JOURNAL OF VIROLOGY, Oct. 2007, p. 1020910219
19
0022-538X/07/$08.000 doi:10.1128/JVI.00872-07
Copyright 2007, American Society for Microbiology. All Rights Reserved.
MINIREVIEW
Human Immunodeficiency Virus Type 1 Subtype Distribution in the
Worldwide Epidemic: Pathogenetic and Therapeutic Implications
L. Buonaguro,* M. L. Tornesello, and F. M. Buonaguro
Laboratory of Viral Oncogenesis and Immunotherapy and AIDS Reference Center, Ist. Naz. Tumori Fond. G. Pascale, Naples, Italy
Human immunodeficiency virus type 1 (HIV-1) is the caus-
ative agent of AIDS (10, 38, 105, 114). It is characterized by
extensive and dynamic genetic diversity, generating variants
falling into distinct molecular subtypes as well as recombinant
forms; these forms display an uneven global distribution (55).
This diversity has implications for our understanding of viral
transmission, pathogenesis, and diagnosis and profoundly in-
fluences strategies for vaccine development.
Here we review selected aspects of the genetic diversity of
HIV-1, with particular emphasis on its pathogenetic and ther-
apeutic implications.
HIV-1 GENETIC SUBTYPES
HIV-1 is characterized by extensive genetic heterogeneity
driven by several factors, such as the lack of proofreading
ability of the reverse transcriptase (RT) (96, 108), the rapid
turnover of HIV-1 in vivo (56), host selective immune pres-
sures (84), and recombination events during replication (122).
Due to this variability, HIV-1 variants are classified into three
major phylogenetic groups: group M (main), group O (outlier),
and group N (non-M/non-O) (6, 52, 116). Group M, which is
responsible for the majority of infections in the worldwide
HIV-1 epidemic, can be further subdivided into 10 recognized
phylogenetic subtypes, or clades (A to K), which are approxi-
mately equidistant from one another (Fig. 1). Within group M,
the average intersubtype genetic variability is 15% for the gag
gene and 25% for the env gene (58, 64, 68, 70, 92, 109).
Moreover, within a subtype, it is possible to identify groups
of viral isolates forming genetically related sister clades,
termed subsubtypes (109), which appear to be phylogenetically
more closely related to each other than to other subtypes. This
is the case with the A and F clades, whose members are cur-
rently classified into subsubtypes A1 to A2 and F1 to F2,
respectively (42, 123). Clades B and D are more closely related
to each other than to other subtypes, and clade D is considered
the early clade B African variant, but their original designation
as subtypes is retained by authors for consistency with earlier
published works (40, 74).
Classification of HIV-1 subtypes was originally based on the
subgenomic regions of individual genes. However, with an in-
* Corresponding author. Mailing address: Lab. of Viral Oncogenesis
and Immunotherapy & AIDS Ref. Center, Ist. Naz. Tumori Fond. G.
Pascale, Via Mariano Semmola, 1, 80131 Naples, Italy. Phone: 39-
081-5903.609. Fax: 39-081-545.1276. E-mail: irccsvir@unina.it.
Published ahead of print on 18 July 2007.
10209
Vol. 81, No.
creasing number of viral isolates available worldwide and im-
provements in sequencing methods, HIV-1 phylogenetic clas-
sifications are currently based either on nucleotide sequences
derived from multiple subgenomic regions (gag, pol, and env)
of the same isolates or on full-length genome sequence analysis.
This approach has revealed virus isolates in which phylogenetic
relations with different subtypes switch along their genomes.
These intersubtype recombinant forms are thought to have orig-
inated in individuals multiply infected with viruses of two or more
subtypes. When an identical recombinant virus is identified in at
least three epidemiologically unlinked people and is characterized
by full-length genome sequencing, it can be designated as a cir-
culating recombinant form (CRF) (99, 110) (Fig. 1).
