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Since the ignition of the HIV-1 group M pandemic in the beginning of the 20th century, group M lineages have spread heterogeneously throughout the world. Subtype C spread rapidly through sub-Saharan Africa and is currently the dominant HIV lineage worldwide. Yet the epidemiological and evolutionary circumstances that contributed to its epidemiological expansion remain poorly understood. Here, we analyse 346 novel pol sequences from the DRC to compare the evolutionary dynamics of the main HIV-1 lineages, subtypes A1, C and D. Our results place the origins of subtype C in the 1950s in Mbuji-Mayi, the mining city of southern DRC, while subtypes A1 and D emerged in the capital city of Kinshasa, and subtypes H and J in the less accessible port city of Matadi. Following a 15-year period of local transmission in southern DRC, we find that subtype C spread at least three-fold faster than other subtypes circulating in Central and East Africa. In conclusion, our results shed light on the origins of HIV-1 main lineages and suggest that socio-historical rather than evolutionary factors may have determined the epidemiological fate of subtype C in sub-Saharan Africa.

Background A serum-free, highly purified Vero rabies vaccine–next generation (PVRV-NG2) is under development. We conducted a phase III trial to describe the safety and immunogenicity profile of PVRV-NG2 compared with those of licensed purified Vero rabies vaccine (PVRV) in a simulated rabies postexposure prophylaxis (PEP) Zagreb regimen in Thailand. Methods Healthy adults aged ≥18 years (n = 201) were randomized in a 2:1 ratio to receive PVRV-NG2 or PVRV in a rabies PEP Zagreb (days 0, 7, 21 [2-1-1]) regimen, with concomitant human rabies immunoglobulin (HRIG) at day 0. Immunogenicity end points included the proportion of participants with rabies virus–neutralizing antibody (RVNA) titers ≥0.5 IU/mL at days 0, 14, and 35. Safety outcomes were also assessed. Results A total of 199 participants completed the study (PVRV-NG2 n = 133, PVRV n = 66). In the PVRV-NG2 group and PVRV group, respectively, 91.0% (95% CI, 84.1%–95.6%) and 94.6% (95% CI, 85.1%–98.9%) had RVNA titers ≥0.5 IU/mL at day 14, increasing to 100% (95% CI, 96.8%–100%) and 100% (95% CI, 93.5%–100%) by day 35. The vaccines had similar safety profiles, and there were no safety concerns. Conclusions PVRV-NG2 showed acceptable safety and immunogenicity profiles when co-administered with HRIG in a simulated PEP Zagreb regimen in healthy adults in Thailand. [ABSTRACT FROM AUTHOR]

Background: Portugal has one of the most severe HIV-1 epidemics in Western Europe. Two subtypes circulate in parallel since the beginning of the epidemic. Comparing their transmission patterns and its association with transmitted drug resistance (TDR) is important to pinpoint transmission hotspots and to develop evidence-based treatment guidelines. Methods: Demographic, clinical and genomic data were collected from 3599 HIV-1 naive patients between 2001 and 2014. Sequences obtained from drug resistance testing were used for subtyping, TDR determination and transmission clusters (TC) analyses. Results: In Portugal, transmission of subtype B was significantly associated with young males, while transmission of subtype G was associated with older heterosexuals. In Portuguese originated people, there was a decreasing trend both for prevalence of subtype G and for number of TCs in this subtype. The active TCs that were identified (i.e. clusters originated after 2008) were associated with subtype B-infected males residing in Lisbon. TDR was significantly different when comparing subtypes B (10.8% [9.5–12.2]) and G (7.6% [6.4–9.0]) (p = 0.001). Discussion: TC analyses shows that, in Portugal, the subtype B epidemic is active and fueled by young male patients residing in Lisbon, while transmission of subtype G is decreasing. Despite similar treatment rates for both subtypes in Portugal, TDR is significantly different between subtypes. [ABSTRACT FROM AUTHOR]

