As of 2017, there were 36.9 million people living with HIV worldwide with a majority of these infections in sub-Saharan Africa . AIDS is a global pandemic caused by two genetically diverse lentiviruses, HIV-1 and HIV-2 , that were introduced through multiple cross-species transmissions of simian immunodeficiency viruses from nonhuman primates to humans. These distinct zoonotic viral transmissions gave rise to separate HIV-1 groups M (Major), O (Outlier), N (non-M, non-O) and the most recent group P . The origin of HIV-1 has been documented around Kinshasa in the present day Democratic Republic of Congo around the 1920s from where it spread along a transport network to other areas in sub-Saharan Africa, West Africa, Europe and the rest of the world . This global spread was marked by a geographically defined distribution of several genetically distinct viruses. For instance, subtype B became prevalent in almost all parts of Europe and the Americas while a variety of subtypes and intersubtype recombinants are found in Africa with the highest diversity reported in West Central Africa. Whereas group M viruses have dominated the global HIV pandemic since its inception, other group N, O and P viruses have not been disseminated widely. Group M viruses are further subdivided into nine subtypes (A-D, F-H, J, K) . The genetic distance within a subtype can be between 15 and 20%, whereas genetic distances across subtypes are usually 25 and 35% . HIV-2 remains largely restricted to the western part of Africa although viral introductions have been reported elsewhere in Europe (Portugal and France), India and the United States of America . HIV-2 has also been documented to be less infectious than HIV-1 [6,7]; it is comprised of at least nine groups (formerly referred to as subtypes; A to I) of which groups A and D are presently circulating . HIV-2 subtype data is still limited and only a few recombinants have been described [5,8].
CIRCULATING RECOMBINANT FORMS
Recombination is an important phenomenon for viral diversification that allows the virus to evade the host immune system and antiretroviral treatment . A recombinant is a viral sequence that has regions from two or more distinct parental strains . A circulating recombinant form or circulating recombinant form (CRF) is a combination of viral genomes of different subtypes in dually infected people that results in a mosaic genome composed of regions from each of the different subtypes. When these recombinants are transmitted and spread within a population, they are recognized as circulating strains in the HIV epidemic and are classified as CRFs . The virus must be isolated from at least two unlinked individuals and fully sequenced . The designation ‘cpx’ (complex) is used when more than three subtypes are present . To date, 98 CRFs have been identified and updated in the Los Alamos National Laboratory HIV sequence database . These are designated with sequential numbering as they are discovered and reported.
UNIQUE RECOMBINANT FORMS
Unique recombinant forms (URFs) consist of a mixture of subtypes, but unlike the CRFs, they were sampled only once from a single multiply-infected individual . Hence, all sequences corresponding to a CRF have the same recombination break points in the genome while each URF shows unique breakpoints. Intrasubtype recombination does occur but as it does not lead to subtype recombination, these viruses are not described as URFs. Dual infections with HIV-1 and HIV-2 have frequently been reported in regions where both viruses circulate  although no recombinants between them have been described. Several AD and AC intersubtype recombinants have been described in Eastern Africa [16,17], where these three subtypes cocirculate. BF intersubtype recombinants have been found in Brazil and Argentina, where subtypes B and F are both common [18,19]. Subtypes A and C cocirculate in India with AC recombinants .
We performed a structured literature search in PubMed using MeSH terms. A combination of keywords related to the subject of ‘HIV genetic diversity worldwide’ were used with Boolean operators (OR and AND) in PubMed's advanced search builder. The results generated in the search builder at each level were combined to output all articles that overlapped across all the search words for the specified review period (Fig. 1). This article focused mainly on HIV-1 as there was limited data on HIV-2 during the review period.
GLOBAL DISTRIBUTION OF HIV-1 BY REGION
The greatest genetic diversity of HIV-1 has been found in Africa especially in West Central Africa ; however, other parts of the continent show an assortment of diverse viral strains. In Southern Africa, subtype C collectively predominates [22,23], whereas in Eastern Africa subtype A is the most dominant [24▪▪] although other subtype D and C viruses cocirculate as well . An increase in subtype C and a decrease in subtype D have been reported in Kenya together with extensive intersubtype recombination [24▪▪]. A recent study in Uganda reported an increased prevalence of HIV-1 intersubtype recombinants of about 46% based on near full length HIV sequences [26▪▪]. A separate study by the Phylogenetic And Networks for Generalized HIV Epidemics in Africa (PANGEA)-HIV consortium [27▪] showed a high proportion (about 50%) of HIV-1 intersubtype recombinants in Uganda based on deep sequencing of near full-length viral genomes (unpublished data). In West and West Central Africa, the majority of viruses are CRF02_AG [21,28]. Subtypes A and G cocirculate in some countries such as Nigeria . Mosaic viruses involving CFR02_AG have been reported in several African countries  and an increase of subtype F2 and other recombinant forms in Cameroon  (Fig. 2).
