HIV-1 group P infection: towards a dead-end infection?

HIV/1 group P (HIV-1/P) is the last HIV/1 group discovered and to date, comprises only two strains. To obtain new insights into this divergent group, we screened for new infections by developing specific tools, and analysed phenotypic and genotypic properties of the prototypic strain RBF168. In addition, the follow-up of the unique patient monitored so far, has raised the knowledge of the natural history of this infection and its therapeutic management. We developed an HIV-1/P specific sero-molecular strategy and screened over 29,498 specimen samples. Infectivity and evolution of the gag-30 position, considered as marker of adaptation to human, were explored by successive passages of RBF168 strain onto human PBMCs. Natural history and immuno-virological responses to combined antiretroviral therapy (cART) were analysed based on CD4 counts and plasmatic viral load evolution. No new infection was detected. Infectivity of RBF168 was found lower, relative to other main HIV groups and the conservative methionine found in the gag-30 position revealed a lack of adaptation to human. The follow-up of the patient during the five-year ART-free period, showed a relative stability of CD4 cell count with a mean of 326 mm. Initiation of cART led to rapid RNA undetectability with a significant increase of CD4, reaching 687 mm after 8 years. Our results showed that HIV-1/P strains remain extremely rare and could be less adapted and pathogenic than other HIV strains. These data lead to the hypothesis that HIV-1/P infection could evolve towards, or even already correspond to, a dead-end infection

Diversité et Évolution Génétique des VIH-1 de Groupe O

International audienc

Diversité et Évolution Génétique des VIH-1 de Groupe O

International audienc

SIVagm Infection in Wild African Green Monkeys from South Africa: Epidemiology, Natural History, and Evolutionary Considerations

Pathogenesis studies of SIV infection have not been performed to date in wild monkeys due to difficulty in collecting and storing samples on site and the lack of analytical reagents covering the extensive SIV diversity. We performed a large scale study of molecular epidemiology and natural history of SIVagm infection in 225 free-ranging AGMs from multiple locations in South Africa. SIV prevalence (established by sequencing pol, env, and gag) varied dramatically between infant/juvenile (7%) and adult animals (68%) (p<0.0001), and between adult females (78%) and males (57%). Phylogenetic analyses revealed an extensive genetic diversity, including frequent recombination events. Some AGMs harbored epidemiologically linked viruses. Viruses infecting AGMs in the Free State, which are separated from those on the coastal side by the Drakensberg Mountains, formed a separate cluster in the phylogenetic trees; this observation supports a long standing presence of SIV in AGMs, at least from the time of their speciation to their Plio-Pleistocene migration. Specific primers/probes were synthesized based on the pol sequence data and viral loads (VLs) were quantified. VLs were of 104-106 RNA copies/ml, in the range of those observed in experimentally-infected monkeys, validating the experimental approaches in natural hosts. VLs were significantly higher (107-108 RNA copies/ml) in 10 AGMs diagnosed as acutely infected based on SIV seronegativity (Fiebig II), which suggests a very active transmission of SIVagm in the wild. Neither cytokine levels (as biomarkers of immune activation) nor sCD14 levels (a biomarker of microbial translocation) were different between SIV-infected and SIV-uninfected monkeys. This complex algorithm combining sequencing and phylogeny, VL quantification, serology, and testing of surrogate markers of microbial translocation and immune activation permits a systematic investigation of the epidemiology, viral diversity and natural history of SIV infection in wild African natural hosts. © 2013 Ma et al

Protein structural disorder of the envelope V3 loop contributes to the switch in human immunodeficiency virus type 1 cell tropism

