Classification of HIV and geographic distribution of HIV1 variants

Classification of HIV

On the basis of phylogenetic analyses of numerous isolates obtained from diverse geographic origins, HIV is subdivided into types (HIV-1 and HIV-2), groups, subtypes, sub-subtypes, CRFs and unique recombinants (URFs) [8]. The initial epicenters of HIV-1 and HIV-2 infection appear to have been Central Africa and West Africa, respectively, reflecting the natural habitats of chimpanzees and sooty mangabeys. HIV-2 is still primarily found in West Africa, and currently the HIV-2 prevalence is stable or even decreasing [9]. In contrast, HIV-1 has spread throughout Africa, including West Africa, and some lineages of HIV-1 have dispersed around the world, so that HIV-1 is predominant globally.

Three HIV-1 groups (M, N, O) exist. Group M (for major) represents the vast majority of HIV-1 strains found worldwide and is responsible for the pandemic [10]. Variability between the three groups is estimated at 30% overall,

Figure 1. HIV gp120 intra-patient variability for six patients infected with different HIV-1 subtypes and characterized at different time points. Three patients were infected with subtype C (C1, C2, and C3) and three by subtype E (E1, E2, and E3) (called CRF01_AE). Genetic characterization (V1-V5) was performed at twice (black and gray), with an period of 13-22 months between samples, for each patient.

Figure 1. HIV gp120 intra-patient variability for six patients infected with different HIV-1 subtypes and characterized at different time points. Three patients were infected with subtype C (C1, C2, and C3) and three by subtype E (E1, E2, and E3) (called CRF01_AE). Genetic characterization (V1-V5) was performed at twice (black and gray), with an period of 13-22 months between samples, for each patient.

and 50% for the env gene. HIV-1 groups O and N are genetically very divergent from group M. Group O is endemic to Cameroon and neighboring countries in West Central Africa, but even there these viruses represent a minority of HIV-1 strains: their highest prevalence is 1-5% of HIV-1-positive samples [11]. Phylogenetic analyses of group O strains have not revealed the same substructure as that found within the evolutionary tree of group M. At present, it is unclear whether group O should be divided into subtypes because only a limited number of full genomes are available, which do not describe the full spectrum of group O diversity that is suggested through analysis of partial genome sequences [12]. Group N forms an independent lineage most closely related to group M, using the sequence from the 5' end of the genome, and clusters more closely with a chimpanzee virus (SIVcpz), using the sequence from the 3' end of the genome [13]. These viruses have only been identified in Cameroon, and represent only a minority of HIV-1 infections, with about 10 patients identified to date.

Group M can be further subdivided in subtypes (A-D, F-H, J and K), sub-subtypes (A1 and A4; F1 and F2), and mosaic viruses, called CRFs when they play a major role in an epidemic (Fig. 2). Currently, more than 30 different CRFs have been reported. Figure 3 shows the complex recombinant structures

Figure 2. Phylogenetic tree analysis of gp120 and gp41.
Figure 3. Schematic representation of the env mosaic structure of circulating recombinant forms (CRFs).

for 19 CRFs in the env gene. The variability between subtypes within M varies for different genes; inter-subtype nucleotide sequence divergence may exceed 20%, 15% and 30% for gag, pol, and env, respectively. The subtypes are approximately equidistant from each other over their entire genome and, by definition, CRFs should resemble each other also over the entire genome, with similar breakpoints reflecting common ancestry from the same recombination event. In addition, many unique recombinants have been documented.

Worldwide distribution of HIV-1 group M variants

Subtype and CRF designations have been powerful molecular epidemiological markers to track the course of the HIV-1 pandemic. Extensive efforts have been made to collect and characterize HIV-1 isolates from around the world, and a broad picture of the distribution of HIV-1 variants has emerged (Fig. 4). Globally, the predominant viral forms are subtypes A and C, followed by subtype B and the recombinants CRF01_AE and CRF02_AG [14]. The heterogenous distribution of HIV-1 variants is probably the result of founder effects. The greatest genetic diversity of HIV-1 has been found in Africa, consistent with this continent being the source of the epidemic.