More than 20 CRFs whose origins can be tracked to areas
where the parental strains are cocirculating have been reported
(Fig. 2). Cocirculation of multiple subtypes and CRFs in the
same populations increases the probability that individuals will
become superinfected with different HIV-1 genetic forms
which can swap parts of their genetic material, resulting in the
generation of several recombinants, called unique recombi-
nant forms, or URFs, which, if spread to other people, will
lead to their classification as CRFs (79).
GEOGRAPHIC DISTRIBUTION OF HIV-1 SUBTYPES
Molecular epidemiological studies show that, with the excep-
tion of sub-Saharan Africa, where almost all subtypes, CRFs, and
several URFs have been detected, there is a specific geographic
distribution pattern for HIV-1 subtypes (55, 97). This distribution
pattern seems to be the consequence of either accidental traffick-
ing (viral migration), with a resulting founder effect, or a prev-
alent route of transmission, which results in a strong advantage
for and local predominance of the prevalent subtype transmitted
in that population (17, 81, 91, 93, 98).
According to recent studies, on a global scale the most
prevalent HIV-1 genetic forms are subtypes A, B, and C, with
subtype C accounting for almost 50% of all HIV-1 infections
worldwide (Fig. 3). Subtype A viruses are predominant in areas
of central and eastern Africa (Kenya, Uganda, Tanzania, and
Rwanda) and in eastern European countries formerly consti-
tuting the Soviet Union. Subtype B is the main genetic form in
western and central Europe, the Americas, and Australia and
is also common in several countries of Southeast Asia, north-
ern Africa, and the Middle East and among South African and
Russian homosexual men. Subtype C viruses are predominant
in those countries with 80% of all global HIV-1 infections,
10210 MINIREVIEW J. VIROL.

FIG. 1. Evolutionary relationships among nonrecombinant HIV-1 strains. The phylogenetic tree shows HIV-1 groups M, O, and N and subtypes
and CRFs within the M group. The phylogenetic analysis was performed on nearly full-length sequences and is based on the neighbor-joining
method. The internal branches defining a subtype have been estimated from 1,000 bootstrap replicates.

such as southern Africa and India. The relevance of CRFs in
the global HIV-1 pandemic is increasingly recognized, ac-
counting for 18% of infections (55, 97) and representing the
predominant local form in Southeast Asia (CRF01-AE) (82,
89, 104) and in West and West Central Africa (CRF02-AG)
(80, 87) (Fig. 4).
HIV-1 DIVERSITY AND ITS ORIGIN
Strong phylogenetic evidence suggests that HIV-1 originated
by zoonotic cross-species transmission of the simian lentivirus
simian immunodeficiency virus SIVcpz from the chimpanzee
subspecies Pan troglodytes troglodytes to humans (39). This
cross-species transmission could have occurred in West Equa-
torial Africa from direct exposure to animal blood as a conse-
quence of hunting, butchering, and consumption of raw meat
(53). In fact, this region includes countries (Gabon, Equatorial
Guinea, Cameroon, and the Republic of Congo) where the
following conditions in support of this hypothesis are found: (i)
HIV-1 groups M, N, and O cocirculate in human populations;
(ii) HIV-1 group M viruses show the greatest diversity (28, 59,
85, 86, 88, 101, 127); and (iii) chimpanzees (Pan troglodytes
VOL. 81, 2007
FIG. 2. Mosaic structure of HIV-1 CRFs. All CRFs that have been described to date are shown (modified from http://www.hiv.lanl.gov/content
/hiv-db/CRFs/CRFs.html). The letters and graphic patterns represent the different subtypes of HIV-1 involved in the recombination events. U,
unknown.
troglodytes) have been found to be infected with genetically
closely related viruses (26, 39, 78, 102, 116). These conditions
both support long-lasting circulation of the whole spectrum of
the known HIV-1 genetic forms, possibly resulting from mul-
FIG. 3. Global prevalence of HIV-1 genetic forms. The global
prevalence of each form, expressed as a percentage of the total number
of HIV-1 isolates identified worldwide, is shown. Isolates from HIV-1
groups O and N were not included in this analysis.
