Extreme genetic fragility of the HIV-1 capsid

Genetic robustness, or fragility, is defined as the ability, or lack thereof, of a biological entity to maintain function in the face of mutations. Viruses that replicate via RNA intermediates exhibit high mutation rates, and robustness should be particularly advantageous to them. The capsid (CA) domain of the HIV-1 Gag protein is under strong pressure to conserve functional roles in viral assembly, maturation, uncoating, and nuclear import. However, CA is also under strong immunological pressure to diversify. Therefore, it would be particularly advantageous for CA to evolve genetic robustness. To measure the genetic robustness of HIV-1 CA, we generated a library of single amino acid substitution mutants, encompassing almost half the residues in CA. Strikingly, we found HIV-1 CA to be the most genetically fragile protein that has been analyzed using such an approach, with 70% of mutations yielding replication-defective viruses. Although CA participates in several steps in HIV-1 replication, analysis of conditionally (temperature sensitive) and constitutively non-viable mutants revealed that the biological basis for its genetic fragility was primarily the need to coordinate the accurate and efficient assembly of mature virions. All mutations that exist in naturally occurring HIV-1 subtype B populations at a frequency >3%, and were also present in the mutant library, had fitness levels that were >40% of WT. However, a substantial fraction of mutations with high fitness did not occur in natural populations, suggesting another form of selection pressure limiting variation in vivo. Additionally, known protective CTL epitopes occurred preferentially in domains of the HIV-1 CA that were even more genetically fragile than HIV-1 CA as a whole. The extreme genetic fragility of HIV-1 CA may be one reason why cell-mediated immune responses to Gag correlate with better prognosis in HIV-1 infection, and suggests that CA is a good target for therapy and vaccination strategies

Discrimination as a frame-of-reference effect in overlapping friendship communities of ethnically diverse youth.

OBJECTIVES: To what extent is the frame of reference of overlapping friendship communities important for young people's feelings of discrimination and subjective well-being? That is, do youth feel better or worse to the extent that they feel less or more discrimination than their friends? METHOD: Participants (N = 898; Mage = 14.13; SDage = 3.37; 46% females; 46% Whites; 20% Indigenous; 34% other minorities) were high school students of three ethnically diverse, low socioeconomic status public schools in New South Wales, Australia. Cross-sectional data were collected to measure felt discrimination, mental health, subjective well-being, social support, and nominations of close friends. A state-of-the-art method of clustering links was used to identify overlapping friendship communities, and multiple membership multilevel models were run to examine whether community-level discrimination moderated the link between individual-level discrimination and well-being. RESULTS: When the community level discrimination was low, there was no well-being related cost or benefit of individual-level discrimination. But when the community-level discrimination was high, individuals in those communities who themselves felt low discrimination had better well-being than individuals who themselves felt high discrimination. CONCLUSIONS: We provide evidence for a frame-of-reference effect involving discrimination. Individuals' relative standing in their friendship communities with high group-level discrimination reliably predicted the individuals' well-being levels, regardless of ethnicity. The results highlight the importance of identifying overlapping friendship communities for understanding the dynamics of discrimination and well-being of ethnically diverse youth. (PsycINFO Database Record (c) 2020 APA, all rights reserved)