Background. Understanding the mechanism(s) by which broadly neutralizing antibodies (bNAbs) emerge naturally following infection is crucial for the development of a protective vaccine against human ...immunodeficiency virus (HIV). Although previous studies have implicated high viremia and associated immune activation as potential drivers for the development of bNAbs, here we sought to unlink the effect of these 2 parameters by evaluating the key inflammatory predictors of bNAb development in HIV-infected individuals who spontaneously control HIV in the absence of antiretroviral therapy ("controllers"). Methods. The breadth of antibody-mediated neutralization against 11 tier 2 or 3 viruses was assessed in 163 clade B spontaneous controllers of HIV. Plasma levels of 17 cytokines were screened in the same set of subjects. The relationship of the inflammatory signature was assessed in the context of viral blips or viral RNA levels in peripheral blood or gastrointestinal biopsies from aviremic controllers (<50 copies RNA/mL) and in the context of viral sequence diversity analysis in the plasma of viremic controllers (<50–2000 copies RNA/mL). Results. A unique inflammatory profile, including high plasma levels of CXCL13, sCD40L, IP10, RANTES, and TNFα, was observed in HIV controllers who developed bNAbs. Interestingly, viral load and tissue viremia, but not intermittent viral blips, were associated with these cytokine profiles. However, viral diversity was not significantly associated with increased breadth in controllers. Conclusion. These results suggest that low antigenic diversity in the setting of a unique inflammatory profile associated with antigen persistence may be linked to the evolution of neutralizing antibody breadth.
Coral reefs provide numerous ecosystem services and host more than 20% of marine biodiversity. However, the impact of recreational SCUBA diving on coral reefs is not often quantified in marine ...protected areas. We quantified the impact of divers on coral reefs in five sites within the National Park Reefs of Puerto Morelos, Mexico during high and low tourist seasons. We recorded the number and types of impacts on coral reefs done by divers during 30 minutes and the occurrence of endangered Acropora spp. The impacts most frequently recorded were "touching coral" and "creating sediment clouds" in the shallowest site, during the low season. A warning system was adopted by the Park based on the results. Making this information available for decision-making is crucial for ensuring the sustainable management of tourism, contributes to the conservation of fragile coral reef ecosystems, and ensures the sustianbility of livelihoods that rely on them.
Marine megafauna (elasmobranchs, marine mammals, turtles, and seabirds) are important ecologically and economically because many species often occupy upper trophic levels as adults and are essential ...for marine-based tourism in many areas of the world. This group of species is also heavily impacted by fishing because most have late sexual maturity, longevity, and low reproductive output, which affects their ability to recover from depletion. In Galapagos, marine megafauna species are protected from fishing throughout the marine reserve and are the main attraction for marine-based tourism, helping generate millions of dollars in revenue annually. Despite their importance in the archipelago, these species are being caught as bycatch in the multiple artisanal longlining projects that have been carried out since the implementation of the reserve in 1998. Longlining was originally proposed as a way of redirecting fishing effort from the severely depleted coastal-demersal species to pelagic fish such as yellowfin tuna and swordfish. Although all these projects have resulted in high bycatch of megafauna, longline fishing projects have continued without independent scientific studies to evaluate their impact, largely due to poor objective definition, data collection, and enforcement. To fill in this knowledge gap, we analyzed data of the fifth experimental longline fishing project undertaken in 2012–2013 to describe the fishery, identify variables affecting the composition and quantity of bycatch, and suggest mitigation strategies. This experimental project had twelve vessels, which deployed 42,007 hooks catching 4893 individuals of 33 species, mostly yellowfin tuna and swordfish. Of those, 16 species were protected megafauna, particularly blacktip sharks (Carcharhinus limbatus) and oceanic manta (Mobula birostris). These species were regularly captured during the two seasons and in the three bioregions that occur in the archipelago, suggesting little potential to mitigate their catch. As an alternative, we identified 14 hotspots where yellowfin tuna and swordfish could be harvested in large numbers sustainably through more selective fishing techniques such as pole fishing, a method that is also more economical for artisanal fishers. In an archipelago where the main economic activity is marine wildlife tourism, the implementation of an extractive and unselective activity such as pelagic longing fishing should be avoided to ensure the sustainability of the Galapagos marine ecosystem and its booming tourism industry.