MINIREVIEW 10211
tiple founders, and make zoonotic transmission from infected
animals to humans plausible.
Moreover, the interspersion of HIV-1 group M, N, and O
sequences among different SIVcpz (Pan troglodytes troglodytes)
lineages in phylogenetic trees requires that HIV-1 viruses from
the three groups originated from no fewer than three separate
SIVcpz transmission events (Fig. 5). However, while group M
viruses appear to have efficiently adapted to the new host
species, spreading all around the world and generating multi-
ple genetic subtypes, the other two groups show less efficient
adaptations to humans. HIV-1 group O seems to be endemic
to Cameroon and neighboring countries in West Central Af-
rica, where it represents only approximately 1 to 5% of HIV-
1-positive samples (102); likewise, group N viruses have been
identified only in a limited number of individuals from Cam-
eroon (6, 116). Moreover, group N viruses appear to be the
result of a recombination event between an SIVcpz-like and an
HIV-1-like virus (39), and their high degree of similarity to
chimpanzee viruses may indicate a significantly recent zoonotic
cross-species transmission. This evidence suggests that cross-
10212 MINIREVIEW J. VIROL.

FIG. 4. Global geographical distribution of HIV-1 genetic forms. Genetic forms predominant in different world regions are shown. The pie
charts show the prevalence of individual genetic forms in each region.

species zoonotic transmissions to humans of additional pri- Considering that African primates are the natural hosts of
mate lentiviruses and/or recombinations between HIV-1 vi- several different lentiviruses (100), it is quite reasonable that
ruses and primate lentiviruses may still occur, giving rise to such cross-species zoonotic lentivirus transmissions to humans
new HIV-1 groups with unpredictable virulence. have periodically occurred through the centuries in West

FIG. 5. Phylogenetic tree of primate lentivirus sequences. Phylogenetic tree analysis was performed by using the neighbor-joining method, based on
a 550-base pair pol fragment from SIV and HIV isolates. One isolate per each HIV-1 group M subtype was used. Branch lengths are drawn to scale (the
bar indicates 10% divergence). The branches were estimated from 1,000 bootstrap replicates, and only bootstrap values of 80% are shown.
VOL. 81, 2007
Equatorial Africa. Exposure to SIV in natural settings is com-
mon for individuals exposed to blood and body fluids of nat-
urally SIV-infected nonhuman primates. However, although
there is a significant percentage of seropositivity to SIV anti-
gens in such high-risk groups (17.1%), no productive infection
has been detected (60). It has been proposed that the lack of
productive infections is a consequence of either exposure to
nonviable or defective SIV, a nonproductive cleared infection,
or sequestering of the virus in lymphoid tissues. The reason
why HIV-1 gave rise to the AIDS pandemic only in the 20th
century has not yet been determined but could reasonably be
the sum of significant cultural and socio-behavioral changes,
the use of nonsterile needles for parenteral injections and
vaccinations, and the unwitting contamination of biological
products for medical treatments (e.g., oral polio vaccine) (46,
57). The earliest case of HIV-1 infection, dating from 1959,
was identified in the Democratic Republic of Congo (134), and
using different methods of molecular clock analysis, it has been
estimated that HIV-1 group M began to radiate from its source
around the 1930s (63, 113).
HIV-1 SUBTYPES AND TRANSMISSION
Diverse risk behaviors sustain HIV-1 transmission in differ-
ent regions of the world, and within the same region, multiple
transmission routes can be involved in spreading the epidemic.
For example, in Eastern Europe and Central Asia in 2005, 67%
of HIV infections were due to needle sharing among intrave-
nous drug users (IDUs). In South and Southeast Asia, not
including India, 49% of HIV infections reported were in com-
mercial sex workers and their clients, while 22% were in IDUs.
In Latin America, 26% of HIV infections were in men who
have sex with men (MSM), and 19% were in IDUs (http://www
.unaids.org/en/HIV_data/2006GlobalReport/default.asp). In
Western Europe, unprotected intercourse among heterosex-
uals accounted for 45%, and among MSM, 28%, of HIV in-
fections (http://www.eurohiv.org/reports/report_73/pdf/report
_eurohiv_73.pdf).
