www.thelancet.com/infection Vol 11 January 2011 45 Review Lancet Infect Dis 2011; 11: 45–56 Published Online December 1, 2010 DOI:10.1016/S1473- 3099(10)70186-9 See Online/Comment Lancet DOI:10.1016/S0140- 6736(10)62180-0 and Lancet DOI:10.1016/S0140- 6736(10)62183-6 Division of Infectious Disease, Case Western Reserve University, Cleveland, OH, USA (D M Tebit PhD, Prof E J Arts PhD) Correspondence to: Prof Eric J Arts, Division of Infectious Disease, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, USA [email protected]Tracking a century of global expansion and evolution of HIV to drive understanding and to combat disease Denis M Tebit, Eric J Arts Since the isolation of HIV, multiple transmissions are thought to have occurred between man and other old-world primates. Assessment of samples from apes and human beings with African equatorial forest ancestry has traced the origin of HIV-1 to chimpanzees, and dated its most recent common ancestor to 1908. The evolution of HIV-1 has been rapid, which has resulted in a complex classification, worldwide spread, and intermixing of strains; at least 48 circulating recombinant forms are currently identified. In addition to posing a nearly insurmountable challenge for diagnosis, treatment, vaccine development, and prevention, this extreme and divergent evolution has led to differences in virulence between HIV-1 groups, subtypes, or both. Coincidental changes in human migration in the Congo river basin also affected spread of disease. Research over the past 25 years and advances in genomic sequencing methods, such as deep DNA sequencing, have greatly improved understanding and analysis of the thousands to millions of full infectious HIV-1 genomes. Introduction HIV is highly heterogeneous within infected individuals owing to rapid turnover rates, high viral load, and an error- prone reverse transcriptase enzyme that lacks proofreading activity. 1–4 High variability is also the consequence of recombination, which can shuttle mutations between viral genomes and lead to major antigenic shifts or alterations in virulence. 5–7 Ultimately, therefore, the continual, divergent evolution of HIV-1 in man to epidemic levels over the past 100 years originates from the swarms of HIV-1 strains (or quasipecies) within each human host. Since the isolation of HIV-1 in the early 1980s, rapid development and application of various molecular tools, such as nucleic acid isolation and purification techniques in frozen, faecal, and urine samples or paraffin- fixed tissue samples, have substantially improved understanding of the origins and evolution of HIV-1. 8,9 In the first two decades of HIV-1 research, sequencing was limited to short HIV-1 genomic regions, which could only provide crude estimates of the geographical distribution of HIV-1 subtypes and gene evolution. Advances in amplification and sequencing of the complete HIV-1 genome, however, have enabled specific classification of HIV-1 subtypes and recombinants. Within infected individuals analyses of quasispecies (ten to 50 clones) typically relied on bacterial cloning or sequencing or on single-genome amplification, but thousands of clones may now be analysed by pyrosequencing methods. 10,11 This Review summarises the emergence of new HIV strains in the worldwide pandemic, with emphasis on the circulating recombinant forms (CRFs), discusses the progress made in the methods used to track the global molecular evolution of HIV, and appraises the importance of these new strains and methods in the future control and prevention of HIV. Origin and classification The likely progenitor of HIV-1, simian immunodeficiency virus (SIV) in chimpanzees (SIVcpz), seems to be a recombinant virus derived from lentiviruses of the red capped mangabey and greater spot-nosed monkey, or a closely related species. 12 Characterisation of SIVcpz has been complicated by the presence of lentiviruses in more than 30 species of non-human primates in sub-Saharan Africa. 13 The SIVs could have crossed to man multiple times over several decades and led to divergence (figure 1). On the basis of phylogenetic analysis HIV has been classified into two types—HIV-1 and HIV-2. The latter is separated into eight groups, of which A and B are the most prominent, and HIV-1 into the groups M (main), N (non-M, non-O), and O (outlier). 14,15 Group M is further categorised into nine subtypes (A–D, F–H, J, and K), sub- subtypes, and 48 CRFs (table 1, figure 1) 16 that are identified by numbers (ascending in order of discovery) followed by letters of the parental subtypes. The origins of HIV-1 groups M and N have been traced to SIV-infected Pan troglodytes troglodytes (Ptt) chimpanzees inhabiting the eastern equatorial forests of Cameroon, in west central Africa. 17–20 The same geographical region was probably also the site of origin for group O HIV-1; the closest SIV relative was found in gorillas (Gorilla gorilla; SIVgor), although chimpanzees are likely to have been the original hosts (figure 1). 21 Another HIV-1 group-O-like variant that is more closely related to SIVgor than to group O, has been identified in a Cameroonian living in France and has been designated to a tentative new group, P. 15 HIV-2 originated from SIV in sooty mangabeys (Cercocebus atys; figure 1). 22–24 By use of molecular clocks, the estimated times of the most recent common ancestors of HIV-1 groups M, O, and N in central Africa are 1908 (range 1884–1924), 1920 (1890–1940), and 1963 (1948–77), respectively, and for HIV-2 groups A and B the dates are 1932 (1906–55) and 1935 (1907–61), respectively (figure 2). 25–31 The HIV-2 epidemic probably started in Guinea Bissau (figures 1 and 2), 23,25–27,32 but Santiago and co-workers 33 reported significant clustering of HIV-2 group A and groups with strains of sooty mangabey SIV in the Tai forest, Côte d’Ivoire. HIV-1 and HIV-2 both spread exponentially early in the epidemic, but the patterns of infection have
Transcript
www.thelancet.com/infection Vol 11 January 2011 45
Review
Lancet Infect Dis 2011; 11: 45–56
Published OnlineDecember 1, 2010DOI:10.1016/S1473-3099(10)70186-9
