APOBEC3G-Induced Hypermutation of Human Immunodeficiency Virus Type-1 Is Typically a Discrete “All or Nothing” Phenomenon

The rapid evolution of Human Immunodeficiency Virus (HIV-1) allows studies of ongoing host–pathogen interactions. One key selective host factor is APOBEC3G (hA3G) that can cause extensive and inactivating Guanosine-to-Adenosine (G-to-A) mutation on HIV plus-strand DNA (termed hypermutation). HIV can inhibit this innate anti-viral defense through binding of the viral protein Vif to hA3G, but binding efficiency varies and hypermutation frequencies fluctuate in patients. A pivotal question is whether hA3G-induced G-to-A mutation is always lethal to the virus or if it may occur at sub-lethal frequencies that could increase viral diversification. We show in vitro that limiting-levels of hA3G-activity (i.e. when only a single hA3G-unit is likely to act on HIV) produce hypermutation frequencies similar to those in patients and demonstrate in silico that potentially non-lethal G-to-A mutation rates are ∼10-fold lower than the lowest observed hypermutation levels in vitro and in vivo. Our results suggest that even a single incorporated hA3G-unit is likely to cause extensive and inactivating levels of HIV hypermutation and that hypermutation therefore is typically a discrete “all or nothing” phenomenon. Thus, therapeutic measures that inhibit the interaction between Vif and hA3G will likely not increase virus diversification but expand the fraction of hypermutated proviruses within the infected host

The Genealogical Population Dynamics of HIV-1 in a Large Transmission Chain:Bridging within and among Host Evolutionary Rates

Transmission lies at the interface of human immunodeficiency virus type 1 (HIV-1) evolution within and among hosts and separates distinct selective pressures that impose differences in both the mode of diversification and the tempo of evolution. In the absence of comprehensive direct comparative analyses of the evolutionary processes at different biological scales, our understanding of how fast within-host HIV-1 evolutionary rates translate to lower rates at the between host level remains incomplete. Here, we address this by analyzing pol and env data from a large HIV-1 subtype C transmission chain for which both the timing and the direction is known for most transmission events. To this purpose, we develop a new transmission model in a Bayesian genealogical inference framework and demonstrate how to constrain the viral evolutionary history to be compatible with the transmission history while simultaneously inferring the within-host evolutionary and population dynamics. We show that accommodating a transmission bottleneck affords the best fit our data, but the sparse within-host HIV-1 sampling prevents accurate quantification of the concomitant loss in genetic diversity. We draw inference under the transmission model to estimate HIV-1 evolutionary rates among epidemiologically-related patients and demonstrate that they lie in between fast intra-host rates and lower rates among epidemiologically unrelated individuals infected with HIV subtype C. Using a new molecular clock approach, we quantify and find support for a lower evolutionary rate along branches that accommodate a transmission event or branches that represent the entire backbone of transmitted lineages in our transmission history. Finally, we recover the rate differences at the different biological scales for both synonymous and non-synonymous substitution rates, which is only compatible with the 'store and retrieve' hypothesis positing that viruses stored early in latently infected cells preferentially transmit or establish new infections upon reactivation.status: publishe

The 'chicken and egg' problem of co-evolution of peptides and their cognate receptors: which came first?

As will be evident from the other chapters in this Volume, small peptide molecules regulate a wide variety of biological processes in both vertebrate and invertebrate species. For each bioactive peptide there exists one or more specific membrane-bound receptors, which transduce(s) the signal of peptide binding into a cellular response. The majority of these receptors share a common topology with seven membrane-spanning domains, an extracellular amino terminus and a cytoplasmically located carboxy terminus. Since this class of receptors translates the process of peptide binding into an intracellular response through an interaction with one or more of a family of GTP-binding proteins (G-proteins), they have been named G-protein-coupled receptors (see Probst et al. 1992; Meyerhof et al. 1993). Other types of peptide receptor are known, including those for growth factors, such as epidermal growth factor, which have a single membrane-spanning domain and an intracellular ligand-activated tyrosine kinase domain (see McInnes and Sykes 1997), that for the peptide Phe-Met-Arg-Phe-amide which contains an integral ligand-gated sodium channel (Lingueglia et al. 1995), and the 200-kDa head-activator receptor of hydra which exhibits sequence similarity to members of the low-density lipoprotein receptor family (Hampe et al., this Vol.). The role of the latter may be that of a carrier protein, binding and presenting head-activator, which is a small hydrophobic peptide, to the ‘true’ head-activator receptor

Towards an HIV cure: a global scientific strategy.

Given the limitations of antiretroviral therapy and recent advances in our understanding of HIV persistence during effective treatment, there is a growing recognition that a cure for HIV infection is both needed and feasible. The International AIDS Society convened a group of international experts to develop a scientific strategy for research towards an HIV cure. Several priorities for basic, translational and clinical research were identified. This Opinion article summarizes the group's recommended key goals for the international community.JOURNAL ARTICLESCOPUS: re.jinfo:eu-repo/semantics/publishe