As reported in the previous paragraph, the HIV-1 epidemic
in these regions is sustained by different subtypes, and within
each region, segregation of subtypes to different risk groups
has been reported. For example, the cocirculation of subtype B
among IDUs and CRF01_AE (originally defined as subtype E)
among heterosexuals was originally described in Thailand (41);
the segregation of subtype B to homosexuals and subtype C to
heterosexuals was described in South Africa (126); more re-
cently, two concurrent epidemics in Argentina have been re-
ported, one among MSM, sustained by subtype B, and the
other among heterosexuals and IDUs, sustained by BF recom-
binants (5). In Europe, where subtype B has sustained the
HIV-1 epidemic among the historical IDU and homosexual
risk groups, non-B subtypes and CRFs are progressively being
introduced in association with increased heterosexual trans-
mission of HIV-1 between migrants and/or immigrants from
regions where HIV-1 is endemic and their European partners
(19, 20, 121).
All these observations, reported at different phases of the
HIV-1 epidemic around the world, may suggest different bio-
logical properties for the subtypes, resulting in their segrega-
tion among individuals with different risk behaviors for HIV-1
MINIREVIEW 10213
infection. Nevertheless, a consistent demonstration of this as-
sociation has not been given. There is clearly no predeter-
mined linkage between a specific subtype and a unique mode
of transmission. In fact, subtype A is transmitted among het-
erosexuals in sub-Saharan Africa and IDUs in Eastern Europe;
similarly, subtype B is transmitted among all the historical risk
groups in Western countries.
Therefore, the apparent segregation of HIV-1 subtypes by
type of risk behavior rather than as a result of virologic factors
(cell tropism, coreceptor specificity) could derive from genetic,
demographic, economic, and social factors that separate the
different risk groups for HIV-1 infection. Moreover, the over-
whelming predominance of the C subtypes in areas where
unprotected heterosexual intercourse is the main transmission
route could result from a founder effect with a fast-coloniza-
tion outcome.
IMPACT OF HIV-1 GENETIC DIVERSITY ON
SPECIFICITY AND SENSITIVITY OF
DIAGNOSTIC TESTS
The genetic variability of HIV-1 may pose significant prob-
lems for the specificity and/or sensitivity of serological and
molecular diagnostic tests, which may represent a serious risk
factor for the spreading of unidentified infections.
Fourth-generation HIV immunoassays are designed to de-
tect both the HIV p24 antigen and antibody in a single test in
order to reduce the seroconversion window (131). The sensi-
tivity of these assays for the p24 antigen and seroconversion,
however, can vary significantly (76, 130). Nevertheless, recent
comparative studies have shown that some of these immuno-
assays have levels of specificity and sensitivity comparable to
those of second- and third-generation assays designed to detect
either antigens or antibodies and can identify most of the known
group M subtypes, the most diffused CRFs (CRF01_AE and
CRF02_AG), and group O viruses (69).
In parallel, a similar comparative study reported on molec-
ular diagnostic tests, which might be even more affected by the
high variability of the target HIV-1 nucleotide sequences.
Analysis has shown that the widely used real-time RT-PCR for
viral load measurements is able to identify all the tested group
M and group O isolates within a target concentration ranging
from approximately 316,230 copies/ml (5.5 log10) to below 50
copies/ml (1.6 log10), with a coefficient of correlation between
0.991 and 0.999 (120).
Therefore, these reports indicate that the currently used
serological and molecular diagnostic tests for HIV-1 are still
sufficiently specific and sensitive to detect the most prevalent
HIV-1 genetic forms worldwide. Nevertheless, anecdotal un-
identified HIV-1 isolates have been reported in primary HIV-1
infection cohorts in monoclade HIV epidemics (21). There-
fore, the continuous genetic variation and intersubtype recom-
bination events make frequent evaluation analyses of the di-
agnostic tests and, possibly, national registries to report
undiagnosed cases necessary. These measures would help
greatly in keeping the diagnostic capacity of the tests up to
date.