See Online/CommentLancet DOI:10.1016/S0140-6736(10)62180-0 andLancet DOI:10.1016/S0140-6736(10)62183-6
Division of Infectious Disease, Case Western Reserve University, Cleveland, OH, USA (D M Tebit PhD, Prof E J Arts PhD)
Correspondence to:Prof Eric J Arts, Division of Infectious Disease, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, [email protected]
Tracking a century of global expansion and evolution of HIV to drive understanding and to combat diseaseDenis M Tebit, Eric J Arts
Since the isolation of HIV, multiple transmissions are thought to have occurred between man and other old-world primates. Assessment of samples from apes and human beings with African equatorial forest ancestry has traced the origin of HIV-1 to chimpanzees, and dated its most recent common ancestor to 1908. The evolution of HIV-1 has been rapid, which has resulted in a complex classifi cation, worldwide spread, and intermixing of strains; at least 48 circulating recombinant forms are currently identifi ed. In addition to posing a nearly insurmountable challenge for diagnosis, treatment, vaccine development, and prevention, this extreme and divergent evolution has led to diff erences in virulence between HIV-1 groups, subtypes, or both. Coincidental changes in human migration in the Congo river basin also aff ected spread of disease. Research over the past 25 years and advances in genomic sequencing methods, such as deep DNA sequencing, have greatly improved understanding and analysis of the thousands to millions of full infectious HIV-1 genomes.
IntroductionHIV is highly heterogeneous within infected individuals owing to rapid turnover rates, high viral load, and an error-prone reverse transcriptase enzyme that lacks proofreading activity.1–4 High variability is also the consequence of recombination, which can shuttle mutations between viral genomes and lead to major antigenic shifts or alterations in virulence.5–7 Ultimately, therefore, the continual, divergent evolution of HIV-1 in man to epidemic levels over the past 100 years originates from the swarms of HIV-1 strains (or quasipecies) within each human host.
Since the isolation of HIV-1 in the early 1980s, rapid development and application of various molecular tools, such as nucleic acid isolation and purifi cation techniques in frozen, faecal, and urine samples or paraffi n-fi xed tissue samples, have substantially improved understanding of the origins and evolution of HIV-1.8,9 In the fi rst two decades of HIV-1 research, sequencing was limited to short HIV-1 genomic regions, which could only provide crude estimates of the geographical distribution of HIV-1 subtypes and gene evolution. Advances in amplifi cation and sequencing of the complete HIV-1 genome, however, have enabled specifi c classifi cation of HIV-1 subtypes and recombinants. Within infected individuals analyses of quasispecies (ten to 50 clones) typically relied on bacterial cloning or sequencing or on single-genome amplifi cation, but thousands of clones may now be analysed by pyrosequencing methods.10,11
This Review summarises the emergence of new HIV strains in the worldwide pandemic, with emphasis on the circulating recombinant forms (CRFs), discusses the progress made in the methods used to track the global molecular evolution of HIV, and appraises the importance of these new strains and methods in the future control and prevention of HIV.
Origin and classifi cation The likely progenitor of HIV-1, simian immunodefi ciency virus (SIV) in chimpanzees (SIVcpz), seems to be a recombinant virus derived from lentiviruses of the red
capped mangabey and greater spot-nosed monkey, or a closely related species.12 Characterisation of SIVcpz has been complicated by the presence of lentiviruses in more than 30 species of non-human primates in sub-Saharan Africa.13 The SIVs could have crossed to man multiple times over several decades and led to divergence (fi gure 1). On the basis of phylogenetic analysis HIV has been classifi ed into two types—HIV-1 and HIV-2. The latter is separated into eight groups, of which A and B are the most prominent, and HIV-1 into the groups M (main), N (non-M, non-O), and O (outlier).14,15 Group M is further categorised into nine subtypes (A–D, F–H, J, and K), sub-subtypes, and 48 CRFs (table 1, fi gure 1)16 that are identifi ed by numbers (ascending in order of discovery) followed by letters of the parental subtypes. The origins of HIV-1 groups M and N have been traced to SIV-infected Pan troglodytes troglodytes (Ptt) chimpanzees inhabiting the eastern equatorial forests of Cameroon, in west central Africa.17–20 The same geographical region was probably also the site of origin for group O HIV-1; the closest SIV relative was found in gorillas (Gorilla gorilla; SIVgor), although chimpanzees are likely to have been the original hosts (fi gure 1).21 Another HIV-1 group-O-like variant that is more closely related to SIVgor than to group O, has been identifi ed in a Cameroonian living in France and has been designated to a tentative new group, P.15 HIV-2 originated from SIV in sooty mangabeys (Cercocebus atys; fi gure 1).22–24
By use of molecular clocks, the estimated times of the most recent common ancestors of HIV-1 groups M, O, and N in central Africa are 1908 (range 1884–1924), 1920 (1890–1940), and 1963 (1948–77), respectively, and for HIV-2 groups A and B the dates are 1932 (1906–55) and 1935 (1907–61), respectively (fi gure 2).25–31 The HIV-2 epidemic probably started in Guinea Bissau (fi gures 1 and 2),23,25–27,32 but Santiago and co-workers33 reported signifi cant clustering of HIV-2 group A and groups with strains of sooty mangabey SIV in the Tai forest, Côte d’Ivoire. HIV-1 and HIV-2 both spread exponentially early in the epidemic, but the patterns of infection have
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Figure 1: Relations between and genetic diversity in HIV-1 groups M, N, O, and P, HIV-2, and SIVs, and patterns of cross-species transmissionCRF=circulating recombinant form. cpz=chimpanzee. gor=gorilla. cpx=complex. SIV=simian immunodefi ciency virus.