•Bycatch of protected marine megafuna species that are the main tourism attraction.•Errors in dataset suggest important issues with enforcement and compliance.•No variables were identified that influence bycatch.•Suggested hotspots for main target species to use with other fishing method.
Multiple genome-wide association studies (GWAS) have been performed in HIV-1 infected individuals, identifying common genetic influences on viral control and disease course. Similarly, common genetic ...correlates of acquisition of HIV-1 after exposure have been interrogated using GWAS, although in generally small samples. Under the auspices of the International Collaboration for the Genomics of HIV, we have combined the genome-wide single nucleotide polymorphism (SNP) data collected by 25 cohorts, studies, or institutions on HIV-1 infected individuals and compared them to carefully matched population-level data sets (a list of all collaborators appears in Note S1 in Text S1). After imputation using the 1,000 Genomes Project reference panel, we tested approximately 8 million common DNA variants (SNPs and indels) for association with HIV-1 acquisition in 6,334 infected patients and 7,247 population samples of European ancestry. Initial association testing identified the SNP rs4418214, the C allele of which is known to tag the HLA-B*57:01 and B*27:05 alleles, as genome-wide significant (p = 3.6 × 10⁻¹¹). However, restricting analysis to individuals with a known date of seroconversion suggested that this association was due to the frailty bias in studies of lethal diseases. Further analyses including testing recessive genetic models, testing for bulk effects of non-genome-wide significant variants, stratifying by sexual or parenteral transmission risk and testing previously reported associations showed no evidence for genetic influence on HIV-1 acquisition (with the exception of CCR5Δ32 homozygosity). Thus, these data suggest that genetic influences on HIV acquisition are either rare or have smaller effects than can be detected by this sample size.
The development of immunomonitoring models to determine HIV-1 vaccine efficacy is a major challenge. Studies suggest that HIV-1–specific CD8 T cells play a critical role in subjects achieving ...spontaneous viral control (HIV-1 controllers) and that they will be important in immune interventions. However, no single CD8 T-cell function is uniquely associated with controller status and the heterogeneity of responses targeting different epitopes further complicates the discovery of determinants of protective immunity. In the present study, we describe immunomonitoring models integrating multiple functions of epitope-specific CD8 T cells that distinguish controllers from subjects with treated or untreated progressive infection. Models integrating higher numbers of variables and trained with the least absolute shrinkage and selection operator (LASSO) variant of logistic regression and 10-fold cross-validation produce “diagnostic tests” that display an excellent capacity to delineate subject categories. The test accuracy reaches 75% area under the receiving operating characteristic curve in cohorts matched for prevalence of protective alleles. Linear mixed-effects model analyses show that the proliferative capacity, cytokine production, and kinetics of cytokine secretion are associated with HIV-1 control. Although proliferative capacity is the strongest single discriminant, integrated modeling of different dimensions of data leverages individual associations. This strategy may have important applications in predictive model development and immune monitoring of HIV-1 vaccine trials.
•Immune monitoring models integrating multiple functions of HIV-1–specific CD8 T cells distinguish controllers from subjects with progressive HIV-1 infection.•This strategy may have important applications in predictive model development and immune monitoring of HIV-1 vaccine trials.
