Phylogenetic inferences on HIV-1 transmission
Year: 2013
Type: review
Abstract: Introduction In 30 years, the HIV-1/AIDS pandemic has evolved into an increasingly complex disease composed of multiple epidemics, each influenced by a complex array of biological, behavioural and cultural factors [1–4]. The concentrated subtype B epidemics in Western world settings have been largely restricted to MSM and IDU populations [3]. The generalized heterosexual (HET) epidemics in Africa and Asia have expanded and diversified to include nine major HIV-1 subtypes (A–D, F–H, J and K) and mosaic circulating recombinant forms (e.g. CRF01_AE and CRF02_AG) [1,5,6]. Migration and globalization has contributed to the spread of non-B subtypes contributing to 20–60% of new infections in Europe, Asia and America [1,2,7]. Highly active antiretroviral therapy (HAART) remains the key to the management of epidemics, reducing mortality, opportunistic diseases and HIV-1 transmission [8–17]. Global health initiatives to scale up antiretroviral therapy (ART) in Africa and Asia have led to population-level reductions in HIV-1 transmission despite weak healthcare systems [8,10,18,19]. The HIV Prevention Trials Network (HPTN) 052, CAPRISA 004, Preexposure Prophylaxis Initiative (iPREX) and Botswana Preprophylaxis Trial (TDF2) randomized clinical trials have shown the potential benefit of early ART initiation, microbicides and prexposure prophylaxis (PrEP) in averting HIV-1 transmission [10,13–16,20,21]. This has led to revisions in treatment guidelines recommending early initiation of ART to all HIV-infected persons and PrEP for high-risk HIV-seronegative populations [15,16]. The failure of the Female Preprophylaxis Trial (FEM-PrEP) underscores the importance of ART adherence and retention [13,14,21,22]. The resurgence of MSM epidemics in the post-HAART era emphasizes the importance of linking ART with other prevention control modalities [23,24]. The development, implementation and maintenance of effective prevention and treatment interventions will require a thorough understanding of the driving forces of individual epidemics [25,26]. Phylogenetics is a molecular epidemiological strategy that characterizes epidemics on the basis of the genetic interrelatedness of HIV-1 viral sequences, capturing the underlying structure of transmission networks or ‘clusters’ within a given population [27–32]. Molecular phylogenetic analysis can be combined with epidemiological, demographical and behavioural data to describe the spatial, temporal and biological dynamics of individual epidemics [7,27–34]. Phylogenetics provides an important dimension in HIV-1 surveillance by delineating: The introduction and dissemination of HIV-1 viral subtypes in different regional settings; The range of transmission patterns fuelling HET, MSM and IDU epidemics; The interrelationships of biological, demographical and social determinants on viral ‘cluster’ networks; The role of disease stage in transmission dynamics; and Underlying trends in regional epidemics, important in the selection of control interventions to limit HIV transmission [26,35,36]. Biological basis of phylogenetic ‘clustering’ High genetic diversity within and across HIV-1 viruses and subtypes can be ascribed to rapid rates of viral replication and turnover with an error-prone reverse transcriptase having high recombination potential [37–41]. Viral evolution within and across HIV-1 subtypes occurs under host, immunological and antiretroviral drug selection pressures, contributing to up to 40, 20 and 10% variations in HIV-1 envelope (env), gag and pol domains, respectively [37,41,42]. Open access websites, such as the Los Alamos (http://www.hiv-lanl.gov), Stanford (http://hivdb.stanford.edu) and REGAdb (http://jose.med.kuleuven.be/subtypetool/html/) databases, have sequence datasets and computer tools for classification of viral subtypes, immune epitopes and antiretroviral drug resistance pathways [5,7,43]. Antithetically, despite the amazing potential of HIV to diversify, surprisingly few viral variants and subtypes have contributed to individual infections and regional epidemics [27,44,45]. Severe bottlenecks in HIV transmission lead to a single transmitted/founder (T/F) virus seeding and dominating the virus population (quasispecies) [46–54]. Single-genome amplification and next-generation sequencing technologies have shown that 80% of MSM and HET infections may be attributed to a single virus [48,49,55–59]. An understanding of the genotypic and phenotypic signatures