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A mutation in VRC01, a broadly neutralizing, HIV-1-specific antibody, confers enhanced binding to the neonatal Fc receptor, increasing the antibody half-life in the serum and localization in mucosal tissues, where it provides superior protection against rectal simian HIV-1 infection in macaques. Enhanced anti-HIV activity in mutant VRC01 antibody The recent discovery of broad and potent anti-HIV-1 antibodies has renewed interest in their use for passive protection against human immunodeficiency virus-1 in humans. This paper describes a mutation in the HIV-specific broadly neutralizing antibody VRC01 that confers enhanced binding to the neonatal Fc receptor and increases the antibody half-life in serum and mucosal tissues. It conferred superior protection in a rectal simian-HIV challenge model in macaques when compared to wild-type VRC01. To protect against human immunodeficiency virus (HIV-1) infection, broadly neutralizing antibodies (bnAbs) must be active at the portals of viral entry in the gastrointestinal or cervicovaginal tracts. The localization and persistence of antibodies at these sites is influenced by the neonatal Fc receptor (FcRn) 1 , 2 , whose role in protecting against infection in vivo has not been defined. Here, we show that a bnAb with enhanced FcRn binding has increased gut mucosal tissue localization, which improves protection against lentiviral infection in non-human primates. A bnAb directed to the CD4-binding site of the HIV-1 envelope (Env) protein (denoted VRC01) 3 was modified by site-directed mutagenesis to increase its binding affinity for FcRn. This enhanced FcRn-binding mutant bnAb, denoted VRC01-LS, displayed increased transcytosis across human FcRn-expressing cellular monolayers in vitro while retaining FcγRIIIa binding and function, including antibody-dependent cell-mediated cytotoxicity (ADCC) activity, at levels similar to VRC01 (the wild type). VRC01-LS had a threefold longer serum half-life than VRC01 in non-human primates and persisted in the rectal mucosa even when it was no longer detectable in the serum. Notably, VRC01-LS mediated protection superior to that afforded by VRC01 against intrarectal infection with simian–human immunodeficiency virus (SHIV). These findings suggest that modification of FcRn binding provides a mechanism not only to increase serum half-life but also to enhance mucosal localization that confers immune protection. Mutations that enhance FcRn function could therefore increase the potency and durability of passive immunization strategies to prevent HIV-1 infection.

The gastrointestinal tract harbors large and diverse populations of bacteria that vary among individuals and within individuals over time. Numerous internal and external factors can influence the contents of these microbial communities, including diet, geography, physiology, and the extent of contact among hosts. To investigate the contributions of such factors to the variation and changes in gut microbial communities, we analyzed the distal gut microbiota of individual chimpanzees from two communities in Gombe National Park, Tanzania. These samples, which were derived from 35 chimpanzees, many of whom have been monitored for multiple years, provide an unusually comprehensive longitudinal depth for individuals of known genetic relationships. Although the composition of the great-ape microbiota has been shown to codiversify with host species, indicating that host genetics and phylogeny have played a major role in its differentiation over evolutionary timescales, the geneaological relationships of individual chimpanzees did not coincide with the similarity in their gut microbial communities. However, the inhabitants from adjacent chimpanzee communities could be distinguished based on the contents of their gut microbiota. Despite the broad similarity of community members, as would be expected from shared diet or interactions, long-term immigrants to a community often harbored the most distinctive gut microbiota, suggesting that individuals retain hallmarks of their previous gut microbial communities for extended periods. This pattern was reinforced in several chimpanzees sampled over long temporal scales, in which the major constituents of the gut microbiota were maintained for nearly a decade.

Plasmodium falciparum is the most prevalent and lethal of the malaria parasites infecting humans, yet the origin and evolutionary history of this important pathogen remain controversial. Here we develop a single-genome amplification strategy to identify and characterize Plasmodium spp. DNA sequences in faecal samples from wild-living apes. Among nearly 3,000 specimens collected from field sites throughout central Africa, we found Plasmodium infection in chimpanzees ( Pan troglodytes ) and western gorillas ( Gorilla gorilla ), but not in eastern gorillas ( Gorilla beringei ) or bonobos ( Pan paniscus ). Ape plasmodial infections were highly prevalent, widely distributed and almost always made up of mixed parasite species. Analysis of more than 1,100 mitochondrial, apicoplast and nuclear gene sequences from chimpanzees and gorillas revealed that 99% grouped within one of six host-specific lineages representing distinct Plasmodium species within the subgenus Laverania . One of these from western gorillas comprised parasites that were nearly identical to P. falciparum . In phylogenetic analyses of full-length mitochondrial sequences, human P. falciparum formed a monophyletic lineage within the gorilla parasite radiation. These findings indicate that P. falciparum is of gorilla origin and not of chimpanzee, bonobo or ancient human origin. Human malaria parasite traced to a fellow primate The evolutionary origin of Plasmodium falciparum , the most prevalent and lethal of the malaria parasites infecting humans, is much debated. Genetic analysis of thousands of fecal samples from wild-living African apes show that the parasites found in the western gorillas — rather than those of chimpanzees or bonobos — are most closely related to the human parasite. The data suggest that all extant human strains of the parasite evolved from a single host transfer event. The new findings are also relevant to the current antimalaria campaign, as they point to potential Plasmodium reservoirs in apes. The evolutionary origin of the human malaria parasite Plasmodium falciparum has been much debated. Genetic analysis of a large number of faecal samples from wild-living African apes now shows that Plasmodium parasites from Western gorillas are most closely related to the human parasite. The data suggest that human P. falciparum evolved from a gorilla parasite after a single host transfer event.