Pan troglodytes troglodytes (chimpanzee)Homo sapiens
Gorilla gorillaCercocebus atys (sooty mangabey)
CRF0
1_AE
CRF02_A
GCRF09_cpxCRF18_cpx
CRF11_cpx
CRF06_cpx
CRF13_cpxCRF14_BG
CRF05_DF CRF1
9_cp
x
CRF0
3_AB
CRF10_CD
CRF07_BC
CRF08_BC
Group P (RBF 168)
Group O
SIVgor
Subtype DD-like
Subt
ype B
B-like
HIV-2
Group N
SIVcpz
SIVcpz
C-likeSubtype C
Subtype H
F1
F2
K
G
F-like
A1
J
A2
G-like
J-like
A-like
1900s
1930s
1920s
0·05
Group M
CeCercrcococebebusus a atyys ( (sooty mangg babeyy))0·05
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diff ered over time: HIV-1 group M currently accounts for more than 30 million infections, but HIV-2 presently accounts for fewer than 1 million of all HIV infections;34–37 in Guinea Bissau, the epicentre of HIV-2, prevalence has dropped from 8·9% in 1987,38 to 7·4% in 1996,39 to 4·4% in 2006, whereas that for HIV-1 has increased from 2·3% in 1996 to 4·6% in 2006.40
HIV-1 groups M, N, O, and P are phylogenetically interspersed along SIVcpzPtt and SIVgor lineages, which suggests they arose from four independent ape-to-human transmissions.18,41,42 The distributions in human beings diff er strikingly: group O infections are most concentrated in Cameroon, with spread being restricted mainly to neighbouring central African countries; groups N and P have been found in a small number of Cameroonians; and group M strains have spread worldwide and multiple subtypes have been identifi ed (fi gure 2).27,32 Group M viruses encode protein sequences in gag, pol, and env that have 14–35% divergence from their closest known SIVcpz relatives.43 Genetic diversity is frequent but the consequences are unknown, although Wain and colleagues43 identifi ed a viral genetic change in the p17 matrix protein encoded by the gag gene that might have facilitated the adaptation of SIVcpz to its human host. In particular, the aminoacid residue 30 of Gag has a conserved Arg or Lys in all HIV-1 groups (except subtype M-C, which has a conserved Met), whereas Met30 is seen in Gag of SIVgor and SIVcpzPtt, and Lys30 is seen in SIV-infected Pan troglodytes schweinfurthii.43 HIV-1 with Met30Lys Gag replicated better in human peripheral blood mononuclear cells (PBMCs) than in chimpanzee PBMCs.44 The matrix protein could, therefore, modulate virus fi tness after cross-species transmission, with primate lentiviruses being subject to host selection pressure.
Molecular epidemiology Group M causes most HIV-1 infections, owing to its high numbers of subtypes and CRFs. These subtypes form phylogenetic clusters with aminoacid diff erences of 25–30% in env, 20% in gag, and 10% in pol.45 Some subtypes are linked geographically. Variation within group M is greatest in the Congo river basin, which is probably the site of initial zoonotic jumps and regional diversifi cation (table 2,8,9,12,15,17–22,32,42,46–69 fi gure 2).32,46,70,71 Two HIV-1 sequences—a 1960 sample from the current Democratic Republic of Congo (DRC) and a 1959 sample from the DRC (labelled as being from Zaire)—have helped to root the subtype A and D phylogenetic lineages, respectively, and to age the epidemic in the region (fi gure 2).32,46 Initial subtype distribution indicated dominance of subtype B in the western world and of subtype A in sub-Saharan Africa. Subtype A eventually extended into the former Soviet Union (fi gure 2). In the past 15 years, however, the rapid emergence of new subtypes and intermixing of strains has altered the geographical distribution of subtypes.14,72 In addition, some pre-existing subtypes, such as A and F, have
continued to evolve into sub-subtypes—for instance A1–A4 and F1–F2 (fi gure 1),16 that form distinct lineages within a given subtype but that have lesser degrees of genetic divergence.