10214 MINIREVIEW
CORRELATION BETWEEN HIV-1 GENETIC DIVERSITY
AND DRUG RESISTANCE
The genetic variability characterizing the different HIV-1
subtypes and CRFs also affects the protease and RT genes
coding for the viral enzymes that are the main targets of anti-
retroviral drugs. These polymorphisms, if conferring drug re-
sistance, can be selected by drug-selective pressure and dra-
matically influence the therapeutic outcome. Alternatively, the
polymorphisms do not confer drug resistance but may change
the genetic barrier, which is defined as the number of viral
mutations required to develop escape mutations able to over-
come the drug-selective pressure. In general, several mutations
are generally required for the virus to become resistant to
protease inhibitors (high genetic barrier), whereas a single
amino acid substitution can induce resistance to nonnucleoside
reverse transcriptase inhibitors (NNRTIs) (low genetic bar-
rier) (12).
The frequency and pattern among HIV-1 subtypes of poly-
morphisms inducing resistance per se or leading to a faster
emergence of drug resistance under pharmacological pressure
have been evaluated in several recent studies. In particular,
considering the lack of extensive information on non-B sub-
types, which predominate in countries where the availability of
antiretroviral therapy (ART) is very limited, great emphasis
has been given to comparative studies of B versus non-B sub-
types. In a large European study performed on approximately
2,000 protease and RT gene sequences (600 non-B) from
antiretroviral-nave patients, a genetic barrier similar for B and
non-B subtypes was found at almost all positions (125).
In addition, specific data are available for individual ART
drug classes. In regard to the few positions of the protease
sequence where differences were found, such as the 82A and
82T polymorphism, the genetic barrier was either lower for
subtype C or higher for subtype G, suggesting that non-B
subtypes may require even more mutations than B subtypes to
develop drug resistance. Moreover, specific polymorphisms in
protease positions may confer greater susceptibility to protease
inhibitors to other non-B subtypes. In particular, subtype C
and CRF02_AG recombinant viruses from drug-nave patients
show an in vitro hypersusceptibility to protease inhibitors (1,
48), a finding which needs to be confirmed by in vivo clinical
studies.
Extensive differences between the subtypes were found for
the minor protease substitutions, which do not impair drug
susceptibility but may affect the genetic pathway of resistance
once the virus generates a relevant major substitution (47, 83,
106). This finding implies that a faster emergence of drug
resistance to a particular protease inhibitor could be expected
in some non-B subtypes.
In regard to nucleoside reverse transcriptase inhibitor com-
pounds, non-B subtypes do not show a lower genetic barrier in
any resistance-associated substitutions, indicating evolution to
the drug-resistance phenotype at a rate comparable to that of
subtype B isolates. For NNRTI resistance-related substitu-
tions, the most relevant finding is the reduced genetic barrier
for the V106M substitution in subtype C, which has been ob-
served in different studies and which confers high-level resis-
tance to all NNRTIs (16, 124, 125). In particular, the V106M
mutation in RT is facilitated in subtype C by a single transition
J. VIROL.
(GTG to ATG), compared to two transitions in viruses of other
subtypes (GTA to ATG). Moreover, natural resistance to
NNRTIs has been observed in patients carrying group O
HIV-1 viruses (29, 107), and it is believed to have a genetic
basis relating to the natural RT Y181C polymorphism, similar
to the Y181I divergence seen in naturally NNRTI-resistant
HIV-2 (117).
All these in vitro genetic studies showing both the absence of
nave drug resistance mutations in non-B subtypes and sub-
stantial similarity between B and non-B subtypes in the degree
of probability that they will develop drug resistance are con-
firmed by a generally conserved drug susceptibility in vivo. In
fact, HIV-1 subtypes do not appear to affect the efficacy of
first-line therapy and currently available protease and RT in-
hibitors are equally active on all HIV-1 subtypes (3, 13, 37,
103). A global collaborative study based on non-B subtype
sequences from 3,686 individuals showed (i) that most of the
protease and RT positions associated with drug resistance in
subtype B viruses are selected by ART in one or more non-B
subtypes as well and (ii) that no evidence is available that
non-B viruses develop resistance by mutations at positions that
are not associated with resistance in subtype B viruses (61).
