Unravelling Selection Shifts Among Foot-and-Mouth Disease Virus (FMDV) Serotypes

FMDV virus has been increasingly recognised as the most economically severe animal virus with a remarkable degree of antigenic diversity. Using an integrative evolutionary and computational approach we have compelling evidence for heterogeneity in the selection forces shaping the evolution of the seven different FMDV serotypes. Our results show that positive Darwinian selection has governed the evolution of the major antigenic regions of serotypes A, Asia1, O, SAT1 and SAT2, but not C or SAT3. Co-evolution between sites from antigenic regions under positive selection pinpoints their functional communication to generate immune-escape mutants while maintaining their ability to recognise the host-cell receptors. Neural network and functional divergence analyses strongly point to selection shifts between the different serotypes. Our results suggest that, unlike African FMDV serotypes, serotypes with wide geographical distribution have accumulated compensatory mutations as a strategy to ameliorate the effect of slightly deleterious mutations fixed by genetic drift. This strategy may have provided the virus by a flexibility to generate immune-escape mutants and yet recognise host-cell receptors. African serotypes presented no evidence for compensatory mutations. Our results support heterogeneous selective constraints affecting the different serotypes. This points to the possible accelerated rates of evolution diverging serotypes sharing geographical locations as to ameliorate the competition for the host

Leveraging genomic surveillance to enhance elimination strategies for hepatitis C virus.

The COVID-19 pandemic has accelerated genomic surveillance of viruses, which has been lauded for its use in improving pandemic preparedness and informing public health strategy. WHO estimates that 68% of countries globally now have the capacity for viral genomic surveillance and the ability to rapidly share genetic information with the global community. The scaling up of genomic surveillance during the past 2 years offers an unparalleled opportunity for initial investment and mobilisation of capacity towards other pathogens, such as hepatitis C virus

Characteristics of HCV Co-Infection among HIV Infected Individuals from an Area with High Risk of Blood-Borne Infections in Central China

Objective: Hepatitis C virus (HCV) and human immunodeficiency virus (HIV) co-infection has been proved to be a growing public health concern. The prevalence and genotypic pattern vary with geographic locations. Limited information is available to date with regard to HCV genotype and its clinical implications among those former commercial blood donor communities. The aims of this study were to genetically define the HCV genotype and associated clinical characteristics of HIV/HCV co-infected patients from a region with commercial blood donation history in central China. Methods: A cross sectional study, including 164 HIV infected subjects, was conducted in Shanxi province central China. Serum samples were collected and HCV antibody testing, AST and ALT testing were performed. Seropositive samples were further subjected to RT-PCR followed by direct sequence coupled with phylogenetic analysis of Core-E1 and NS5B regions performed in comparison with known reference genotypes. Findings: A total of 139 subjects were HCV antibody positive. Genotype could be determined for 88 isolates. Phylogenetic analysis revealed that the predominant circulating subtype was HCV 1b (65.9%), followed by HCV 2a (34.1%). The HCV viral load in the subjects infected with HIV1b was significantly higher than those infected with HCV 2a (P = 0.006). No significant difference for HCV RNA level was detected between ART status, CD4+ cell count level and HIV RNA level. Serum AST and ALT level were likely to increase with HCV RNA level, although no significance was observed. Those who had conducted commercial donation later than 1991 (OR 3.43, 95% CI: 1.12–10.48) and had a short duration of donation (OR 0.35, 95% CI: 0.13–0.96) were more likely to be infected with HCV 1b. Conclusion: These results suggest that HCV subtype 1b predominates in this population, and the impact of HIV status and ART on HCV disease progression is not significantly correlated

Low-Abundance Resistant Mutations in HIV-1 Subtype C Antiretroviral Therapy-Naïve Individuals as Revealed by Pyrosequencing

