Dynamics of Envelope Evolution in Clade C SHIV-Infected Pig-Tailed Macaques during Disease Progression Analyzed by Ultra-Deep Pyrosequencing

Understanding the evolution of the human immunodeficiency virus type 1 (HIV-1) envelope during disease progression can provide tremendous insights for vaccine development, and simian-human immunodeficiency virus (SHIV) infection of non-human primate provides an ideal platform for such studies. A newly developed clade C SHIV, SHIV-1157ipd3N4, which was able to infect rhesus macaques, closely resembled primary HIV-1 in transmission and pathogenesis, was used to infect several pig-tailed macaques. One of the infected animals subsequently progressed to AIDS, whereas one remained a non-progressor. The viral envelope evolution in the infected animals during disease progression was analyzed by a bioinformatics approach using ultra-deep pyrosequencing. Our results showed substantial envelope variations emerging in the progressor animal after the onset of AIDS. These envelope variations impacted the length of the variable loops and charges of different envelope regions. Additionally, multiple mutations were located at the CD4 and CCR5 binding sites, potentially affecting receptor binding affinity, viral fitness and they might be selected at late stages of disease. More importantly, these envelope mutations are not random since they had repeatedly been observed in a rhesus macaque and a human infant infected by either SHIV or HIV-1, respectively, carrying the parental envelope of the infectious molecular clone SHIV-1157ipd3N4. Moreover, similar mutations were also observed from other studies on different clades of envelopes regardless of the host species. These recurring mutations in different envelopes suggest that there may be a common evolutionary pattern and selection pathway for the HIV-1 envelope during disease progression

The human cytomegalovirus ul11 protein interacts with the receptor tyrosine phosphatase cd45, resulting in functional paralysis of t cells

Human cytomegalovirus (CMV) exerts diverse and complex effects on the immune system, not all of which have been attributed to viral genes. Acute CMV infection results in transient restrictions in T cell proliferative ability, which can impair the control of the virus and increase the risk of secondary infections in patients with weakened or immature immune systems. In a search for new immunomodulatory proteins, we investigated the UL11 protein, a member of the CMV RL11 family. This protein family is defined by the RL11 domain, which has homology to immunoglobulin domains and adenoviral immunomodulatory proteins. We show that pUL11 is expressed on the cell surface and induces intercellular interactions with leukocytes. This was demonstrated to be due to the interaction of pUL11 with the receptor tyrosine phosphatase CD45, identified by mass spectrometry analysis of pUL11-associated proteins. CD45 expression is sufficient to mediate the interaction with pUL11 and is required for pUL11 binding to T cells, indicating that pUL11 is a specific CD45 ligand. CD45 has a pivotal function regulating T cell signaling thresholds; in its absence, the Src family kinase Lck is inactive and signaling through the T cell receptor (TCR) is therefore shut off. In the presence of pUL11, several CD45-mediated functions were inhibited. The induction of tyrosine phosphorylation of multiple signaling proteins upon TCR stimulation was reduced and T cell proliferation was impaired. We therefore conclude that pUL11 has immunosuppressive properties, and that disruption of T cell function via inhibition of CD45 is a previously unknown immunomodulatory strategy of CMV

TOI-431/HIP 26013: a super-Earth and a sub-Neptune transiting a bright, early K dwarf, with a third RV planet

We present the bright (Vmag = 9.12), multiplanet system TOI-431, characterized with photometry and radial velocities (RVs). We estimate the stellar rotation period to be 30.5 ± 0.7 d using archival photometry and RVs. Transiting Exoplanet Survey Satellite (TESS) objects of Interest (TOI)-431 b is a super-Earth with a period of 0.49 d, a radius of 1.28 ± 0.04 R⊕, a mass of 3.07 ± 0.35 M⊕, and a density of 8.0 ± 1.0 g cm−3; TOI-431 d is a sub-Neptune with a period of 12.46 d, a radius of 3.29 ± 0.09 R⊕, a mass of 9.90+1.53−1.49 M⊕, and a density of 1.36 ± 0.25 g cm−3. We find a third planet, TOI-431 c, in the High Accuracy Radial velocity Planet Searcher RV data, but it is not seen to transit in the TESS light curves. It has an Msin i of 2.83+0.41−0.34 M⊕, and a period of 4.85 d. TOI-431 d likely has an extended atmosphere and is one of the most well-suited TESS discoveries for atmospheric characterization, while the super-Earth TOI-431 b may be a stripped core. These planets straddle the radius gap, presenting an interesting case-study for atmospheric evolution, and TOI-431 b is a prime TESS discovery for the study of rocky planet phase curves

Sexual orientation and psychiatric vulnerability: A twin study of neuroticism and psychoticism

Recent evidence indicates that homosexuals and bisexuals are, on average, at greater risk for psychiatric problems than heterosexuals. It is assumed with some supporting evidence that prejudice often experienced by nonheterosexuals makes them more vulnerable to psychiatric disorder, but there has been no investigation of alternative explanations. Here we used Eysenck's Neuroticism and Psychoticism scales as markers for psychiatric vulnerability and compared heterosexuals with nonheterosexuals in a community-based sample of identical and nonidentical twins aged between 19 and 52 years (N = 4904). Firstly, we tested whether apparent sexual orientation differences in psychiatric vulnerability simply mirrored sex differences-for our traits, this would predict nonheterosexual males having elevated Neuroticism scores as females do, and nonheterosexual females having elevated Psychoticism scores as males do. Our results contradicted this idea, with nonheterosexual men and women scoring significantly higher on Neuroticism and Psychoticism than their heterosexual counterparts, suggesting an overall elevation of psychiatric risk in nonheterosexuals. Secondly, we used our genetically informative sample to assess the viability of explanations invoking a common cause of both nonheterosexuality and psychiatric vulnerability. We found significant genetic correlation between sexual orientation and both Neuroticism and Psychoticism, but no corresponding environmental correlations, suggesting that if there is a common cause of both nonheterosexuality and psychiatric vulnerability it is likely to have a genetic basis rather than an environmental basis