However, a few exceptions to this general rule have been
reported in ART-treated patients. Subtype C viruses show a
faster emergence of drug resistance to NNRTIs resulting from
the appearance of the V106M mutation (73). A Ugandan study
to prevent mother-to-child transmission of HIV-1 showed that
a single dose of nevirapine induced more frequent selection of
genotypic mutations associated with resistance to nevirapine in
women infected with subtype D than in women infected with
subtype A viruses (34).
In contrast to the overall extensive genetic variability along
the HIV-1 genome, the overall observed genetic similarities in
the drug resistance-related codons among HIV-1 subtypes can
be explained by the biological relevance of such sites. In fact,
sequences containing major drug resistance-associated substi-
tutions show reduced fitness, which results in less efficient
replication and spread of these viral populations (75, 128).
HIV-1 GENETIC DIVERSITY AND
VACCINE DEVELOPMENT
Transmission of HIV in the general population can possibly
be blocked by an effective, safe, and affordable anti-HIV-1
vaccine, which should induce a strong humoral, as well as
cellular, immune response against the whole array of HIV-1
genetic forms.
The significant intra- and intersubtype variability of the
HIV-1 envelope protein (58, 64, 68, 70, 92, 109), the main
target of a preventive and possibly sterilizing vaccine approach,
together with the undeniable fiasco of the first clinical trial of
a phase III vaccine based on a monomeric gp120 (35, 50), has
drastically driven the HIV-1 vaccine field in recent years to-
ward the development of cytotoxic T-lymphocyte (CTL)-induc-
ing vaccine approaches. This approach is also based on early
observations of the strong correlation between the anti-HIV-1
CTL response and disease progression (67, 90, 95). Moreover,
CTL responses can be raised against Gag and Pol proteins,
which are less variable proteins, possibly circumventing the
variability of the virus as well as the necessity of using HIV
VOL. 81, 2007
vaccine candidates that correspond to the HIV-1 strains prev-
alent in the target population.
In support of this strategy, promising broad cross-clade cel-
lular immunity against specific HIV-1 epitopes has been de-
scribed (27, 45, 51, 133); however, only a few epitopes are
conserved across different subtypes, and single amino acid sub-
stitutions are selected by the CTL immune pressure, allowing
the virus to escape with a dramatic deterioration of clinical
conditions (8, 9). Moreover, several studies have identified
sequence variability within, as well as proximal to, character-
ized optimal epitopes, which can either modulate binding to
the HLA molecule, reduce the binding affinity to the cognate
T-cell receptor, or interfere with efficient antigen processing,
resulting in escape from CTL surveillance (4, 14, 31, 71).
As a consequence, it is now currently believed that an anti-
HIV-1 vaccine should elicit efficient cellular, as well as hu-
moral, immune responses and, in particular, broadly anti-en-
velope neutralizing antibodies able to target the largest number
of HIV-1 genetic forms. Most of the envelope immunogens
developed, however, have failed to achieve this objective (11,
23, 77).
Broadly neutralizing monoclonal antibodies targeting differ-
ent epitopes in gp120 and gp41 have been obtained from nat-
urally infected individuals (for a comprehensive review, see
Srivastava et al., [119]), suggesting that envelope immunogens
able to raise such a broad neutralizing response can be gener-
ated. However, polyspecific reactivity of some of these mono-
clonal antibodies with autoantigens has recently been reported,
raising serious doubts about the possibility of eliciting such
broad anti-HIV humoral responses in vaccinees (2, 54). Nev-
ertheless, using this concept, a few laboratories are currently
focusing on designing an HIV vaccine by following a working
backwards strategy, consisting of isolating and characterizing
human/animal antibodies that can neutralize a broad range of
HIV strains and then using these antibodies to identify the
HIV target regions to be incorporated into vaccines. The ef-
fectiveness of such vaccine candidates in developing protective
immunity will be tested in the near future.