Sub-Saharan Africa bears the highest burden of HIV-1 in terms of prevalence and diversity (fi gure 3).37,73–76 The epidemics in west and central Africa seem to have stabilised in prevalence, but these regions, along with the Congo river basin, continue to be hot spots for HIV diversity (fi gure 3). Most, if not all, subtypes, sub-subtypes and CRFs have been reported in the DRC and Cameroon.71,77–80 As in the DRC, HIV-1 strains in Angola are highly diverse, and classifi cation into sub-subtypes A5 and A6 might be required.81 From Cameroon, moving westwards to Nigeria, HIV-1 diversity decreases, as shown by the dominance of CRF02_AG subtypes A and G (fi gure 3). This trend continues with western migration to Côte d’Ivoire, Ghana, Senegal, and Mali, where CRF02_AG predominates, with reports of isolated cases of CRF06 _cpx (complex subtype).82–85 Finally, CRF06_cpx and the second-generation recombinants CRF02_AG/CRF06_cpx dominate the epidemic in Burkina Faso, with subtypes A and G rarely being reported.86–90
Although the HIV-1 genetic diversity is high in west and central Africa, HIV-1 prevalence remains surprisingly lower than in most other regions of sub-Saharan Africa (fi gure 3). The highest prevalence shifted in the late 1990s from east Africa (Uganda, Kenya, and Tanzania) to the southern African region. On average, close to 20% of the human population in South Africa, Lesotho, Botswana, and Zimbabwe are thought to be infected with HIV-1.37 This shift provides strong evidence for the founder-eff ect theory (a single introduction followed by a rapid spread)
Circulating recombinant forms (geographic distribution)
Table 1: Classifi cation and distribution of various circulating recombinant forms, according to phylogenetic clustering with pure (non-recombinant) subtypes or fi rst-generation recombinants
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since the southern African epidemic is due almost entirely to the spread of HIV-1 subtype C (fi gure 3).89 Independent, rapid spread of subtype C in east Asia has also contributed to this subtype being responsible for more than 51% of all HIV-1 infections worldwide (fi gure 4).90 Although initially absent, HIV-1 subtype C now circulates at low levels as a pure (non-recombinant) subtype or a recombinant form in Kenya and Uganda. The overall HIV-1 incidence is, however, decreasing (fi gures 2 and 3).91–93
The HIV epidemic in Asia is dynamic and all subtypes that circulate are due to multiple founder events.16 Subtype B was the fi rst introduced into Asia in the mid-1980s, and was seen mainly in China, India, and Thailand. This strain has been named B (also known as Thai B) because
of its divergence from the subtype B that occurs in the Americas (fi gure 2). Deng and colleagues31 reported this divergence occurred about 15 years after the B subtype began to spread, which roughly coincides with CRF01_AE being introduced into Thailand (fi gure 2). CRF01_AE has now gained dominance in Thailand; likewise, subtype C is currently dominant in most east Asian countries.94,95 Subtype C was reportedly introduced into India from South Africa, and then into China from India (fi gure 2).95 Subtypes B and C have recombined to form CRF07_B C and CRF08_B C in China (fi gure 4). The northern triangle of Burma seems to have the greatest HIV-1 diversity in Asia, with seeding of CRF01_AE and subtype B from Thailand, possibly subtypes A, B, and C from India, and CRF07 and CRF08_B C, from Yunnan province in China.
O
O Ca
mer
oon/
Gabo
n to
Fran
ce/G
erm
any ~
1985
Spai
n 19
90s
Nor
way
~19
60
M–C
Congo river basin
M–B western Europe late 1970s/1980s Thailand ~1980s
Figure 2: Estimated time line of global evolution and spread of HIV types, groups, and subtypes Enlarged parts of map show the main disease epicentres. The time line indicates the key events in the evolution of HIV-1 groups M, N, and O and of HIV-2. CRF=circulating recombinant form.
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A shortage of well organised needle exchange programmes for injecting illicit-drug users in this region could contribute to the complexity of HIV-1 subtype recombination there and further afi eld.
In eastern Europe the breakdown of the former Soviet Union has coincided with a rise of HIV-1 infections and, most notably, the spread of sub-subtype A1, which has been linked to intravenous drug use, and of subtype B (and to a lesser extent CRF03_AB), mainly through sexual transmission. In western Europe, as in North America and Australia, subtype B predominates. The prevalence of non-B strains has, however, increased owing to the infl ux of immigrants from Africa and Asia.73,96,97 Portugal has the highest prevalence of HIV-2 and other non-B subtypes in Europe, which might be related to the colonial war in Angola in the mid-1970s.81
In South America, prevalence and diversity of HIV-1 are highest in Brazil and Argentina, with substantial circulation of subtypes B, C, and F, and BC and BF recombinants. Two reports showed close relations between the subtype C viruses in South America and those in Kenya, Ethiopia,95 and Burundi.98 The subtype C epidemic is estimated to have originated in 1958 (fi gure 2),28 and was fi rst reported from Ethiopia in 1990 (fi gure 2),99 from where it spread to Israel; the virus also spread from eastern Africa to Brazil, and then to Argentina and Uruguay (fi gure 2).95 Subtype C was thought to originally have been introduced to Brazil from Mozambique, but this theory is not supported by phylogenetic analysis.100,101 The subtype C epidemic is now the fastest emerging epidemic in South America: in the Rio do Sol region of southern Brazil, subtype C or a BC recombinant accounted for 35% of cases in 1996, 52% in 2002,102 and nearly 59% in 2008,103 and the current estimate is nearly 70%.104
The HIV-1 epidemic in the Caribbean might be the clearest refl ection of diff erent founder events, given notable immigration, travel, and trade. Longstanding links between the DRC and Haiti and between Angola and Cuba might explain the presence and age of certain HIV-1 strains in the Caribbean. Gilbert and co-workers29 applied a relaxed molecular clock to sequences derived from a 1982 Haitian DNA sample and calculated that subtype B was introduced into Haiti between 1962 and 1970, probably from the DRC, and from Haiti into the USA in 1972 (fi gure 2). Likewise, the oldest known HIV-1 subtype B infection in the entire epidemic was identifi ed in a sample from 1982 or 1983, from Haitian immigrants in the USA (fi gure 2). Unlike the Haitian epidemic, that in Cuba is diversifi ed, with CRF18_cpx and CRF19_cpx and subtype C all circulating, but is marked mainly by the CRF20, CRF23, and CRF24, for which subtypes B and G are parental (table 1).105 HIV-1 was probably introduced into Cuba via troops who fought in the Angola war of independence.81 Relative to Cuba and Haiti, HIV-1 has recently arrived through true founder event in other Caribbean islands, such as Trinidad and Tobago and the Dominican Republic.