Human immunodeficiency virus type 1 (HIV-1) envelope gp120 is partly an intrinsically disordered (unstructured/disordered) protein as it contains regions that do not fold into well-defined protein structures. These disordered regions play important roles in HIV's life cycle, particularly, V3 loop-dependent cell entry, which determines how the virus uses two coreceptors on immune cells, the chemokine receptors CCR5 (R5), CXCR4 (X4) or both (R5X4 virus). Most infecting HIV-1 variants utilise CCR5, while a switch to CXCR4-use occurs in the majority of infections. Why does this 'rewiring' event occur in HIV-1 infected patients? As changes in the charge of the V3 loop are associated with this receptor switch and it has been suggested that charged residues promote structure disorder, we hypothesise that the intrinsic disorder of the V3 loop is permissive to sequence variation thus contributing to the switch in cell tropism. To test this we use three independent data sets of gp120 to analyse V3 loop disorder. We find that the V3 loop of X4 virus has significantly higher intrinsic disorder tendency than R5 and R5X4 virus, while R5X4 virus has the lowest. These results indicate that structural disorder plays an important role in HIV-1 cell tropism and CXCR4 binding. We discuss the potential evolutionary mechanisms leading to the fixation of disorder promoting mutations and the adaptive potential of protein structural disorder in viral host adaptation

Intrinsic protein disorder reduces small-scale gene duplicability

Whereas the rate of gene duplication is relatively high, only certain duplications survive the filter of natural selection and can contribute to genome evolution. However, the reasons why certain genes can be retained after duplication whereas others cannot remain largely unknown. Many proteins contain intrinsically disordered regions (IDRs), whose structures fluctuate between alternative conformational states. Due to their high flexibility, IDRs often enable protein–protein interactions and are the target of post-translational modifications. Intrinsically disordered proteins (IDPs) have characteristics that might either stimulate or hamper the retention of their encoding genes after duplication. On the one hand, IDRs may enable functional diversification, thus promoting duplicate retention. On the other hand, increased IDP availability is expected to result in deleterious unspecific interactions. Here, we interrogate the proteomes of human, Drosophila melanogaster, Caenorhabditis elegans, Saccharomyces cerevisiae, Arabidopsis thaliana and Escherichia coli, in order to ascertain the impact of protein intrinsic disorder on gene duplicability. We show that, in general, proteins encoded by duplicated genes tend to be less disordered than those encoded by singletons. The only exception is proteins encoded by ohnologs, which tend to be more disordered than those encoded by singletons or genes resulting from small-scale duplications. Our results indicate that duplication of genes encoding IDPs outside the context of whole-genome duplication (WGD) is often deleterious, but that IDRs facilitate retention of duplicates in the context of WGD. We discuss the potential evolutionary implications of our results

Plot of predicted structural disorder tendency of the consensus envelope protein.

<p>Disorder tendency for each amino acid is predicted by four prediction methods (0 represents complete order; 1 represents complete disorder; scores over 0.4 represent intrinsically disordered). Disorder tendency scores are plotted for consensus R5, R5X4 and X4 envelope sequence for DISOPRED3 (A), IUPred (B), PONDR VL-XT (C) and PONDR VSL2 (D), respectively. (E) The consensus protein sequences of R5, R5X4 and X4 are aligned to HXB2 envelope sequence (gp120 and gp41) for indicating the structure locations of the disordered residues (adapted from Jiang et al. 2015 [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0185790#pone.0185790.ref061" target="_blank">61</a>]). Gp120 and gp41 protein domains are numbered and color-coded for visualisation. Note that here the length of the Env sequence is longer than the normal one because gaps are introduced in the sequence alignment and dashed lines are used for linking sites with missing prediction scores in the gaps.</p

Boxplot and nonparametric comparisons of the V3 loop disorder tendency between R5 and X4 viruses from Shankarappa et al. data [7].

<p>Boxplot and statistical comparisons are shown for patient 2 (A) and 9 (B), respectively (*<i>p</i><0.05, **<i>p</i><0.01, <i>***p</i><0.001, asterisks colored with blue and red represent results for R5 and X4 virus, respectively; X means <i>p</i>>0.05).</p