Major histocompatibility complex (MHC) class I molecules determine immune responses to viral infections. These polymorphic cell-surface glycoproteins bind peptide antigens, forming ligands for cytotoxic T and natural killer cell receptors. Under pressure from rapidly evolving viruses, hominoid MHC class I molecules also evolve rapidly, becoming diverse and species-specific. Little is known of the impact of infectious disease epidemics on MHC class I variant distributions in human populations, a context in which the chimpanzee is the superior animal model. Population dynamics of the chimpanzees inhabiting Gombe National Park, Tanzania have been studied for over 50 years. This population is infected with SIVcpz, the precursor of human HIV-1. Because HLA-B is the most polymorphic human MHC class I molecule and correlates strongly with HIV-1 progression, we determined sequences for its ortholog, Patr-B, in 125 Gombe chimpanzees. Eleven Patr-B variants were defined, as were their frequencies in Gombe's three communities, changes in frequency with time, and effect of SIVcpz infection. The growing populations of the northern and central communities, where SIVcpz is less prevalent, have stable distributions comprising a majority of low-frequency Patr-B variants and a few high-frequency variants. Driving the latter to high frequency has been the fecundity of immigrants to the northern community, whereas in the central community, it has been the fecundity of socially dominant individuals. In the declining population of the southern community, where greater SIVcpz prevalence is associated with mortality and emigration, Patr-B variant distributions have been changing. Enriched in this community are Patr-B variants that engage with natural killer cell receptors. Elevated among SIVcpz-infected chimpanzees, the Patr-B*06:03 variant has striking structural and functional similarities to HLA-B*57, the human allotype most strongly associated with delayed HIV-1 progression. Like HLA-B*57, Patr-B*06:03 correlates with reduced viral load, as assessed by detection of SIVcpz RNA in feces.

Like human immunodeficiency virus type 1 (HIV-1), simian immunodeficiency virus of chimpanzees (SIVcpz) can cause CD4+ T cell loss and premature death. Here, we used molecular surveillance tools and mathematical modeling to estimate the impact of SIVcpz infection on chimpanzee population dynamics. Habituated (Mitumba and Kasekela) and non-habituated (Kalande) chimpanzees were studied in Gombe National Park, Tanzania. Ape population sizes were determined from demographic records (Mitumba and Kasekela) or individual sightings and genotyping (Kalande), while SIVcpz prevalence rates were monitored using non-invasive methods. Between 2002-2009, the Mitumba and Kasekela communities experienced mean annual growth rates of 1.9% and 2.4%, respectively, while Kalande chimpanzees suffered a significant decline, with a mean growth rate of -6.5% to -7.4%, depending on population estimates. A rapid decline in Kalande was first noted in the 1990s and originally attributed to poaching and reduced food sources. However, between 2002-2009, we found a mean SIVcpz prevalence in Kalande of 46.1%, which was almost four times higher than the prevalence in Mitumba (12.7%) and Kasekela (12.1%). To explore whether SIVcpz contributed to the Kalande decline, we used empirically determined SIVcpz transmission probabilities as well as chimpanzee mortality, mating and migration data to model the effect of viral pathogenicity on chimpanzee population growth. Deterministic calculations indicated that a prevalence of greater than 3.4% would result in negative growth and eventual population extinction, even using conservative mortality estimates. However, stochastic models revealed that in representative populations, SIVcpz, and not its host species, frequently went extinct. High SIVcpz transmission probability and excess mortality reduced population persistence, while intercommunity migration often rescued infected communities, even when immigrating females had a chance of being SIVcpz infected. Together, these results suggest that the decline of the Kalande community was caused, at least in part, by high levels of SIVcpz infection. However, population extinction is not an inevitable consequence of SIVcpz infection, but depends on additional variables, such as migration, that promote survival. These findings are consistent with the uneven distribution of SIVcpz throughout central Africa and explain how chimpanzees in Gombe and elsewhere can be at equipoise with this pathogen.

