Indian J. Virol. (Jan-June 2010) 21(1):3–7
DOI 10.1007/s13337-010-0001-4
REVIEW ARTICLE
Evolution of HIV-1 in India
Pradeep Seth
Received: 4 February 2010 / Accepted: 23 May 2010 / Published online: 22 September 2010
Ó Indian Virological Society 2010
Abstract Nearly 25 years after the discovery of the human
immunodeficiency virus type 1 (HIV-1) effective control of
the AIDS pandemic remains elusive. At the root of this
challenge is the evolution of this virus to elude immune
control. Error-prone nature of replication and retrotranscription is the hallmark of this virus. This fidelity of
replication in HIV-1 is due to the absence of proof-reading/
repair and post-replicative error correction mechanisms that
normally operate during replication of DNA viruses.
Advances in sequencing technology and expanded disease
surveillance have allowed researchers to characterize the
variation in HIV-1 around the world and within individual
patient overtime. Although HIV-1 has been classified into
distinct subtypes, the classification does not reflect dynamic
genetic evolution of HIV-1 through which new strains are
constantly emerging. The resultant viral diversity has
implications for differential rates of disease progression in
different geographical areas, differential responses to antiretroviral therapy (including the development of resistance),
and vaccine development. In this review evolution of HIV-1
in India is discussed.
Keywords HIV Evolution Phylogenetic analysis
HIV-1 subtypes HIV-1 diversity HIV-1 subtype C
Introduction
Since the unfolding of the AIDS epidemic in the early
1980s, there has been an increasing interest in the
P. Seth (&)
Seth Research Foundation, H 8/3 First Floor, DLF Phase-I,
Gurgaon, Haryana 122002, India
e-mail: sethpradeep42@yahoo.com;
consultant@pradeepseth.com
emergence and evolution of infectious diseases. It has
become extremely important to investigate the factors that
allowed new infections like HIV to appear, or older ones
to reappear and then to track their spread through populations. These tracks form part of science of molecular
epidemiology.
Traditionally serology has been used to trace the spread of
infectious diseases. These days comparative analysis of gene
sequence data is being undertaken to study spread of infectious diseases. Meaning thereby, phylogenetic-trees have
become an important analytical tool to track the spread of
infections through populations. Since DNA sequences provide the most detailed information possible for any organism
in evolutionary studies, this information is recognized as an
invaluable document of history of life on earth.
There are two types of HIV: a highly virulent global
type (HIV-1) and a somewhat less virulent strain HIV-2
found mostly in West Africa. Both these viruses impose
major burdens on the health and economic status of many
developing countries. Many African monkeys are commonly infected at high frequencies with HIV like viruses
known as simian immunodeficiency viruses (SIVs). The
SIVs are widespread in a large number of African simian
primates where they do not appear to cause disease. Phylogenetic analyses indicate that these SIVs are the reservoirs for the human viruses, with SIVsm from the sooty
mangabey monkey the most likely source of HIV-2, and
SIVcpz from the common chimpanzee the progenitor
population for HIV-1. Sootey mangabey monkeys are
likely the direct source of HIV-2 since these are West
African monkeys and HIV-2 also is found predominantly in
West Africa. On the other hand, since chimpanzees are
rarely infected with SIVcpz in the wild they are less likely
to be the direct source of HIV-1. However, it is possible
that an unknown SIV from other monkey species may be
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the ancestor of both HIV-1 and SIVcpz. Nonetheless,
separation of HIV-1 and HIV-2 on phylogenetic tree suggests that they must have entered human populations on
different occasions.
In infected humans the process of HIV evolution takes
place at a very fast pace, with the virus continually fixing
mutations by natural selection which allows it to escape
from host immune responses. In SIV-infected monkeys the
pace is not that intense, since a weaker immune response
generates less selective pressure on the virus. This difference in virus–host interaction, together with a wide coreceptor usage such that HIV strains are able to infect cells
with both CCR5 and CXCR4 chemokine receptors, may be
responsible for increased virulence of HIV in humans
compared to SIV in other primates.
HIV-1 genetic diversity over time is driven by two
factors namely the high error rate of the viral reverse
transcriptase and the rapid turn over of HIV-1 in infected
individuals. Recombination events, pressures generated by
the host immune responses, and antiviral drugs further
contribute to differential viral genetic evolution.