Recombination CRFs and unique recombinant forms (URFs) are created after co-infection with at least two diff erent HIV-1 isolates. Initially, identifi cation of multiple infections was diffi cult and reports were rare. New technologies, such as the heteroduplex tracking assay and real-time PCR, however, improved detection. URFs comprise more than 30% of infections in regions where several HIV subtypes co-circulate (fi gure 3).106 Isolates were initially classifi ed into diff erent subtypes on the basis of clusters of partial gag and env sequences. A shared node in a phylogenetic tree suggested a common ancestry. Sequencing of longer and near-full length of HIV genomes has led to clearer understanding of lineages. CRFs and URFs have genome segments derived from more than one subtype (fi gure 4), but members of a CRF group share the same mosaic HIV-1 genomic structure and are derived from at least three epidemiologically unlinked ancestors, whereas URFs do not. CRFs currently comprise about 20% of all
Event or fi nding
1983 Isolation of HIV-18
1984 CD4 identifi ed as HIV receptor52
AIDS reported in Africa54,55
1985 Sequence of HIV and genetic diversity reported9,56
Development of the fi rst blood screening assays57
1986 Isolation of HIV-222
1987 First antiretroviral drug, zidovudine, approved by the FDA58
1989 Second HIV drug, didanosine, approved by the FDA58
1990 First report of a divergent form of HIV-1 (group O)50
First full-genomic sequence of HIV-related virus in chimpanzees59
1991 Zalcitabine approved by the FDA; zidovudine and didanosine used in combination for the fi rst time58
1993 Transmission of zidovudine-resistant virus documented60
1994 Detailed characterisation of two reference group O viruses49,51
1996 Discovery of CXCR4 and CCR5 as HIV co-receptors61,62
Substantial protection from HIV infection by homozygous 32 bp deletion in CCR5 gene63
Introduction of combination highly active antiretroviral therapy 64
1997 Group O isolated from 1970s frozen Norwegian human samples65
1998 Sequencing of a 1959 HIV-1 sample from the DRC46
Identifi cation of HIV-1 group N66
1999 First detailed proof that HIV-1 originated from SIVcpzPtt19
Description of group M/O recombinant viruses in two unlinked patients47,48
Single-dose nevirapine shown to reduce transmission of HIV from mother to child67
2000 Description of SIVcpz env sequences similar to those in HIV-1 group N17
2002 SIVcpz identifi ed in wild chimpanzees18
Discovery of APOBEC-3G, an anti-HIV host factor68
2003 SIVcpz described as a recombinant between SIVrcm and SIVgsn12
2004 Discovery of TRIM5 α, a factor that prevents HIV from infecting monkey cells69
2005 High SIV prevalence in wild-caught chimpanzees in equatorial Africa42
2006 Confi rmation that HIV-1 group N and M exist in chimpanzees in equatorial forests of Africa 20
2006 HIV-1 group-O-like sequences found among gorillas in southeastern Cameroon21
2008 Sequencing of a 1960 HIV strain from a paraffi n-embedded tissue sample from the DRC32
2009 Identifi cation of gorilla-like group O sequences in human beings, named group P15
SIVcpz infection is pathogenic in wild eastern chimpanzee sub-species53
FDA=Food and Drug Administration. DRC=Democratic Republic of Congo. SIV=simian immunodefi ciency virus.