of these ancestral strains will be important in understanding critical events contributing to their preferential establishment of infection and evolution in the earliest stages of infection [50,52,56,60–62]. The critical determinant of HIV-1 transmission is viral burden in blood, genital fluid and semen [46,63,64]. Acute/primary stage infection has been postulated to disproportionately contribute to onward transmission related in part to high viraemia (>4.5 log copies/ml) and homogeneity of T/F variants [11,46,57,65,66]. ART limits transmission of chronic stage infection by reducing viral load at an individual and population level [11]. Geospatial bottlenecks add a further constraint, limiting the range of viral subtypes in different risk populations and demographic groups [67–71]. Taken together, high genetic diversity coupled with stringent transmission bottlenecks contribute a single ancestral species seeding infections. Phylogenetic ‘clustering’ elucidates transmission dynamics of individual epidemics and the geospatial expansion of viral subtypes in different regional settings. Geospatial expansion of HIV-1 subtypes Molecular phylogeny approaches were first used to classify HIV-1 subtypes and circulating recombinant forms (CRFs) [1,2,5,6,72]. In Western world settings, subtype B epidemics have predominated; in Africa, non-B subtypes have expanded and diversified. Phylogenetic analysis can follow the introduction and spread of specific subtypes and CRFs into local MSM, IDU and HET epidemics [2,71,73–80]. The subtype diversity of the global pandemic is reflected in the distribution of non-B subtypes in Quebec originating from francophone countries in West and Central Africa (Fig. 1) [1,2,6]. Subtype C infections account for half of infections worldwide, whereas subtypes A (12%), CRF01_AE (5%), CRF02_AG (8%) and G (5%) collectively contribute to 30% of the global pandemic [1,2,6]. The remainder of the non-B pandemic is composed of subtype D (Uganda), subtype F (Angola, Romania and South America) and CRFs [1,6]. Subtypes B MSM epidemics dominate in Europe and America, accounting for 9% of global infections. The intermixing of viral subtypes leads to the expansion of novel recombinant mosaics in different regions.Fig. 1: Phylogenetic analysis of the Quebec non-B subtype epidemic (n = 858) originating from West and Central Africa.Clustering (27%) was limited to conjugal families (n = 2–4 infections/cluster). Domestic spread of a subtype D (n = 13) heterosexual cluster and a CRF_AB (n = 30) MSM transmission clusters have been circled.The fastest growing epidemics worldwide are the IDU epidemics in Eastern Europe where subtypes A1 and CRF03_AB are most prevalent [81]. In heavily populated regions, including India, China and Southeast Asia, epidemics have rapidly shifted from predominant IDU to HET epidemics with selective expansion of subtype C, CRF07_BC, CRF08_BC and CRF01_AE subtypes [82,83]. Non-B subtype epidemics comprise 20–60% of new infections in Europe, Asia and America [71,73–78,84]. Crossover of non-B subtype epidemics into domestic MSM, IDU and/or HET epidemics has been observed in the United Kingdom, France, Germany, Spain, Israel, Greece, the Balkans and Asia [74,84–90]. Domestic spread of non-B subtype infections was rarer in Holland, Switzerland and Quebec [91,92]. As illustrated in Fig. 2, secondary spread of non-B subtypes into Quebec has been limited to one founder CRF_AB (n = 33) MSM cluster and one subtype D (n = 9) HET cluster. This highlights the importance of providing healthcare to migrant populations.Fig. 2: Phylogenetic clustering of MSM and IDU epidemics in Montreal.(a) Phylogenetic tree of MSM infections (n = 1359) with large clusters [6–30 primary HIV infection (PHI)/cluster, n = 553] and small clusters (2–4 PHI, n = 272) denoted in blue and orange, respectively. (b) Section of MSM tree (arrowed) showing three unique transmissions, three small clusters and one large cluster harbouring the K103N resistance mutations. (c) Phylogenetic tree of IDU infections (n = 244) with small (n = 90) and large (n = 77) clusters denoted in blue and orange, respectively. One mixed cluster (n = 17) is arrowed.Transmission dynamics of MSM epidemics Phylogenetic analysis has provided a framework for an in-depth evaluation of transmission dynamics of MSM epidemics. Drug-resistance programmes, introduced in the 2000s, have provided large pol (RT/protease) sequence datasets for analysis of transmission trends of regional epidemics [27–29,31,90,93–96]. Molecular