Europe and North America
In North America , Europe [32–36] and Australia , subtype B is still the most widespread viral strain. Other subtypes have also been introduced. For example, in Spain, subtype F1 was identified in a cohort of MSM  or CRF02_AG among immigrant populations .
Subtype B predominates in South America [40,41]. Other intersubtype BF recombinants have also been recently reported . An increase in pure subtype C compared with subtype B has also been reported among HIV/viral hepatitis coinfected patients in Southern Brazil .
Several subtypes circulate in Asia and it has been described as the ‘hotbed’ of recombinant viruses with several CRFs . Subtype A predominates in Russia and other former Soviet Union countries although CRF02_AG is common in Kyrgyzstan . CRF01_AE and CRF07_BC predominate in China [46–48]; new CRFs have been found in China more than in any other country [49–52]. In southeast Asia, CRF01-AE is the most prevalent [53,54] while subtype C predominates in India with reports of increased URFs in the north eastern part of the country .
Middle East and North Africa
Middle East and North Africa countries are grouped together because subtype B is the predominant subtype in the region and these countries show relatively low prevalence and limited sampling of infections [56▪,57].
Previous reviews have shown that subtype C accounts for more than 50% of all infections worldwide with a concentration in East and Southern Africa and India, CRF01_AE as the major strain throughout Southeast Asia, CRF02_AG as the dominant virus in West Africa and about 30% of strains in East Africa to consist of URFs [13,21]. However, there is increased and extensive HIV-1 genetic diversity in Asia [47,49–52,58] and Eastern Africa [24▪▪,26▪▪]. By 2010, there were about 45 reported CRFs , this figure has more than doubled within a 7-year period with at least 98 CRFs that have currently been described . This fast rate of increase in the prevalence of CRFs and the fact that several subtypes cocirculate globally suggests that these numbers will likely continue to grow in the future. The largest source of HIV sequence data (subtype B) is from Europe and the Americas with less data coming from the Middle East (Table 1). As a result, HIV sequence databases like Los Alamos  tend to represent a biased sampling and therefore do not necessarily reflect the distribution of subtypes worldwide. For instance, subtype B accounted for 55% of HIV sequences in the Los Alamos database  which is about five times its frequency in the world . Information on subtype diversity based on near full-length genomes is still relatively scarce with majority of the available data still based on partial HIV fragments. In East Africa, classification of HIV based on near full-length sequences showed a prevalence of 46% of recombinant viruses in Uganda [26▪▪]. The classification of HIV variants based on near full-length genomes is still relatively low (Table 1) although some consortia have generated data that spans entire HIV genomes . One such consortium is the PANGEA HIV [27▪] which is a multinational project funded by the Bill and Melinda Gates Foundation to study the transmission dynamics of HIV within generalized epidemics in Africa. PANGEA aimed at generating close to 20 000 HIV near full-length sequences mainly from sub-Saharan Africa which have been valuable in characterizing HIV variants and understanding the subtype diversity in several African countries. Preliminary results have reported close to 50% of HIV-1 intersubtype recombinants in Uganda based on near full-length genomes (unpublished data from PANGEA-HIV, [27▪]).
Recent data suggest a significant increase in the prevalence of recombinants in some countries [26▪▪,55,63▪▪] and several newly discovered CRFs/URFs in parts of Asia and Africa [49–52,58,59]. This suggests that coinfection or superinfection by divergent HIV-1 strains has become more common in regions where multiple subtypes cocirculate [26▪▪,42,49,52,64]. Viral sequences from recombinant forms have been shown to affect the accuracy of phylogenetic reconstructions [65,66]. This is due to the different regions of the aligned recombinant genome having distinct evolutionary relationships that affect tree topology and branch lengths . Furthermore, such sequences introduce errors in phylodynamic inferences  by biasing ancestral state reconstruction and estimations for the most recent common ancestor . As the prevalence of recombinant forms increases, these challenges are expected to become more important for molecular epidemiological-based investigations. The scale up of cheaper near full-length genome sequencing approaches is critical in improving the accuracy of viral classification. It is important to consider how the fast-increasing emergence of HIV recombinant forms will impact accurate diagnosis, phylogenetic reconstruction, antiretroviral treatment and future vaccine development.
Financial support and sponsorship
The work was supported by the UK MRC and the UK Department of International Development (DFID) under the MRC/DFID Concordat agreement. Further support is from a Career Development Fellowship (grant number TMA 2015 CDF-982) to Deogratius Ssemwanga from the European and Developing Countries Clinical Trials Partnership.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
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