Publications

Heme is vital to our aerobic universe. Heme cellular content is finely tuned through an exquisite control of synthesis and degradation. Heme deficiency is deleterious to cells, whereas excess heme is toxic. Most of the cellular heme serves as the prosthetic moiety of functionally diverse hemoproteins, including cytochromes P450 (P450s). In the liver, P450s are its major consumers, with >50% of hepatic heme committed to their synthesis. Prosthetic heme is the sine qua non of P450 catalytic biotransformation of both endo- and xenobiotics. This well-recognized functional role notwithstanding, heme also regulates P450 protein synthesis, assembly, repair, and disposal. These less well-appreciated aspects are reviewed herein.

The genetic heterogeneity of HIV-1 poses a major obstacle to vaccine development. Although most horizontally acquired HIV-1 infections are initiated by a single homogeneous virus, marked genetic diversification and evolution occur following transmission. The relative contribution of the antiviral immune response to intrahost viral evolution remains controversial, in part because the sequence of the transmitted virus and the array of T-cell epitopes targeted by both donor and recipient are seldom known. We directly compared predominant viral sequences derived from 52 mother-child transmission pairs following vertical infection and identified 1,475 sites of mother-infant amino acid divergence within Nef, Gag, and Pol. The cumulative number of mutations away from the consensus subtype B sequence increased linearly with time since transmission, whereas reversions toward the consensus sequence accumulated more slowly with increasing duration of infection. Comprehensive mapping of T-cell epitopes targeted by these mothers and infants revealed that 14% of nonsynonymous mutations away from the consensus sequence were located within regions targeted by the infant, whereas 24% of nonsynonymous mutations toward the consensus sequence were located in regions targeted by the mother. On the basis of analysis of optimal epitopes listed in the HIV Molecular Immunology Database, fewer than 10% of epitopes containing maternal escape mutations reverted to the consensus sequence following transmission to an infant lacking the restricting HLA allele. This surprisingly low reversion rate of mutated epitopes following transmission suggests that the fitness cost associated with many CD8 epitope mutations may be modest.

The insulin/IGF-1 pathway has been shown to affect lifespan and rate of aging in a variety of animals including worms, flies and mice. Genetic variation in this pathway may also affect human longevity. We review the evidence for the effect of this pathway on longevity with a focus on the genetic studies in humans to date. One gene, FOXO3A, a transcriptional factor homologous to daf-16, has been repeatedly associated with increased lifespan in several studies in different ethnic populations.