phylogeny approaches using neighbour-joining, maximum-likelihood and/or Bayesian (BEAST) methodologies have retraced transmission ‘clusters’ or networks that could not be otherwise identified [28,32]. Systematic surveillance has enhanced our understanding of MSM transmission dynamics by highlighting the role of primary/recent stage infection in onward spread of regional epidemics (Table 1) [27,29,90,93,94,97–101]. The temporal spread of clustered transmissions has been evaluated on the basis of chronological and stage of infection time scales.Table 1: Comparison of the phylodynamic patterns of MSM, IDU and non-B heterosexual epidemics.Comparative analysis of MSM transmission dynamics has been confounded by the use of different selection criteria and methodology. Molecular phylogeny studies have been performed on different groups: acute/primary HIV infection (PHI), PHI (<6 months), recent infection (<12–18 months) and combined PHI and chronic cohorts. Statistical criteria have varied combining high bootstrap values (>95–98%) and low genetic distance (<0.015–0.045) for the designation of ‘clusters’ [28,29,93,101]. Correction for drug resistance is necessary when using chronic treatment experienced populations. Robust criteria delineate ‘transmission clusters’ with internal controls for repeat sampling and include known source-index partnerships [28,29,93,101]. Clustering can be cross-validated by analysis of sequence congruency in natural polymorphisms and reproduction of pol gene clustering in gag, env and integrase domains [28,29,93,101]. The expansion of the MSM epidemic in Montreal evaluated clustering of primary infections (PHI < 6 months) over the last decade. Three patterns of onward spread of MSM epidemics were observed: unique transmissions, small clusters (2–4 PHI) and large clusters (5–60 PHI) (Fig. 2a, b) [27,29]. Large clusters were the driving force sustaining the MSM epidemic, increasing from 25% of primary infections in 2005 to 51% of infections by the end of 2011. The high rates of PHI-related clustering may be related to suppressed viraemia at a population level wherein 85% of diagnosed MSM are receiving HAART. Episodic expansion of large clusters (7–60, median 14 PHI) has arisen through the stepwise formation of new clusters unrelated to prior clusters, as well as secondary outbreaks of older clusters (Fig. 3) [27,29]. Whereas small clusters expanded over 4.75-month intervals (1–11.5 interquartiles), large clusters expanded over 11-month intervals (3.5–25.5 interquartiles).Fig. 3: Temporal expansion of 29 large MSM clusters (7+ primary infections) over the last decade.Box and whiskers plots represent the episodic transmission intervals of each cluster, with Tukey whiskers showing 1.5 time interquartile intervals and severe outliers (●). Four transmission clusters showed biphasic expansion with initial (light grey) and secondary outbreaks (dark grey). Clusters harbouring resistance to nonnucleoside reverse transcriptase inhibitors have been dashed. The sizes of each transmission cluster are denoted in parenthesis. Clusters 68, 50 and 99 harbouring transmitted resistance to NNRTIs are dashed.Phylodynamic features of other regional MSM epidemics were consistent with that observed in Montreal (Table 1) [27,29,31,93,94,102–104]. Cluster membership (17–70%) and size of clusters showed regional variation based, in part, on the depth of population sampling and incidence rates (Table 1) [27,31,93,101,102,105–110]. Transmission clustering was highest in concentrated urban settings and lowest in diffuse nationwide epidemics. Time-resolved phylogenies on date-stamped sequences in the United Kingdom, Netherlands, France and Montreal cohorts indicated that 25–30% of clustering arose over 6-month time spans with median cluster intervals occurring over 14–17 month time spans (Table 1) [27,29,31,93,94,102]. Phylogenetic clustering in other studies was also related to acute/PHI/recent infection status and high CD4 cell count [29,101,103,111]. Temporal dynamics of MSM transmissions Phylogenetic inferences project a role of primary infection (<6 months) and recent stage infection (<14–18 months) in sustaining MSM epidemics (Table 1, Fig. 4). This time span goes well beyond empirical and mathematical models that emphasize a disproportionate contribution role of the 3-week infectious period of ‘acute’ infection in onward transmission [46,112,113]. Newly infected persons in primary and recent stage infection may harbour homogeneous pools of ancestral founder viruses that may