk HIV-1-seronegative persons (0.11), and blood donors (0.06). No significant difference was observed in annual CD4 T-cell decline, CD4 T-cell counts at the time of AIDS, in AIDS-free survival as well as survival with AIDS, between 64I allele carriers and wild-type individuals. Among 9 long-term nonprogressors, 2 carried the 64I allele, while none of 9 fast progressors carried the 64I allele. However, this was not significantly different (p=.47). Long-term nonprogression could not be explained by CXCR4 polymorphism or other polymorphisms in the CCR5 gene than the CCR5delta32 allele. Furthermore, we were not able to detect any significant independent effect of the 64I allele on development to AIDS, overall survival, and annual CD4 T-cell decline in this cohort.

  • Making predictions in a changing world-inference, uncertainty, and learning.

    25 December 2017

    To function effectively, brains need to make predictions about their environment based on past experience, i.e., they need to learn about their environment. The algorithms by which learning occurs are of interest to neuroscientists, both in their own right (because they exist in the brain) and as a tool to model participants' incomplete knowledge of task parameters and hence, to better understand their behavior. This review focusses on a particular challenge for learning algorithms-how to match the rate at which they learn to the rate of change in the environment, so that they use as much observed data as possible whilst disregarding irrelevant, old observations. To do this algorithms must evaluate whether the environment is changing. We discuss the concepts of likelihood, priors and transition functions, and how these relate to change detection. We review expected and estimation uncertainty, and how these relate to change detection and learning rate. Finally, we consider the neural correlates of uncertainty and learning. We argue that the neural correlates of uncertainty bear a resemblance to neural systems that are active when agents actively explore their environments, suggesting that the mechanisms by which the rate of learning is set may be subject to top down control (in circumstances when agents actively seek new information) as well as bottom up control (by observations that imply change in the environment).

  • A potential spatial working memory training task to improve both episodic memory and fluid intelligence.

    19 February 2018

    One current challenge in cognitive training is to create a training regime that benefits multiple cognitive domains, including episodic memory, without relying on a large battery of tasks, which can be time-consuming and difficult to learn. By giving careful consideration to the neural correlates underlying episodic and working memory, we devised a computerized working memory training task in which neurologically healthy participants were required to monitor and detect repetitions in two streams of spatial information (spatial location and scene identity) presented simultaneously (i.e. a dual n-back paradigm). Participants' episodic memory abilities were assessed before and after training using two object and scene recognition memory tasks incorporating memory confidence judgments. Furthermore, to determine the generalizability of the effects of training, we also assessed fluid intelligence using a matrix reasoning task. By examining the difference between pre- and post-training performance (i.e. gain scores), we found that the trainers, compared to non-trainers, exhibited a significant improvement in fluid intelligence after 20 days. Interestingly, pre-training fluid intelligence performance, but not training task improvement, was a significant predictor of post-training fluid intelligence improvement, with lower pre-training fluid intelligence associated with greater post-training gain. Crucially, trainers who improved the most on the training task also showed an improvement in recognition memory as captured by d-prime scores and estimates of recollection and familiarity memory. Training task improvement was a significant predictor of gains in recognition and familiarity memory performance, with greater training improvement leading to more marked gains. In contrast, lower pre-training recollection memory scores, and not training task improvement, led to greater recollection memory performance after training. Our findings demonstrate that practice on a single working memory task can potentially improve aspects of both episodic memory and fluid intelligence, and that an extensive training regime with multiple tasks may not be necessary.