Globally circulating strains exhibit an extraordinary
degree of genetic diversity, which may influence several
aspects of their biology such as infectivity, transmissibility
and immunogenicity. Molecular analyses of various HIV
isolates reveal sequence variations over many parts of the
viral genome. Sequences derived from these HIV-1 strains
have historically been classified on the basis of their Phylogenetic relationship. The groups were originally named M
(major), O (outlier), and N (non-M, non-O) [23]. The last
two groups (N and O) remain essentially restricted to West
Africa, whereas the M group comprises a number of viruses
that dominate the global AIDS epidemic. Since HIV-1 M
group began its expansion in humans roughly 70 years ago,
it has diversified rapidly, now comprising a number of
different subtypes and circulating recombinant forms
(CRFs). Based on the sequence of the envelope glycoproteins, genetic subtypes including CRFs have been identified
in group M, whereas subtypes within group O remain
unidentified. Subtypes are genetically defined lineages that
can be resolved through phylogenetic analysis of the HIV-1
M group viruses as well-defined clades or branches in a tree.
CRF describes a recombinant lineage that plays an important role in the HIV-1 epidemic. The CRF members must
share an identical mosaic structure, that is, they have descended from the same recombination event/s.
HIV-1 Genetic Subtypes
On the basis of their Phylogenetic relationships, group M
viruses have been classified into nine subtypes or clades (A
to K; except E and I). Virus strains representing the genetic
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P. Seth
subtypes E and I have not yet been found. The viruses
originally identified as subtype E (the predominant group
of viruses involved in heterosexual transmission in
Thailand) and I (a small group of viruses from Mediterranean region) are now considered inter-subtype recombinants and have been termed CRF01_AE and CRF04_cpx,
respectively.
Disproportionate spread of different lineages of group M
viruses has been taken to indicate that specific biological
differences may exist among various subtypes. Therefore,
the phylogenetic analysis of subtype sequences remains an
important molecular epidemiological tool with which we
may track the course of group M pandemic. Existence of
viral subtypes or clades may be the result of a ‘‘founder
effect’’ in which certain variants of the virus become
founders of a sub-epidemic because they happen to be
involved in an extensive transmission chain. In this scenario, the subtypes may be similar biologically even though
they are genetically very different. Alternatively, it is likely
that certain characteristics of subtypes allowed them to outcompete less-fit viral variants.
Despite the lack of clear correlation between subtypes
and overt biological characteristics, other more subtle
phenotypic distinctions have been reported such as the
pattern of co-receptors usage. Firstly there is growing
evidence that the subtype C has a preponderance of ‘‘nonsyncytia inducing’’ viruses which bind to CCR5 receptors
in addition to CD4 receptors present on the target cells and
lack ‘‘syncytia inducing’’ viruses that use CXC4 and CD4
receptors to infect the target cells. Secondly distinctive
RNA secondary structure in the important regulatory
domain, TAR, is a property associated uniquely with subtype A and viruses having AE mosaic. Thirdly different
subtypes differ in susceptibilities to antiretroviral drugs. In
addition, difference between subtypes is reflected in subtype specific pattern of genetic variation. There is an elevated rate of non-synonymous substitution in the third
variable loop of subtype D viruses, compared with other
subtypes [11].
Most interesting feature of these subtypes is geographic
predilection of their distribution worldwide. It is possible
that these subtypes may have spread through different
populations at different times and by different routes. For
example, subtype A is composed of further two subtypes
(A1 and A2), both of which appear to have a widespread
geographic distribution [5] and is commonly found in subSaharan Africa and Russia where it is predominantly
transmitted through heterosexual intercourse [1]. It may be
one of the oldest of all subtypes. In contrast, subtype B is
associated with the HIV epidemic among homosexual men
and injecting drug users in North and South Americas,
Europe, Japan and Australia. The most prevalent HIV-1
subtype in the global epidemic is subtype C which is
Evolution of HIV-1 in India
dominant in India, Ethiopia, South Africa, Zimbabwe,
Botswana and China and is transmitted through heterosexual intercourse. Interestingly HIV-1 viral lineages of O
and N are mainly confined to West Africa and phylogenetically these are separated from the other HIV-1
sequences suggesting multiple entry of the viruses into
humans.