have a higher transmissible ‘dose’ of virus for an extended period of time. These early disease stages are distinct from chronically infected source partners that harbour a vast array of quasispecies, including variants having impaired replicative competence and/or fitness [54,114].Fig. 4: Phylogenetic insights on future possibilities in HIV prevention.Temporal expansion of small (2–4 PHI) and large (5–60) clusters are denoted by solid and dashed lines, respectively. Testing must be frequent to capture individuals in a timely fashion for ‘Treatment for as Prevention’ (TasP) paradigms. Antiretroviral drug (ART) pharmacokinetics and patient adherence to ART is necessary to prevent viral bound and chronic stage transmissions.Accurate dating remains a serious caveat in time-resolved phylogenies and modelling of transmission dynamics. Acute infection is rarely detected in real time, as newly infected persons are often symptom-free and unaware of their status [115,116]. Those unaware of their status frequently engage in higher risk behaviour associated with a 3.5-fold increased risk for HIV transmission [117–120]. Control interventions to limit HIV transmission will be predicated on early diagnosis [46,113,121–126]. Serological incidence and p24 assays remain imprecise measures of recency of infection and are limited to those persons recruited into PHI cohorts [68,127–131]. Viral sequence-based assays may assist in estimating recency of infection by monitoring time-dependent evolution from a ‘clonal’ founder event [128,129,132,133]. The frequency of ambiguous calls in bulk sequencing can serve as a surrogate marker that distinguishes recent infection (<0.44% ambiguity in first year) from chronic infection (predictive value 98.7%) [129,133]. Next generation sequencing and high-resolution melting assays may be applied in dating archived specimens [128,134,135]. There remain caveats in Bayesian analysis, time-resolved phylogenies and sequence diversity assays. Issues pertinent to phylogenetic metrics include sequence quality; interval between seroconversion and first genotyping, especially for chronic populations; and effects of ART on quasispecies dynamics. ART suppresses viral replication and quasispecies evolution; treatment failure leads to limited expansion of drug-resistant variants; treatment cessation leads to rebound of previously transmitted ancestral variants [114,136]. Universal genotyping at presentation will become increasingly more important, particularly with the introduction of test–treat paradigms. Genotyping is relatively inexpensive (∼$125, homebrew assays), the frequency of transmitted drug resistance is high (10–20%) and subtype diversity is common. Transmission patterns of IDU and heterosexual epidemics Despite the overall decline in IDU epidemics associated with harm reduction and needle-exchange programmes and antiviral therapy ART, IDU epidemics continue to emerge in North America, Eastern Europe and Asia [85,110,137–141]. Transmission clustering has been implicated in the spread of IDU epidemics, including the spread of drug-resistant subepidemics (Table 1) [110,142–144]. IDU epidemics may bridge the crossover of HET and MSM epidemics, as well as contribute to the introduction and spread of non-B subtype infections and HIV/hepatitis C coinfections [110,137,145–148]. Phylogenetic clustering has been frequently observed in IDU epidemics [103,110,146,149,150] (Fig. 2c). Single-genome analysis has shown that 40–60% of IDU transmissions are associated with a single T/F variant, with remaining infections harbouring three to 16 closely related monophyletic strains [58]. Higher multiplicity of infection among IDU populations may be associated with an absence of the mucosal barriers, prison settings and poor general or mental health [58,149,151]. There is a paucity of data on the phylodynamics of HET non-B subtype epidemics, particularly in endemic Third World settings (Table 1) T/F viruses were observed in of subtype C primary infections from to that observed for MSM cohorts The overall membership size of transmission clusters to among HET cohorts has been that for MSM populations (Table 1) The role of early stage infection may also be in HET partnerships (Table 1) Domestic spread of subtype A and C HET infections size in the United over cluster intervals of with of transmissions occurring over 6-month with extended high viraemia have been observed to disproportionately contribute to expansion of the subtype C epidemic in Botswana A of newly infected persons