Given the recent scale-up of antiretroviral therapy (ART) in sub-Saharan Africa, we sought to determine how often and at what levels do drug-resistant mutant variants exist in ART-naïve HIV subtype C infected individuals. Samples from 10 ART-naïve Zambian individuals were subjected to ultra-deep pyrosequencing (UDPS) to characterize the frequency of low-abundance drug resistance mutations in the pol gene. Low-abundance clinically relevant variants were detected for nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs) in eight of the ten subjects. Intermediate to high-level resistance was predicted for the majority of NRTIs. Mutations conferring resistance to most firstline and some second-line therapy drugs were also observed. UDPS detected a number of additional major resistant mutations suggesting that these individuals may have an increased risk of virological failure after initiating ART. Moreover, the effectiveness of first-line and even some second-line ART may be compromised in this setting

Molecular Determinants of HIV-1 Subtype C Coreceptor Transition from R5 to R5X4

The molecular mechanism(s) underlying transition from CCR5 to CXCR4 usage of subtype C viruses remain largely unknown. We previously identified a subtype C HIV-1 infected child whose virus demonstrated CXCR4 usage along with CCR5 upon longitudinal follow-up. Here we delineated the molecular determinants of Env involved in expanded coreceptor usage. Residue changes in three positions of Env V3 domain are critical for the dual-tropic phenotype. These include: substitution of arginine at position 11, MG or LG insertion between positions 13 and 14, and substitution of threonine at the position immediately downstream of the GPGQ crown. Introducing these mutations into V3 region of another R5 virus also conferred dual tropism. Molecular modeling of V3 revealed a possible structural basis for the dual-tropic phenotype. Determining what defines a subtype C X4 virus will lead to a better understanding of subtype C HIV-1 pathogenesis, and will provide important information relevant to anti-retroviral therapy

Interferon-I: The Pièce de Résistance of HIV-1 Transmission?

Despite the extensive viral quasispecies that develops in an individual during the course of HIV-1 infection, transmission is typically established by a single donor viral variant. Recent studies now provide insight into the phenotypic properties influencing this selection process at transmission, including the contribution of resistance to type I interferons

Phylogenetic interpretation during outbreaks requires caution.

How viruses are related, and how they have evolved and spread over time, can be investigated using phylogenetics. Here, we set out how genomic analyses should be used during an epidemic and propose that phylogenetic insights from the early stages of an outbreak should heed all of the available epidemiological information

Functional Properties of the HIV-1 Subtype C Envelope Glycoprotein Associated with Mother-to-Child Transmission

Understanding the properties of viruses capable of establishing infection during perinatal transmission of HIV-1 is critical for designing effective means of limiting transmission. We previously demonstrated that the newly transmitted viruses (in infant) were more fit in growth, as imparted by their envelope glycoproteins, than those in their corresponding mothers. Here, we further characterized the viral envelope glycoproteins from six mother-infant transmission pairs and determined whether any specific envelope functions correlate with HIV-1 subtype C perinatal transmission. We found that most newly transmitted viruses were less susceptible to neutralization by their maternal plasma compared to contemporaneous maternal viruses. However, the newly transmitted variants were sensitive to neutralization by pooled heterologous plasma but in general were resistant to IgG1 b12. Neither Env processing nor incorporation efficiency was predictive of viral transmissibility. These findings provide further insight into the characteristics of perinatally transmissible HIV-1 and may have implications for intervention approaches

Inferring the multiplicity of founder variants initiating HIV-1 infection:a systematic review and individual patient data meta-analysis