Table 2: Some important milestones in the evolution of HIV
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Total infected
Subtype A1
C
DURFs
Human population
Subtype CTotal infected
Human population
Congo River Basin East/central Africa
West Africa Ethiopia/Eritrea/Somalia/Djibouti
Total infected
A1
A2
CD
F1
F2
G
HJ
K
01_AE
02_AG
05_11_
18_
URFs
Human population
1990 1995 2000 2005 20100
10
100
1000
10 000
100 000
1 000 000
Num
ber o
f peo
ple
(tho
usan
ds)
1990 1995 2000 2005 20100
10
100
1000
10 000
100 000
1 000 000
Num
ber o
f peo
ple
(tho
usan
ds)
1990 1995 2000 2005 20100
10
100
1000
10 000
100 000
1 000 000
Num
ber o
f peo
ple
(tho
usan
ds)
Southern Africa
Human population
Total infected
A1
C
D
GURFs
1990 1995 2000 2005 20100
10
100
1000
10 000
100 000
1 000 000
Num
ber o
f peo
ple
(tho
usan
ds)
CF1
JK01_AE
11_
Human population
CRF04–18
Total infected
A1
D
G02_AG
06_URFs
1990 1995 2000 2005Years
Years Years Years
Years2010
0
10
100
1000
10 000
100 000
1 000 000
Num
ber o
f peo
ple
(tho
usan
ds)
CRF02_AG
D
G
URF
Proportion of HIV-1 subtypes in Africa
A1
C
CRF01_AE
KJH
F2
Figure 3: Evolution of HIV prevalence and genotypes in fi ve regions of sub-Saharan Africa from 1990 to 200737,75,76 CRF=circulating recombinant form. URF=unique recombinant form.
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known HIV infections.14,107,108 However, if CRF02_AG (~2 million infections) and CRF01_AE (~1·6 million infections) are taken to be pure subtypes, on the basis of phylogenetic reclassifi cations,73,75,109 this proportion drops to around 10%.
The fi rst HIV-1 isolate to be identifi ed as a recombinant was MAL, a strain derived from subtypes A and D that was obtained from a 1976 blood sample from the DRC.70,71 Of the 48 CRFs described so far,16 12 (25%) have genomic structures incorporating sequences from more than two HIV subtypes (complex recombinants; table 1). For example, CRF06_cpx includes genomic segments with subtypes A, G, J, and K sequences. The origin of this CRF is unknown, but Burkina Faso, where CRF06_cpx is dominant, might have been an HIV-1 epicentre from which this strain spread to neighbouring countries, such as Niger, Mali, Côte d’Ivoire, and Nigeria, and through a founder event in Kaliningrad, Russia (table 1).87,88,106 In south and southeast Asia (except India), CRFs and other recombinants comprise about 88% of circulating strains.73 In particular, CRF07_B C and CRF08_B C dominate the epidemic in China to the extent that the prevalence of subtypes C and B is very low.110
The well described CRF12, CRF17, CRF28, CRF29, CRF39, CRF40, CRF42, and newly identifi ed CRF44 and CRF46–48 are all derived from subtypes B and F, and have been circulating in Argentina and other bordering countries since the 1980s; the earliest identifi cation was in children (table 1).16,111 Most BF recombinants seem to be in an early transition phase, changing from newly generated, transmissible URFs to more-stable CRFs. Thus, CRF12_BF
might not remain dominant in Argentina, and other BF CRFs might emerge with greater transmissibility. To further complicate the epidemic in Argentina, subtypes A, B, C, and F cause around 20% of HIV infections, and BF CRFs cause the other 80%.30
Initially, HIV-1 groups and types were thought too diverse to recombine even after potential dual infection, but there have been three reports of M/O recombination.47,48,112 In one case, generation of the M/O recombinant led to the gradual elimination of the parental isolates.48 The HIV-1 recombination sites selected during dual infection are thought to be more related to the mechanics of strand transfer during reverse transcription and selection of replication-competent chimeric virus than to sequence conservation between the strains.113 Thus, given suffi cient opportunity through multiple dual infections within one or more host species over hundreds of years, recombination between distantly related SIV strains with diff erent target hosts might have been possible. SIVcpz, for which SIV in the greater spot-nosed monkey is one of its parental strains, is a recombinant in the 3 end of the genome, which includes vpu and env genes.12 HIV-1 group N arose from recombination between an SIVcpz group-N-like strain and a progenitor of HIV-1 group M, which possibly infected a subspecies of chimpanzees before being transmitted to man. Given cross-species introductions, or possibly jumping, of SIV between non-human primates, a future recombination event between HIV-1 and HIV-2, groups N and O, or even with other SIV strains, cannot be ruled out.17,114
Figure 4: Mosaic structure of the most dominant circulating recombinant forms in the HIV pandemic, and the worldwide prevalence of HIV-1 subtypes, circulating recombinant forms, and unique recombinant formsLTR=long terminal repeats. CRF=circulating recombinant form. URF=unique recombinant form. *Has the same parental strain as at least one other circulating recombinant form but has a diff erent recombinant structure.
CRF07_BC*
CRF12_BF*
B
A1
G
CRF06_cpx
CRF07_BC, CRF08_BC
CRF012_BF
CRF09_48
LTR LTRgag
pol
vif env
nefvpr vputat
revtat/rev
CRF02_AG
CRF01_AE
Worldwide prevalence of HIV-1 subtypes, CRFs, and URFs
A1
B
URFs
Subtype: colour code for subtypes in chimeric genomeA B C E F G J K Unclassified
C
D
G
CRF01_AE
CRF02_AG
CRF06_cpx
52 www.thelancet.com/infection Vol 11 January 2011
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Genetic assessmentThe understanding of the worldwide rate and direction of HIV-1 evolution will greatly aff ect future methods and strategies for diagnosis, therapy, and prevention. Serology by commercially available ELISA or EIA is the most widely used diagnostic method. Improvements in methods to identify new and diverse HIV-1 isolates means that the panel of necessary proteins to test has substantially expanded.49–51 Fourth-generation HIV immunoassays now detect p24 antigen and HIV-specifi c antibody simultaneously, and can identify most infections with group M and O strains.115 ELISA does, however, lack sensitivity and specifi city to identify serotypes.