Antibodies capable of neutralizing HIV-1 often target variable regions 1 and 2 (V1V2) of the HIV-1 envelope, but the mechanism of their elicitation has been unclear. Here we define the developmental pathway by which such antibodies are generated and acquire the requisite molecular characteristics for neutralization. Twelve somatically related neutralizing antibodies (CAP256-VRC26.01–12) were isolated from donor CAP256 (from the Centre for the AIDS Programme of Research in South Africa (CAPRISA)); each antibody contained the protruding tyrosine-sulphated, anionic antigen-binding loop (complementarity-determining region (CDR) H3) characteristic of this category of antibodies. Their unmutated ancestor emerged between weeks 30–38 post-infection with a 35-residue CDR H3, and neutralized the virus that superinfected this individual 15 weeks after initial infection. Improved neutralization breadth and potency occurred by week 59 with modest affinity maturation, and was preceded by extensive diversification of the virus population. HIV-1 V1V2-directed neutralizing antibodies can thus develop relatively rapidly through initial selection of B cells with a long CDR H3, and limited subsequent somatic hypermutation. These data provide important insights relevant to HIV-1 vaccine development. A longitudinal study of an individual patient developing neutralizing antibodies against HIV-1 (targeting the V1V2 region of gp120) reveals how such neutralizing antibodies develop and evolve over time, providing important insights relevant to vaccine development. HIV-neutralizing antibody formation examined A better understanding of how HIV-1-neutralizing antibodies are generated could be a useful contribution to the design of improved AIDS vaccines. John Mascola and colleagues have now elucidated the immunological pathway of an important category of HIV-1-neutralizing antibody — those that target the variable V1V2 region of the viral envelope. These antibodies are more frequently elicited than CD4-binding site antibodies in the early stages of HIV infection and feature modest affinity maturation, a process that favours mutations in antibody variable domains that enhance antigen binding.

During a population decline or disease outbreak, the true risk of specific diseases to a wild population is often difficult to determine because of a lack of baseline disease information. To better understand the risk of disease in an endangered and scientifically important population of chimpanzees (Pan trogylodytes schweinfurthii), a health monitoring program was initiated in Gombe National Park, Tanzania. As part of this health monitoring program, comprehensive necropsies with histopathology were conducted on chimpanzees (n = 11; 5 male, 6 female), ranging in age from fetal to 44 yr, that were found dead between August 2004 and January 2010. In contrast to previous reports, respiratory disease was not noted as a cause of morbidity or mortality. Trauma was the most common cause of death in these 11 chimpanzees. All of the chimpanzees greater than 1 yr of age had intestinal and mesenteric parasitic granulomas associated with true strongyles consistent with Oesophagostomum spp. The relative numbers of granulomas increased with age and, in some cases, may have been a cause of weight loss and diarrhea. Simian immunodeficiency virus (SIV)cpz infection was documented in four deceased apes, all of whom exhibited varying amounts of lymphoid depletion including two females with marked CD4+ T cell loss consistent with end-stage SIVmac or human immunodeficiency virus infections. Myocardial megalokaryosis was common in chimpanzees greater than 1 mo of age; yet myocardial interstitial fibrosis, a common lesion in captive chimpanzees, was uncommon and only noted in two aged chimpanzees. These findings provide important information on causes of morbidity and mortality in wild chimpanzees, information that can be used to interpret findings during population declines and lead to better management of this population in the context of disease risk.

Coalitionary aggression occurs when at least two individuals jointly direct aggression at one or more conspecific targets. Scientists have long argued that this common form of cooperation has positive fitness consequences. Nevertheless, despite evidence that social bond strength (which is thought to promote coalition formation) is correlated with fitness in primates, cetaceans, and ungulates, few studies have directly examined whether coalitionary aggression improves reproductive success. We tested the hypothesis that among free-ranging chimpanzees (Pan troglodytes schweinfurthii), participation in coalitionary aggression increases reproductive output. Using 14 years of genetic and behavioral data from Gombe National Park, Tanzania, we found that coalitionary aggression increased a male's chances of (A) siring offspring, compared to other males of similar dominance rank, and (B) ascending in rank, a correlate of future reproductive output. Because male chimpanzees form coalitions with many others within a complex network, we used social network analysis to identify the types of connections correlated with these fitness benefits. The beneficiaries of coalitionary aggression were males with the highest \"betweenness\"—that is, those who tended to have coalition partners who themselves did not form coalitions with each other. This suggests that beyond simply recognizing third-party relationships, chimpanzees may use this knowledge to choose coalition partners. If so, this is a significant step forward in our knowledge of the adaptive value of social intelligence. Regardless of mechanism, however, this is the first evidence of genetic benefits of coalitionary aggression in this species, and therefore has important implications for understanding the evolution of cooperation.