In the meantime, several strategies have been developed to
engineer envelope immunogens presenting epitopes able to
induce neutralizing antibodies with broad efficacy against T-
cell-adapted as well as primary HIV-1 isolates (7, 18, 22, 32, 36,
118, 132).
Furthermore, the genetic diversity of HIV-1 and the distri-
bution of different subtypes in each population is currently
being addressed by vaccine approaches based on either multi-
valent formulations or consensus and ancestral sequences. The
first approach is based on using envelope molecules from dif-
ferent HIV-1 subtypes in order to induce antibodies with a
broader breadth of neutralizing activities (15, 24, 25, 49, 111,
112, 115). The second approach is based on computer-derived
sequences (consensus sequences) generated by aligning cir-
culating primary isolates and selecting the most common nu-
cleotide at each position. The resulting inferred genes are in an
intermediate position within an evolutionary tree, being equi-
distant from the currently circulating isolates (30, 33, 44, 62,
94). However, these presumed consensus sequences are sub-
ject to sampling bias and may include polymorphisms, post-
translational modifications (e.g., glycosylation) that do not re-
flect the naturally spreading viruses, which may severely
MINIREVIEW 10215
influence their antigenicity and immunogenicity. For example,
out of five envelope consensus and ancestral sequences gener-
ated (30, 43, 65, 66, 72, 129), only one envelope consensus of
the group M sequences has been shown to elicit high titers of
neutralizing antibodies effective against primary isolates from
three different group M clades (72).
CONCLUDING REMARKS
The genetic complexity of the worldwide HIV-1 epidemic is
still growing, with continuous molecular evolution of existing
subtypes and identification of new CRFs, as well as URFs. The
B subtype is still predominant in Western countries, with a
progressive introduction of non-B subtypes from countries
with higher levels of epidemic disease, while subtype C repre-
sents the most prevalent form globally. A founder effect with a
fast-colonization outcome, along with genetic, demographic,
economic, and social factors, appears to explain this epidemic
distribution of different subtypes. The available serological and
molecular diagnostic tools show levels of specificity and sensi-
tivity appropriate for identifying the broad spectrum of circu-
lating genetic variants. The antiretroviral drugs currently used
are equally active on all HIV-1 subtypes (with the exception of
group O viruses, which are resistant to NNRTIs), although
subtype-related differences in the rate of drug resistance emer-
gence strongly suggest the need for HIV-1 presubtyping to
guide selection of the appropriate therapeutic strategy. The
development of an effective anti-HIV-1 preventive vaccine
with broad efficacy against the vast array of HIV-1 genetic
forms is still a work in progress. However, it is extremely
relevant that vaccines targeted to subtypes other than B are
now being developed, a model which did not have many fans
until a few years ago. This modified attitude, together with the
growing body of information and better technologies, should
accelerate the process of developing vaccines with the desired
broad immunoprotection efficacy. Efforts to meet the unprec-
edented challenge to develop such vaccines, which is perceived
as a difficult-to-achieve goal, may benefit from understanding
the exceptional cross-species transmission of SIV to humans.
In conclusion, continuing studies of HIV-1 molecular phy-
logenetics are necessary to trace the genetic evolution of the
virus and to keep the diagnostic, preventive (vaccine), and
therapeutic tools necessary to control the spread of the global
HIV-1 epidemic up to date.
ACKNOWLEDGMENTS
This study was supported by grants from the Ministero Italiano della
Sanita (Ricerca Corrente and Progetto Finalizzato AIDS 2006) and
the ICSC-World Lab, Lausanne, Switzerland (project MCD-2/7).
We are grateful to Marv Reitz (Institute of Human Virology, Bal-
timore, MD) for his critical reading of the manuscript.
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