DNA sequencing is highly eff ective, but given the initial high costs and the type of equipment and advanced training needed, this approach was not routine in Africa during the 1990s and remains prohibitive in the developing world. The heteroduplex mobility assay off ered a more-aff oradable option for simple and rapid classifi cation of HIV-1 subtypes,116–118 and was used in many areas with the help of workshops provided by WHO. However, although this method has been improved with the use of radiolabelled probes, heteroduplex analyses cannot defi ne specifi c sequence diff erences between isolates of the same or diff erent subtypes.
Direct DNA sequencing is appropriate to characterise the infecting HIV-1 subtype or recombinant form and to monitor regional and global HIV-1 spread. Although DNA sequencing of a bulk PCR product remains less expensive and faster to perform than a clonal DNA sequence analysis, minor HIV-1 variants (frequency <20–30%) cannot be detected. The development of technologies able to process massive DNA sequences in parallel has obvious advantages for detecting minor HIV-1 variants. The Solexa sequencing approach by Illumina (San Diego, CA, USA) provides the greatest depth in clonal sequencing with the generation of 1 Gbp DNA sequence per lane of analyses. However, a drawback of this technology is poor subtyping and CRF identifi cation because of short sequence reads (ten to 50 nucleotides) and lack of linkage to reconstruct HIV-1 genes or genomes. The Genome Sequencer FLX Titanium series (454 Life Sciences, Roche Applied Science, Branford, CT, USA) provides longer sequence reads (100–500 nucleotides), but the longest current sequencing platform is the PacBio RS (Pacifi c Biosciences, Menlo Park, CA, USA), which provides read lengths longer than 1000 nucleotides with low error rates. If appropriately applied and with accurate tags for sequence identifi cation, this technology can be used to reliably estimate HIV-1 population diversity within patients, provide a high-throughput alternative for HIV-1 subtype identifi cation and track disease spread, readily identify dual infection with HIV-1 subtypes or recombinants, and sequence full HIV-1 genomes.
Even with these extreme advances in DNA sequencing technology, limitations still exist in relation to sample collection. To understand the global and historic
evolution of primate lentiviruses, samples must be collected from the remaining old-world primate species.20,29,32 Collection from HIV-infected human beings is easy, but non-invasive collection of samples from monkeys in the wild has proven extremely diffi cult, although sampling techniques, such as the collection of urine and faecal samples from apes, have improved.20 Furthermore, analyses of current samples might not identify the most recent common ancestors of HIV-1 closer to the zoonotic transmission. Generation of lentiviral sequences from stored human tissue samples, such as Bouin-fi xed, paraffi n-embedded tissue samples from west and central Africa, that predate the rapid expansion of AIDS is crucial.
Finally, phylogenetic methods and algorithms have been improved along with sampling and extraction techniques. For example, new Bayesian methods enabled the co-estimation of HIV-1 divergence times under relaxed or strict molecular clock models, and have been essential for dating the introduction of diff erent HIV-1 types, groups, and even some subtypes of HIV-1 group M.25,27,32,119 The development of second-generation DNA sequencing methods has, however, quickly stretched the capabilities of most phylogenetic algorithms.
PhenotypesThe extreme diversity between HIV-1 groups or subtypes has continually raised questions as to whether genotypes are associated with any specifi c biological or phenotypic traits. Within HIV-1 groups and subtypes, isolates use diff erent co-receptors (CCR5 and CXCR4) in association with CD4 for HIV-1 entry.52,120 In newly infected and asymptomatic individuals most viruses are those that use CCR5, but as the disease progresses, variants that use the CXCR4 co-receptor, or both CCR5 and CXCR4, can emerge and dominate in the HIV-1 population, although the pattern can diff er between subtypes. A switch to CXCR4 usage has been associated with acceleration of disease progression. The ability to use either or both of these co-receptors for viral entry is typically conferred by discrete genetic variation in the V3 loop of the HIV-1 envelope glycoprotein. Subtype C strains predominantly use CCR5 and rarely switch to CXCR4 or dual tropic use. By contrast, subtype D strains use CXCR4 receptors earlier and more frequently in infection than other HIV-1 subtypes, which might be why individuals infected with this subtype progress rapidly to AIDS.121,122 Such diff erences in transmission and disease progression could clearly impact the global distribution and prevalence of these viral strains.
A more general question relates to the possible impact of HIV-1 evolution on disease and global virus distribution. This topic has not been the subject of intense investigation because comparing the natural history of infections by diff erent HIV-1 subtypes could require 5–20 years or longer of intense follow-up and the absence of treatment. Although disease progression in
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Review
HIV-1 subtype B infections is at least partly understood, infections with the dominant subtype A, C, and D, as well as CRF02_AG, have been poorly studied, partly because they are highly prevalent in resource-poor settings. As antiretroviral treatment is now widely available, these studies might never be ethically feasible. However, several studies in Uganda and Kenya have suggested progression to AIDS is faster in people with HIV-1 subtype D than in those with subtype A infections.121,123 In another study subtype C infections in Zimbabwean women progressed two to three times slower than subtype A and D infections in Ugandan women, on the basis of CD4 cell counts, but these fi ndings require confi rmation in follow-up studies.124 The fi nding that subtype D led to faster progression than subtype A in this study, though, might lend support to the theory that subtype C infection leads to slow progression.