HIV-1 reverse transcription represents the predominant target for pharmacological inhibition of viral replication, but cell-intrinsic mechanisms that can block HIV-1 reverse transcription in a ...clinically significant way are poorly defined. We find that effective HIV-1 reverse transcription depends on the phosphorylation of viral reverse transcriptase by host cyclin-dependent kinase (CDK) 2 at a highly conserved Threonine residue. CDK2-dependent phosphorylation increased the efficacy and stability of viral reverse transcriptase and enhanced viral fitness. Interestingly, p21, a cell-intrinsic CDK inhibitor that is upregulated in CD4+ T cells from “elite controllers,” potently inhibited CDK2-dependent phosphorylation of HIV-1 reverse transcriptase and significantly reduced the efficacy of viral reverse transcription. These data suggest that p21 can indirectly block HIV-1 reverse transcription by inhibiting host cofactors supporting HIV-1 replication and identify sites of viral vulnerability that are effectively targeted in persons with natural control of HIV-1 replication.
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•Effective HIV-1 reverse transcription depends on host cyclin-dependent kinase 2•HIV-1 reverse transcriptase is a substrate for CDK2-dependent phosphorylation•CDK2-dependent phosphorylation increases RT stability and viral fitness•Upregulation of the CDK inhibitor p21 in controllers indirectly blocks HIV-1 RT
Cell-intrinsic mechanisms that contribute to spontaneous control of HIV-1 replication in elite controllers remain unclear. Leng et al. show that the cyclin-dependent kinase (CDK) inhibitor p21 can indirectly restrict HIV-1 in CD4 T cells from elite controllers through inhibition of CDK2-driven functional augmentation of HIV-1 reverse transcriptase.
The objective of this study was to determine changes in toll-like receptor (TLR) responses of monocytes, myeloid dendritic cells and plasmacytoid dendritic cells during primary and chronic HIV-1 ...infection. TLRs serve as important innate receptors to sense pathogens, and have been implicated in mediating immune activation in HIV-1 infection. Studies assessing the consequences of HIV-1 infection on the ability of innate immune cells to respond to TLR stimulation have come to varying conclusions.
Using intracellular flow cytometry, cytokine production by cryopreserved peripheral blood mononuclear cells from healthy controls and HIV-1-infected individuals were examined after TLR stimulation.
We observed that the effect of HIV-1 infection on TLR responses not only depended on the stage of HIV-1 infection, but was also dependent on the individual receptor and cell type examined. Monocyte and myeloid dendritic cell responses to TLR8 stimulation were associated with HIV-1 viral load and CD4 T-cell count, whereas plasmacytoid dendritic cell responses to TLR7 stimulation were not. Responses to TLR2 stimulation were not affected by HIV-1 infection, whereas responses to TLR9 stimulation were universally decreased in all HIV-1-infected individuals examined regardless of treatment or clinical parameters.
Responsiveness to TLR7/8 stimulation, which have been shown to recognize HIV-1 ssRNA, did not decrease in chronic infection, and may represent a contributing factor to ongoing T-cell immune activation in the setting of chronic viremic HIV-1 infection.
Abstract
Without antiretroviral therapy, a small fraction of HIV-infected patients does not progress to AIDS. Such elite controllers (EC) or viremic controllers (VC) maintain undetectable or low ...levels of viremia, respectively. Generation of broadly neutralizing antibodies (bNAb) does not correlate with viral control, but might enhance antibody-dependent cellular phagocytosis by monocytes. Monocytes are classified into CD14+CD16-, CD14+CD16+ and CD14dimCD16+ monocytes. The latter show increased inflammatory responsiveness and are elevated during chronic HIV-1 infection. We measured markers of T cell activation and monocyte subset distribution and quantity, and investigated the relationship between these parameters and production of bNAb to identify markers for the development of bNAbs. We showed that VC display increased frequencies of CD38+ CD4+ and CD8+ T cells compared to EC. Our data also show that elevated frequencies of CD8+CD38+HLA-DR+ T cells and CD14dimCD16+ monocytes were associated with both viremic control status and production of bNAbs. bNAb production was also strongly associated with increased frequency of CD57+HLA-DR+ CD8+ T cells, as well as decreased expression of chemokine receptors CCR2 and CX3CR1 on CD14dimCD16+ monocytes in VC compared to EC. Further studies are required to establish the cause and effect of alterations in monocyte populations during HIV-1 infection and whether these could tip the scale towards viral control below detectable levels.
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