In North America, Europe and Australia, subtype B is by far the most common. Therefore, the majority of our knowledge on HIV-1 pathogenesis, diagnosis, antiretroviral treatment and development of antiretroviral drugs is based on subtype B. However, subtype B accounts only for 12% of the total disease burden globally, and various other group M subtypes, and even group O viruses, have been reported in the US and several European countries. HIV-1 subtype C caused globally 47.2% of all new HIV-1 infections [15]. This subtype predominates in all countries in southern Africa, where the AIDS epidemic is explosive, and also in Ethiopia and in India. The second most common clade is subtype A, which caused 30% of all new infections, including CRF01_AE and CRF02_AG [14]. CRF01_AE viruses are responsible for the epidemic in Southeast Asia, and have been documented at low frequencies in several

Figure 4. Geographical distribution of HIV worldwide.

Central African countries. CRF02_AG, a complex mosaic of alternating subtype A and G sequences, is the predominant strain in West and West Central Africa. Subtype D is generally limited to Eastern and Central Africa. Subtype F has been reported in Central Africa, South America and Eastern Europe. Subtype G, and A/G recombinant viruses have been observed in Western and Eastern Africa as well in Central Africa. Subtypes H and K have only been detected in Central Africa. Subtype J has been reported in Central Africa and occasionally also in Central America.

Overall, more than 18% of new infections have been attributed to HIV-1 recombinants [10]. In addition to CRF01_AE and CRF02_AG, many other mosaic viruses circulate around the world, but, in contrast, their prevalence seems to be lower, and they often play a major role in certain local epidemics. CRF03_AB is the predominant CRF among intravenous drug users (IDUs) in Kalingrad, in Russia. CRF04_cpx, found in Cyprus and Greece, is a complex mosaic comprising subtypes A, G, H, K and unknown fragments with multiple breakpoints. CRF05_DF has only been identified in Democratic Republic of Congo. CRF06_cpx is a complex mosaic composed of fragments of diverse subtypes A, G, K and J, and circulates principally in West Africa, where it can represent 30-50% of HIV-1 infections in certain countries like Burkina Faso or Niger. CRF07_BC and CRF08_BC are two different inter-subtype B and C recombinants, detected in Northwestern and in Southern China, respectively, mainly among IDUs. CRF09_cpx has been described in several west African countries (Senegal and Ivory Coast), but at low frequencies. CRF10_CD was identified in Tanzania. CRF11-cpx, involving subtypes A, G, J, and CRF01-AE has been detected in Central Africa. CRF12_BF was observed in Argentina and Uruguay. CRF13_cpx is a complex recombinant comprising subtypes A, G, J, and one CRF, CRF01_AE, and was identified in Cameroon. CRF14_BG was documented in IDUs from Spain and Portugal. CRF15_01B found in Thailand is a complex recombinant, comprising CRF and subtypes. CRF16_A2D was identified in Kenya, South Korea and Argentina. At present, 32 different CRFs are described in the HIV Database, but for many of them, no epidemiological background has been reported yet.

It is interesting that many of the CRFs have a restricted geographic spread and are the result of recombination of local co-circulating strains. This illustrates clearly that the global distribution of different forms of HIV-1 is a dynamic process. As more HIV-1 variants inevitably intermix in different parts of the world, the likelihood of generating new recombinant viruses will increase. The pattern of mosaicism will become even more complex, since recombination involving viruses that are already recombinant will also occur (an example being recombination between CRF02 and CRF06 in West Africa). Continued monitoring is necessary to determine the future role of non-subtype B viruses in North America and Europe where they seem to be increasing with time, and to chart the emergence of new predominant subtypes and CRFs around the world.

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