Subtype C: The Expanding Pandemic
One of the most dramatic changes in the HIV/AIDS has
been the rapid emergence and devastating spread of subtype C viruses. HIV-1 C accounts for 56% of all circulating
viruses and is the most commonly transmitted subtype
worldwide. The subtype C epidemic has now become the
most predominant subtype in Southern African countries
and Indian subcontinent where HIV prevalence is the
highest in the world. The proportionate increase in C
viruses relative to other HIV strains suggest that subtype C
may be more easily transmitted or that it has a higher level
of ‘‘fitness’’ at the population level. One possible explanation is that founder effects relating to the ongoing
introduction of subtype C into new population groups with
different host factors, or different social and sexual practices, may be responsible for the rapid spread. However,
founder and host effects cannot account for the fact that C
viruses are overtaking preexisting virus subtypes in several
different geographical regions. It is increasingly evident
that additional (non-host) viral factors are also contributing
to the rapid spread of HIV-1 C.
Viral studies indicate that subtype C has distinct genetic
and phenotypic properties that differentiate it from other
HIV-1 subtypes. Subtype C viruses have an extra NF-jB
binding site in the long terminal repeat [8], a prematurely
truncated Rev protein or a 5-amino-acid insertion in Vpu [4]
that may influence viral gene expression, altering transmissibility and pathogenesis of C viruses. Factors related to
C viral entry and pathogenesis such as CCR5 and nonsyncytium-inducing properties of C isolates, may also
contribute to the increased spread of C viruses. Interestingly, though both subtype B and C are spreading exponentially in Brazil, the subtype C growth rate is about twice
that of subtype B there; thus providing evidence of a different epidemic potential between two HIV-1 subtypes [19].
Geographical Distribution of HIV-1 Subtypes
Epidemiological and Phylogenetic studies have also shown
that HIV-1 clades are unequally spreading throughout the
world [27]. The HIV epidemic in Africa began in the late
1970s and, during the late 1980s, gradually spread to the
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South of the continent. Though Africa is considered home
of all HIV-1 subtypes, their spread to other continents is
attributed to some groups of individuals, particularly
travelers, who contribute to the initiation of local epidemics worldwide. These groups include, in particular,
immigrants, IV drug users, tourists, truck drivers, military
troops and seamen. The global view on the contribution of
travel to HIV-1 spread usually derives from the prevalence
of non-B subtypes in various countries [25]. The prevalence of non-B infections has indeed markedly increased in
recent years in several European countries [2, 25]. Recent
immigrants from areas of high HIV-1 endemicity and
European travelers have been shown to contribute in large
part to the increase in the prevalence of non-B infections in
western and northern Europe. There is no doubt that it is
high-risk human behavior and not occupation that determines HIV-1 infection risk.
Predominance of subtype B in the western countries
including Japan and Australia is attributed to transmission
among homosexual men and is generally thought to be
spreading separately from that among IV drug users and
heterosexual individuals. However, in India subtype C
predominance even among homosexual men and IV drug
users suggests interplay of host genetic factors and the
virus in determining geographical distribution of HIV-1
subtypes.
Among the HIV-1 group M viruses, HIV-1 subtype C is
by far the most prevalent HIV in the world and is linked to
heterosexual transmission. It was first discovered in North
east Africa in the early 1980s [16, 20] and has since moved
to the southern parts of Africa. In addition, the subtype C
epidemic has spread to East and Central Africa where it is
becoming predominant subtype [18, 28]. From Africa, it
has spread to India, Brazil and South and Central China
where it appears to have been introduced from India [30].
In England and Wales, preponderance of subtype C
infections has been observed among HIV-infected heterosexual STI clinic attendees, particularly in younger age
groups, suggesting recent acquisition of this viral strain
[24].
The Indian Scenario
In India HIV infection was first reported in 1986 in six
commercial sex workers in the State of Tamil Nadu and
since then it has been reported from all the States and
Union Territories. India now holds dubious distinction of
accounting second largest number of HIV infections in the
world following South Africa. With an estimated 2.5 million people living with HIV infection in adult population
(15–49 years) by 2008, India accounts for 13% of global
HIV prevalence [17].
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Tracking the epidemic and implementing effective
programmes is made difficult by the fact that there is no
one epidemic in India. Rather, there are several localized
sub-epidemics reflecting the diversity in social-cultural
patterns and multiple vulnerabilities present in the country.
Though the overall national prevalence is low, six states
have reached high prevalence ([1%): Manipur, Nagaland,
Andhra Pradesh, Tamil Nadu, Karnataka and Maharashtra.
Certain districts in Goa and Gujarat have also reported high
prevalence.