BACKGROUND: HIV-1 infections initiated by multiple founder variants are characterised by a higher viral load and a worse clinical prognosis than those initiated with single founder variants, yet little is known about the routes of exposure through which transmission of multiple founder variants is most probable. Here we used individual patient data to calculate the probability of multiple founders stratified by route of HIV exposure and study methodology. METHODS: We conducted a systematic review and meta-analysis of studies that estimated founder variant multiplicity in HIV-1 infection, searching MEDLINE, Embase, and Global Health databases for papers published between Jan 1, 1990, and Sept 14, 2020. Eligible studies must have reported original estimates of founder variant multiplicity in people with acute or early HIV-1 infections, have clearly detailed the methods used, and reported the route of exposure. Studies were excluded if they reported data concerning people living with HIV-1 who had known or suspected superinfection, who were documented as having received pre-exposure prophylaxis, or if the transmitting partner was known to be receiving antiretroviral treatment. Individual patient data were collated from all studies, with authors contacted if these data were not publicly available. We applied logistic meta-regression to these data to estimate the probability that an HIV infection is initiated by multiple founder variants. We calculated a pooled estimate using a random effects model, subsequently stratifying this estimate across exposure routes in a univariable analysis. We then extended our model to adjust for different study methods in a multivariable analysis, recalculating estimates across the exposure routes. This study is registered with PROSPERO, CRD42020202672. FINDINGS: We included 70 publications in our analysis, comprising 1657 individual patients. Our pooled estimate of the probability that an infection is initiated by multiple founder variants was 0·25 (95% CI 0·21-0·29), with moderate heterogeneity (Q=132·3, p<0·0001, I2=64·2%). Our multivariable analysis uncovered differences in the probability of multiple variant infection by exposure route. Relative to a baseline of male-to-female transmission, the predicted probability for female-to-male multiple variant transmission was significantly lower at 0·13 (95% CI 0·08-0·20), and the probabilities were significantly higher for transmissions in people who inject drugs (0·37 [0·24-0·53]) and men who have sex with men (0·30 [0·33-0·40]). There was no significant difference in the probability of multiple variant transmission between male-to-female transmission (0·21 [0·14-0·31]), post-partum transmission (0·18 [0·03-0·57]), pre-partum transmission (0·17 [0·08-0·33]), and intra-partum transmission (0·27 [0·14-0·45]). INTERPRETATION: We identified that transmissions in people who inject drugs and men who have sex with men are significantly more likely to result in an infection initiated by multiple founder variants, and female-to-male infections are significantly less probable. Quantifying how the routes of HIV infection affect the transmission of multiple variants allows us to better understand how the evolution and epidemiology of HIV-1 determine clinical outcomes. FUNDING: Medical Research Council Precision Medicine Doctoral Training Programme and a European Research Council Starting Grant

Evolutionary characteristics and genetic transmission patterns of predominant HIV-1 subtypes among men who have sex with men in China.

OBJECTIVES: Men who have sex with men (MSM) represent one of the major risk groups for HIV-1 infection in China, and the predominant subtypes among this population has changed over the last two decades. The objective of this study was to determine the evolutionary characteristics and transmission patterns of the dominant HIV-1 strains in the Chinese MSM population. METHODS: A total of 4980 published HIV-1 pol gene sequences from MSM in China were retrieved and comprehensive evolutionary and transmission analyses were then conducted. Bayesian coalescent-based methods and selection pressure analyses were used to reconstruct the time-scale and demographic history and to estimate other evolutionary parameters. Transmission patterns were characterized using network analyses. RESULTS: There were 2546 (51.12%) CRF01_AE, 1263 (25.36%) CRF07_BC, and 623 (12.51%) subtype B, accounting for 88.99% of the total sequences. From 2000 to 2016, the prevalence of CRF01_AE was stable, comprising nearly half of all sequences over time (58.33-45.38%, p=0.071). CRF07_BC increased slightly from 13.3% to 22.49% (p<0.001), while subtype B decreased dramatically from 41.67% to 9.04% (p<0.001). Demographic reconstruction showed that the greatest expansion of the HIV epidemic occurred between 1999 and 2005. CRF01_AE had a higher estimated evolutionary rate (2.97×10-3 substitutions/site/year) and exhibited more sites under positive selection (25/351 codons) compared to the other subtypes. Network analyses showed that CRF07_BC (68.29%, 84/123) had a higher proportion of cross-region networks than CRF01_AE (49.1%, 174/354) and subtype B (36.46%, 35/96) (p<0.001). CONCLUSIONS: The predominant subtypes of HIV-1 in Chinese MSM have different evolutionary characteristics and transmission patterns, which poses a significant challenge to HIV treatment and disease prevention