'AIDS' in chimpanzees There are more than 40 different types of simian immunodeficiency virus (SIV) infecting African primates, two of which crossed the species barrier to produce the AIDS viruses HIV-1 and HIV-2 in humans. Now a comprehensive natural history study of free-ranging chimpanzees in Gombe National Park has overturned a common assumption about SIVcpz, the precursor of HIV-1. It has been widely assumed that all SIVs are non-pathogenic in their natural hosts. But this new study, which followed 94 chimpanzees for over 9 years, shows that SIVcpz infection is associated with AIDS-like signs in chimpanzees, including a more than 10-fold increase in mortality risk, reduced fertility and progressive CD4 + T-cell depletion. By comparing the disease-causing mechanisms of these related retroviruses in humans and chimpanzees it may be possible to identify viral and host factors of interest to developers of drugs and vaccines for the prevention and treatment of HIV infection. There are over 40 different simian immunodeficiency viruses (SIVs) with which African primates are naturally infected; two of these have crossed the species barrier to generate human immunodeficiency virus types 1 and 2 (HIV-1 and HIV-2). Although SIVs do not generally cause AIDS in primates, AIDS-like disease is now shown to occur in chimpanzee populations in the wild who are naturally infected with SIVcpz, a close relative of HIV-1. African primates are naturally infected with over 40 different simian immunodeficiency viruses (SIVs), two of which have crossed the species barrier and generated human immunodeficiency virus types 1 and 2 (HIV-1 and HIV-2) 1 , 2 . Unlike the human viruses, however, SIVs do not generally cause acquired immunodeficiency syndrome (AIDS) in their natural hosts 3 . Here we show that SIVcpz, the immediate precursor of HIV-1, is pathogenic in free-ranging chimpanzees. By following 94 members of two habituated chimpanzee communities in Gombe National Park, Tanzania, for over 9 years, we found a 10- to 16-fold higher age-corrected death hazard for SIVcpz-infected ( n = 17) compared to uninfected ( n = 77) chimpanzees. We also found that SIVcpz-infected females were less likely to give birth and had a higher infant mortality rate than uninfected females. Immunohistochemistry and in situ hybridization of post-mortem spleen and lymph node samples from three infected and two uninfected chimpanzees revealed significant CD4 + T-cell depletion in all infected individuals, with evidence of high viral replication and extensive follicular dendritic cell virus trapping in one of them. One female, who died within 3 years of acquiring SIVcpz, had histopathological findings consistent with end-stage AIDS. These results indicate that SIVcpz, like HIV-1, is associated with progressive CD4 + T-cell loss, lymphatic tissue destruction and premature death. These findings challenge the prevailing view that all natural SIV infections are non-pathogenic and suggest that SIVcpz has a substantial negative impact on the health, reproduction and lifespan of chimpanzees in the wild.

Seasonal influenza vaccines represent a positive intervention to limit the spread of the virus and protect public health. Yet continual influenza evolution and its ability to evade immunity pose a constant threat. For these reasons, vaccines with improved potency and breadth of protection remain an important need. We previously developed a next-generation influenza vaccine that displays the trimeric influenza hemagglutinin (HA) on a ferritin nanoparticle (NP) to optimize its presentation. Similar to other vaccines, HA-nanoparticle vaccine efficacy is increased by the inclusion of adjuvants during immunization. To identify the optimal adjuvants to enhance influenza immunity, we systematically analyzed TLR agonists for their ability to elicit immune responses. HA-NPs were compatible with nearly all adjuvants tested, including TLR2, TLR4, TLR7/8, and TLR9 agonists, squalene oil-in-water mixtures, and STING agonists. In addition, we chemically conjugated TLR7/8 and TLR9 ligands directly to the HA-ferritin nanoparticle. These TLR agonist-conjugated nanoparticles induced stronger antibody responses than nanoparticles alone, which allowed the use of a 5000-fold-lower dose of adjuvant than traditional admixtures. One candidate, the oil-in-water adjuvant AF03, was also tested in non-human primates and showed strong induction of neutralizing responses against both matched and heterologous H1N1 viruses. These data suggest that AF03, along with certain TLR agonists, enhance strong neutralizing antibody responses following influenza vaccination and may improve the breadth, potency, and ultimately vaccine protection in humans.