In other studies the fi ndings related to speed of progression in individuals infected with subtype C vary.125–127 Slow progression would support the reduced virulence of HIV-1 subtype C purported on the basis of in-vitro fi tness studies, which indicate subtype C isolates from human PBMCs had the lowest replicative fi tness when compared directly with other group M isolates.128 Direct correlations have been reported between replicative fi tness of an HIV-1 isolate and its virulence in patients.129 For instance, patients infected with HIV-1 harbouring a deletion in the nef gene and, therefore, with severly impaired replication, had sustained non-progression of disease.130 Defective viruses with reduced cell-entry effi ciency have been identifi ed in patients with elite suppression, who maintain undetectable viral loads without antiretroviral treat ment.131 In-vivo virulence is also related to several host factors, such as immune response and genetic variations in host-derived HIV-1 co-receptors (eg, CCR5). Thus, correlations of disease progression and in-vitro HIV-1 fi tness might not be comparable across patients. How ever, at the population level, low-frequency diff erences in host polymorphisms related to HIV-1 progression are probably negated. As a consequence, clear distinctions in HIV-1 subtype fi tness could be the best correlate of diff erences in disease progression.
Spread of HIV-1 in the human population is determined by virus virulence and host-to-host transmission. For example, prevalence of HIV-2 has been decreasing in west Africa over the past three decades, from 8·9% in 1987 to less than 4·4% by 2006,36,39,40 owing to an apparent decline in virulence. These eff ects could be related to reduced replicative fi tness of certain HIV-2 strains in PBMCs.132,133 Poor HIV-2 fi tness has been noted in ex-vivo dendritic cell cultures, which is a possible model of HIV transmission fi tness.134 By contrast, subtype C HIV-1 isolates are still readily transmitted between human hosts,37 and compete with other HIV-1 group M isolates in various in-vitro models of transmission, such as in penile, vaginal, or rectal tissue, and even Langerhans cell and human skin explants.112 This observation was in
contrast to the pathogenic fi tness model where subtype C HIV-1 isolates replicated with poor effi ciency in PBMCs.
Some host-pathogen models suggest that pathogen spread is associated with duration of infection, transmissibility, and opportunity for transmission.135 For example, as well as being the dominant strain in the initial founder events, subtype C causes disease with a long asymptomatic period, which increases opportunity for transmission compared with that of other group M subtypes. If increased opportunity for transmission remains during chronic disease (5–15 years), it could counteract high transmissibility of other subtypes soon after infection (~1–3 months). Ultimately, HIV could evolve to an attenuated state similar to the persistently non-progressive SIVcpz infections noted in chimpanzees,53 but the time required for this attenuation might be hundreds to millions of years and is still the subject of debate.
Conclusion Of the past century of HIV, the latter 25 years have yielded the greatest number of lessons in evolution and epidemiology, which could be benefi cial in the study of other viruses. Tracing the origin of HIV has confi rmed that viruses can jump from one species to another after a very long period of no transmission and adapt rapidly.27 The spread of HIV-1 to large urban centres occurred during preindependent and postcolonial times in Africa, when massive human emigration out of small villages in the dense tropical forests of Congo river basin occurred, for example to Kinshasa (formerly Leopoldville) in the DRC, which is near the origin of HIV and has notable diversity in HIV subtypes.32 Constant and increasingly easy worldwide travel is a major contributor to HIV diversifi cation. New URFs and CRFs will continue to emerge and will defi nitely have major roles in the development of prevention and control strategies for HIV. Improvements in sampling and monitoring techniques might facilitate the ability to use old archival samples to knit together the complex evolutionary past of the HIV epidemic. Finally, these advanced evolutionary studies on primate lentiviruses must be coupled with phenotypic analyses on the actual viruses and advances in understanding of spread in the population over time, changes in virulence, and transmissibility.
Search strategy and selection criteria
Data for this Review were identifi ed by searches of PubMed, with the search terms “HIV subtypes”, “HIV origin”, “HIV evolution”, “HIV fi tness”, “HIV and recombination”, “HIV diagnosis”, “HIV molecular epidemiology”, and “SIV diversity”. The references of identifi ed articles were manually searched for further relevant papers and we also searched our own reference databases. We only included full-text English-language papers.
54 www.thelancet.com/infection Vol 11 January 2011
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ContributorsEJA and DMT agreed on the structure and content of the Review. DMT
did the initial search for published articles and wrote the fi rst draft. EJA
and DMT revised the fi rst and subsequent drafts and approved the fi nal
version for submission.
Confl icts of interestEJA has received speaker’s fees from the University of Washington, the
University of Massachusetts, and Merck, has a patent under review, and
has received royalties from Diagnostic Hybrids/Quidel for HIV-1
yeast-based cloning and on an oligonucleotide ligation assay. DMT
declares that he has no confl icts of interest.
AcknowledgmentsEJA and DMT are supported by grant R01 from the National Institutes
of Health.
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