Sexual transmission is driving the AIDS epidemic in
India. This route accounts for about 86% of HIV infections
in the country. Remaining 14% are accounted for by other
routes namely blood transfusion, mother–child transmission and IV drug use, particularly in North East India. Over
one-third of all HIV infections occur in young people in the
age group 15–24 years.
Early studies have indicated the presence of both HIV-1
and HIV-2 in India [3, 6]. Subsequent studies further
emphasized a predominance of subtype C strains in India,
which were found to cluster with South African isolates
[13, 29]. Other HIV-1 subtypes, A and B, have been
reported in India between 1980s and early 1990s among the
recipients of blood and blood products and IV drug users,
respectively, suggesting multiple introductions of HIV-1 in
this country. Subtype A strains were found to be related to
Central and East African subtype and subtype B strains
obtained from Manipur were related to subtype B
sequences circulating in Thailand [13]. However, recent
studies have clearly shown that subtype C strains have
displaced subtype B in the IV drug users in that part of
India [7, 15].
The trends across the country show that there is no
explosive HIV epidemic in India as a whole. However,
there are serious sub-national epidemics in various parts of
the country with rapid spread and evidence of high prevalence of HIV among both Sexual Transmitted Infections
(STI) and antenatal clinic attendees in different sites
located in States of Andhra Pradesh, Maharashtra, Tamil
Nadu, Gujarat, Pondicherry, Assam, Bihar, Chhattisgarh,
Delhi, Haryana, Himachal Pradesh, Kerala, Orissa, Goa
and Manipur. In high prevalence states the epidemic
appears to be spreading gradually from urban to rural areas
and from high-risk behavior groups to the general population. The epidemic continues to shift towards women
with an estimated 39% of the infected being women [17].
An explosive epidemic driven by intravenous drug use
has unfolded in the state of Manipur (North East India)
bordering Myanmar and is close to the Golden Triangle
composed of Thailand, East Myanmar and West Laos and
is the hub of international drug trafficking. A recent study
documents two-third of HIV infections in this region of
India are caused by subtype C and subtype B (Thai B)
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P. Seth
accounts for 20% of infections [15]. The presence of
multiple subtypes circulating in Manipur suggests the
likelihood of recombinant viruses evolving in this region.
Indeed, this has been corroborated by a recent study which
reported presence of B/C recombinants from this region
[26]. Apart from north-eastern states there are also sporadic
reports of the presence of A/C and B/C recombinants from
West and South India [12, 22].
The occurrence of HIV-1 recombination in nature is
borne out by the identification of genomes that are
recombinants between different HIV-1 subtypes [14].
Some of these recombinant viruses have become fixed in
the human population and are referred to as CRFs, and in at
least a few cases CRFs have become the predominant strain
in specific geographic areas of infection such as A/E
recombinants in Thailand and B/C recombinants in parts of
Southeast Asia and China. HIV-1 recombinants are estimated to contribute to 10–40% and 10–30% of the infections in Africa and Asia, respectively. The identification of
subtypes and CRFs provides a means of tracking dissemination of the pandemic worldwide.
To delineate the molecular features of HIV-1 strains
circulating in India, Phylogenetic analyses of sequences of
Indian subtype C isolates along with a small number of
subtype sequences from other countries revealed that
almost all sequences from India form a distinct lineage
within subtype C (CIN). Overall CIN lineage sequences
were more closely related to each other (level of diversity,
10.2%) than to subtype C sequences from Botswana,
Burundi, South Africa, Tanzania and Zimbabwe (range
15.3–20.7%). Suggesting thereby, much of the current
Indian epidemic is descended from a single introduction
into the country [21]. In an assessment of the Phylogenetic
relationships among subtype C sequences from eleven
different countries including India, an overall star-like
phylogeny was observed [10]. Unlike sequences from
South Africa and Botswana, which are scattered in
numerous lineages, almost all sequences from India formed
a monophyletic lineage, which is lying close to the
sequences. Sequences from India generally clustered
together more than sequences from other countries.
Genetic characterization of the virus during the early
seroconversion stage is crucial as the virus isolated is closely related to the transmitted strain and hence immunologically naive. Phylogenetic analyses of Indian subtype C
envelope sequences obtained from early seroconverts
indicated that the Indian sequences not only clustered
within the C clade but also clustered away from the African
subtype C sequences [9]. Moreover, a recent study demonstrating lower diversity within immunodominant epitopes
and a tight clustering of Indian isolates [11] suggested that
production of a vaccine particularly against Indian subtype
C may not be an unattainable and daunting task.
Evolution of HIV-1 in India
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