extended high viraemia copies/ml) for median of This that treatment as prevention (TasP) initiatives may be to those persons showing extended viraemia Phylogenetics were important in randomized control prevention showing that of HIV-1 transmissions among partnerships were and partners of virus transmitted in partnerships in the showed that was a preferential transmission of the ancestral founder from the source quasispecies drug resistance drug resistance programmes have been in resistance to and nonnucleoside reverse transcriptase and inhibitors and integrase inhibitors drug resistance remains a serious health of new infections among populations in different regional settings is particularly for NNRTIs wherein single and high level resistance with a on viral replicative fitness There is resistance to NNRTIs in subtype and as well as a for subtype C The use of to prevent transmission may lead to resistance in is the of in subtype C, in with and/or may emerge more rapidly in Third World settings to having poor and High rates of among MSM and IDU populations have been related to clustering to NNRTIs in Montreal can be ascribed to MSM clusters harbouring or (n = and monitoring of the expansion of drug-resistant subepidemics may local treatment frequently transmitted species include the and (e.g. and Phylogenetic insights on future possibilities in HIV prevention The and randomized control trials have the that may HIV incidence and at a population level [10,13–16,20,21]. The of prevention interventions will require metrics that the of individual epidemics models on control interventions will on local networks will require a understanding of transmission patterns of MSM, IDU and HET epidemics in different regional settings [27–29,31,90,93–96]. The to HIV prevention is timely diagnosis of HIV in high-risk populations [15,16]. Acute infection is rarely detected in and half of newly diagnosed individuals are Phylogenetic inferences project a median of 6 and of small and large clusters, respectively (Table 1, Fig. This period a benefit of early ART initiation to HIV clustering are to of poor and presentation (Fig. 4). The of ART adherence and as viral rebound will on treatment cessation that may contribute to episodic in transmission The of secondary outbreaks in the Montreal and epidemics has been to time when treatment trials (e.g. were in (Fig. receiving and early ART must be on adherence and treatment There have been few studies endemic non-B HET epidemics. In to that observed for MSM and IDU epidemics, studies on HET populations clustering and low cluster This that not have as an on reducing The Botswana a potential benefit of for extended high is important to that viral networks that are not to networks and There is of high and populations having high and low of status from the Montreal rapid that was related to cluster membership and size of cluster was related to poor has been that of MSM infections may be contributing in part to unique transmissions treatment and other prevention interventions require major health The of epidemiological clinical and demographic data will be important in the role of to factors and on transmission dynamics Universal genotyping of all newly infected persons could critical to underlying of local epidemics necessary for the and evaluation of control resistance could transmitted resistance and HIV-1 Molecular phylogeny could the role of disease stage and determinants in transmission dynamics [128,129,132,133]. This analysis is particularly important for the of treatment and prevention in settings. Whereas early stage infection may dominate in regional settings having access to healthcare and ART of chronic stage infections may be related to including of status and poor to and treatment can be of importance in surveillance of the MSM epidemics among and Phylogenetic inferences of local epidemics may assist in the of and prevention for distinct HIV-infected populations. may our of underlying to the preferential selection and expansion of transmitted ancestral inferences will be important in the implementation and of and behavioural interventions and the of HIV the and from all in the Montreal PHI and groups and the Quebec genotyping including and and and and are in the Montreal phylogenetic and the of on HIV-1 transmission dynamics in Montreal have been by from the for and the of of The have of to
Source: AIDS
Authors: Bluma Brenner, Mark A. Wainberg, Michel Roger
Language: French
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W1973597065