Background: The HIV pandemic is characterized by extensive genetic variability, which has challenged the development of HIV drugs and vaccines. Although HIV genomes have been classified into different types, groups, subtypes and recombinants, a comprehensive study that maps HIV genome-wide diversity at the population level is still lacking to date. This study aims to characterize HIV genomic diversity in large-scale sequence populations, and to identify driving factors that shape HIV genome diversity. Results: A total of 2996 full-length genomic sequences from 1705 patients infected with 16 major HIV groups, subtypes and circulating recombinant forms (CRFs) were analyzed along with structural, immunological and peptide inhibitor information. Average nucleotide diversity of HIV genomes was almost 50% between HIV-1 and HIV-2 types, 37.5% between HIV-1 groups, 14.7% between HIV-1 subtypes, 8.2% within individual HIV-1 subtypes and less than 1% within single patients. Along the HIV genome, diversity patterns and compositions of nucleotides and amino acids were highly similar across different groups, subtypes and CRFs. Current HIV-derived peptide inhibitors were predominantly derived from conserved, solvent accessible and intrinsically ordered structures in the HIV-1 subtype B genome. We identified these conserved regions in Capsid, Nucleocapsid, Protease, Integrase, Reverse transcriptase, Vpr and the GP41 N terminus as potential drug targets. In the analysis of factors that impact HIV-1 genomic diversity, we focused on protein multimerization, immunological constraints and HIV-human protein interactions. We found that amino acid diversity in monomeric proteins was higher than in multimeric proteins, and diversified positions were preferably located within human CD4 T cell and antibody epitopes. Moreover, intrinsic disorder regions in HIV-1 proteins coincided with high levels of amino acid diversity, facilitating a large number of interactions between HIV-1 and human proteins. Conclusions: This first large-scale analysis provided a detailed mapping of HIV genomic diversity and highlighted drug-target regions conserved across different groups, subtypes and CRFs. Our findings suggest that, in addition to the impact of protein multimerization and immune selective pressure on HIV-1 diversity, HIV-human protein interactions are facilitated by high variability within intrinsically disordered structures. [ABSTRACT FROM AUTHOR]

Background A key challenge in the field of HIV-1 protein evolution is the identification of coevolving amino acids at the molecular level. In the past decades, many sequence-based methods have been designed to detect position-specific coevolution within and between different proteins. However, an ensemble coevolution system that integrates different methods to improve the detection of HIV-1 protein coevolution has not been developed. Results We integrated 27 sequence-based prediction methods published between 2004 and 2013 into an ensemble coevolution system. This system allowed combinations of different sequencebased methods for coevolution predictions. Using HIV-1 protein structures and experimental data, we evaluated the performance of individual and combined sequence-based methods in the prediction of HIV-1 intra- and inter-protein coevolution. We showed that sequence-based methods clustered according to their methodology, and a combination of four methods outperformed any of the 27 individual methods. This four-method combination estimated that HIV-1 intra-protein coevolving positions were mainly located in functional domains and physically contacted with each other in the protein tertiary structures. In the analysis of HIV-1 inter-protein coevolving positions between Gag and protease, protease drug resistance positions near the active site mostly coevolved with Gag cleavage positions (V128, S373-T375, A431, F448-P453) and Gag C-terminal positions (S489-Q500) under selective pressure of protease inhibitors. Conclusions This study presents a new ensemble coevolution system which detects position-specific coevolution using combinations of 27 different sequence-based methods. Our findings highlight key coevolving residues within HIV-1 structural proteins and between Gag and protease, shedding light on HIV-1 intra- and inter-protein coevolution. Reviewers This article was reviewed by Dr. Zoltán Gáspári. [ABSTRACT FROM AUTHOR]

Background: A next-generation, serum-free, highly purified Vero cell rabies vaccine, PVRV-NG2, is in development., Methods: This multicenter, observer-blind, phase 3 study evaluated the immunogenicity and safety of PVRV-NG2, compared with two licensed rabies vaccines (purified Vero cell rabies vaccine [PVRV] and human diploid cell vaccine [HDCV]), as a pre-exposure prophylaxis (PrEP) regimen. Participants were randomized 3:1:1 to PVRV-NG2, PVRV, or HDCV, as a three-dose (Cohort 1; children and adults; day [D] 0, D7, and D28) or two-dose (Cohort 2; adults; D0 and D7) PrEP regimen. The primary objective was non-inferiority of PVRV-NG2 to PVRV and HDCV as three-dose PrEP, based on the proportion of participants with rabies virus neutralizing antibody (RVNA) titer ≥0.5 IU/mL at D42. Non-inferiority of immune response for two-dose PrEP at D28, and non-inferiority of two-dose (D28) versus three-dose (D42) HDCV were also assessed as secondary immunogenicity objectives. Safety was assessed throughout., Results: Overall, 1708 participants were enrolled (Cohort 1: 505 children, 505 adults; Cohort 2: 698 adults). All participants had RVNA titers ≥0.5 IU/mL after three-dose PVRV-NG2 (D42), with non-inferiority to PVRV and HDCV demonstrated. All secondary immunogenicity objectives were achieved, including non-inferiority of two-dose PVRV-NG2 versus two-dose PVRV and HDCV (D28) and three-dose HDCV (D42), and non-inferiority of two-dose HDCV versus three-dose HDCV. The safety profile of PVRV-NG2 was comparable to those of PVRV and HDCV., Conclusions: This study supports the use of PVRV-NG2 in two- or three-dose PrEP regimens, with no safety concerns identified., Clinical Trials Registration: ClinicalTrials.gov identifier: NCT04127786; EudraCT: 2019-000973-22; WHO: U1111-1217-3241., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Since HIV-1 treatment is increasingly considered an effective preventionstrategy, it is important to study local HIV-1 epidemics to formulate tailored preventionpolicies. The prevalence of HIV-1 in Cyprus was historically low until 2005. To investigatethe shift in epidemiological trends, we studied the transmission dynamics of HIV-1 in Cyprususing a densely sampled Cypriot HIV-1 transmission cohort that included 85 percent ofHIV-1-infected individuals linked to clinical care between 1986 and 2012 based on detailedclinical, epidemiological, behavioral and HIV-1 genetic information. Subtyping andtransmission cluster reconstruction were performed using maximum likelihood and Bayesianmethods, and the transmission chain network was linked to the clinical, epidemiological andbehavioral data. The results reveal that for the main HIV-1 subtype A1 and B sub-epidemics,young and drug-naïve HIV-1-infected individuals in Cyprus are driving the dynamics of thelocal HIV-1 epidemic. The results of this study provide a better understanding of thedynamics of the HIV-1 infection in Cyprus, which may impact the development of preventionstrategies. Furthermore, this methodology for analyzing densely sampled transmissiondynamics is applicable to other geographic regions to implement effective HIV-1 preventionstrategies in local settings.

