Live attenuated HIV vaccines: Predicting the tradeoff between efficacy and safety

The utility of live attenuated vaccines for controlling HIV epidemics is being debated. Live attenuated HIV vaccines (LAHVs) could be extremely effective in protecting against infection with wild-type strains, but may not be completely safe as the attenuated strain could cause AIDS in some vaccinated individuals. We present a theoretical framework for evaluating the consequences of the tradeoff between vaccine efficacy (in terms of preventing new infections with wild-type strains) and safety (in terms of vaccine-induced AIDS deaths). We use our framework to predict, for Zimbabwe and Thailand, the epidemiological impact of 1,000 different (specified by efficacy and safety characteristics) LAHVs. We predict that paradoxically: (i) in Zimbabwe (where transmission is high) LAHVs would significantly decrease the AIDS death rate, but (ii) in Thailand (where transmission is low) exactly the same vaccines (in terms of efficacy and safety characteristics) would increase the AIDS death rate. Our results imply that a threshold transmission rate exists that determines whether any given LAHV has a beneficial or a detrimental impact. We also determine the vaccine perversity point, which is defined in terms of the fraction of vaccinated individuals who progress to AIDS as a result of the vaccine strain. Vaccination with any LAHV that causes more than 5% of vaccinated individuals to progress to AIDS in 25 years would, even 50 years later, lead to perversity (i.e., increase the annual AIDS death rate) in Thailand; these same vaccines would lead to decreases in the annual AIDS death rate in Zimbabwe.

The nucleotide changes governing cuticular hydrocarbon variation and their evolution in Drosophila melanogaster

The cuticular hydrocarbon (CH) pheromones in Drosophila melanogaster exhibit strong geographic variation. African and Caribbean populations have a high ratio of 5,9 heptacosadiene/7,11 heptacosadiene (the “High” CH type), whereas populations from all other areas have a low ratio (“Low” CH type). Based on previous genetic mapping, DNA markers were developed that localized the genetic basis of this CH polymorphism to within a 13-kb region. We then carried out a hierarchical search for diagnostic nucleotide sites starting with four lines, and increasing to 24 and 43 lines from a worldwide collection. Within the 13-kb region, only one variable site shows a complete concordance with the CH phenotype. This is a 16-bp deletion in the 5′ region of a desaturase gene (desat2) that was recently suggested to be responsible for the CH polymorphism on the basis of its expression [Dallerac, R., Labeur, C., Jallon, J.-M., Knipple, D. C., Roelofs, W. L. & Wicker-Thomas, C. (2000) Proc. Natl. Acad. Sci. 97, 9449–9454]. The cosmopolitan Low type is derived from the ancestral High type, and DNA sequence variations suggest that the former spread worldwide with the aid of positive selection. Whether this CH variation could be a component of the sexual isolation between Zimbabwe and other cosmopolitan populations remains an interesting and unresolved question.

Incipient speciation by sexual isolation in Drosophila: Concurrent evolution at multiple loci

Drosophila melanogaster from Zimbabwe and nearby regions shows strong but asymmetric sexual isolation from its cosmopolitan counterparts. By creating stable chromosome-substitution lines, earlier studies were able to show that the two major autosomes have very large effects on both male mating success and female mating preference. In this study, we genetically dissect this sexual isolation by recombination analysis between a whole-chromosome substitution line (which carries a Zimbabwe-derived third chromosome) and a strain with seven visible markers on that chromosome. Four loci are responsible for male mating success and three others are found to control female mating preference. Because male and female traits are not closely linked, their strong association among isofemale lines is most likely a reflection of sexual selection in nature. The results suggest that a large number of behavioral loci may evolve concurrently in the incipient stage of speciation before other aspects of reproductive isolation (such as hybrid sterility) have become evident. The results shed light on the population genetic processes underlying the formation of nascent species, as well as modes of speciation.

Discrimination among pheromone component blends by interneurons in male antennal lobes of two populations of the turnip moth, Agrotis segetum.

A difference in female pheromone production and male behavioral response has previously been found in two populations of the turnip moth, Agrotis segetum, originating from Sweden and Zimbabwe, respectively. In this study, we investigated the pheromone response of antennal lobe interneurons of males of the two populations by intracellular recordings, stimulating with single pheromone components and various inter- and intra-populational pheromone blends. Three major physiological types of antennal lobe neurons were established in the two populations according to their responses to different stimuli. One type responded broadly to almost all the stimuli tested. The second type responded selectively to some of the single components and blends. The third type did not respond to any single components but did respond to certain blends. Furthermore, some neurons of the second and third type recognized strain specific differences in ratios between pheromone components. Both projection neurons and local interneurons were found among these three types. Two pheromone responding bilateral projection neurons are reported for the first time in this paper.

Sexual isolation in Drosophila melanogaster: a possible case of incipient speciation.

It is generally believed that Drosophila melanogaster has no closely related species with which it can produce the viable and fertile hybrids that are essential for the genetic analysis of speciation. Following the recent report of molecular differentiation between a Zimbabwe, Africa, population and two United States populations, we provide evidence that strong sexual isolation exists between the D. melanogaster population in Zimbabwe and populations of other continents. In the presence of males of their own kind, females from most isofemale lines of Zimbabwe would not mate with males from elsewhere; the reciprocal mating is also significantly reduced, but to a lesser degree. The genes for sexual behaviors are apparently polymorphic in Zimbabwe and postmating reproductive isolation between this and other populations has not yet evolved. Whole chromosome substitutions indicate significant genetic contributions to male mating success by both major autosomes, whereas the X chromosome effect is too weak to measure. In addition, the relative mating success between hybrid and pure line males supports the interpretation of strong female choice. These observations suggest that we are seeing the early stages of speciation in this group and that it is driven by sexual selection. The genetic and molecular tractability of D. melanogaster offers great promise for the detailed analysis of this apparent case of incipient speciation.