Objective: The latest nonnucleoside reverse transcriptase inhibitor (NNRTI) rilpivirine (RPV) is indicated for human immunodeficiency virus type-1 (HIV-1) patients initiating antiretroviral treatment, but the extent of genotypic RPV resistance in treatment-naive patients outside clinical trials is poorly defined., Study Design: This retrospective observational study of clinical data from Belgium and Portugal evaluates genotypic information from HIV-1 drug-naive patients obtained for the purpose of drug resistance testing. Rilpivirine resistance-associated mutations (RPV-RAMs) were defined based on clinical trials, phenotypic studies, and expert-based resistance algorithms. Viral susceptibility to RPV alone and to the single-tablet regimen was estimated using expert-based resistance algorithms., Results: In 4,631 HIV-1 treatment-naive patients infected with diverse HIV-1 subtypes, major RPV-RAMs were detected in 4.6%, while complete viral susceptibility to RPV was estimated in 95% of patients. Subtype C- and F1-infected patients displayed the highest levels of reduced viral susceptibility at baseline, respectively 13.2% and 9.3%, mainly due to subtype- and geographic-dependent occurrence of RPV-RAMs E138A and A98G as natural polymorphisms. Strikingly, a founder effect in Portugal resulted in a 138A prevalence of 13.2% in local subtype C-infected treatment-naive patients. The presence of transmitted drug resistance did not impact our estimates., Conclusion: RPV is the first HIV-1 inhibitor for which, in the absence of transmitted drug resistance, intermediate or high-level genotypic resistance can be detected in treatment-naive patients. The extent of RPV susceptibility in treatment-naive patients differs depending on the HIV-1 subtype and dynamics of local compartmentalized epidemics. The highest prevalence of reduced susceptibility was found to be 15.7% in Portuguese subtype C-infected treatment-naive patients. In this context, even in the absence of transmitted HIV-1 drug resistance (TDR), drug resistance testing at baseline should be considered extremely important before starting treatment with this NNRTI.

Latin America and the Caribbean countries have increased the scaling-up of antiretroviral treatment in the last years. The increase of transmitted drug resistance has been feared due to the worrisome indicators associated with the emergence of drug resistance and monitored by the World Health Organization (WHO). Consequently, our aim was to review all relevant studies on transmitted drug resistance in Latin America and the Caribbean countries, to analyze its levels, to identify the frequency of transmitted drug resistance mutations, and to put these results in the context of the local Latin American and Caribbean countries settings. A systematic search of Spanish, Portuguese, and English literature was performed in databases and international conferences for the period June 1999 to May 2011. In addition, sequences were downloaded from the Los Alamos and Stanford databases and the transmitted drug resistance was reanalyzed according to the WHO Surveillance Drug Resistance Mutation list 2009. In total, 50 articles, 27 abstracts, and 1,922 patients were included. The resistance varied geographically, but most of the countries have reached the WHO threshold of 5% of resistance. According to the sequences available in public databases, the overall prevalence in Latin America and the Caribbean countries for the period 1996-2009 was 7.7% and by region it was 4.3% for the Caribbean, 3.9% for Mexico, 9.4% for Brazil, 10.5% for the Andean region and 4.9% for the Southern Cone. For the last four investigated years (2006-2009), the information was restricted to Brazilian and Venezuelan studies and revealed an overall transmitted drug resistance of 10%. Throughout the study period, limited information was available for the Caribbean and Central American countries. These findings support the need for developing comprehensive surveys of transmitted drug resistance in these regions.