HIV/AIDS
INVITED ARTICLE
Kenneth H. Mayer, Section Editor
Human Immunodeficiency Virus Superinfection
and Recombination: Current State of Knowledge
and Potential Clinical Consequences
Jason T. Blackard,1 Daniel E. Cohen,1 and Kenneth H. Mayer2
1
Research and Evaluation Department, Fenway Community Health, Boston, Massachusetts; and 2Miriam Hospital, Brown University, Providence, Rhode Island
Superinfection with multiple strains or subtypes of the human and simian immunodeficiency viruses has been documented.
Recent increases in the prevalences of both unprotected anal intercourse and sexually transmitted diseases among men who
have sex with men indicate that these men continue to practice unsafe sex and, therefore, are at risk for superinfection with
the human immunodeficiency virus (HIV). Recurrent exposure to HIV among seropositive individuals who engage in highrisk behaviors can have serious consequences, because superinfection is a necessary first step for viral recombination to
occur. Recombination may produce more virulent viruses, drug-resistant viruses, or viruses with altered cell tropism. Additionally, recombinant viruses and superinfection can accelerate disease progression and increase the likelihood of sexual
transmission by increasing virus load in the blood and genital tract. The extent of superinfection and recombination in
persons living with HIV is unknown. The implications of HIV superinfection and the generation of recombinant viruses are
discussed.
A hallmark of HIV is its extensive genetic diversity. Heterogeneity in nucleic acid sequences is the result of the error-prone
nature of the viral reverse-transcriptase (RT) enzyme as well
as the high rate of virion production. Although many progeny
viruses may be defective in their replicative abilities, their heterogeneity allows for quick adaptation to the human immune
system, antiretroviral drugs, or both. Thus, heterogeneity may
ultimately lead to increased viral fitness in the face of pharmacologic, immunologic, or other environmental selection
pressures.
HIV can be divided into type 1 (HIV-1) and type 2 (HIV2). Moreover, as a result of its extensive genetic variation, HIV1 can further be divided into groups M (major), O (outlier),
and N (non-M, non-O). Within HIV-1 group M, multiple distinct subtypes and circulating recombinant forms have been
identified. Each HIV-1 subtype has approximately the same
Received 20 November 2001; revised 19 December 2001; electronically published 15 March
2002.
Reprints or correspondence: Dr. Jason T. Blackard, Research and Evaluation Dept., Fenway
Community Health, 16 Haviland St., Boston, MA 02115 ([email protected]).
Clinical Infectious Diseases 2002; 34:1108–14
2002 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2002/3408-0011$03.00
1108 • CID 2002:34 (15 April) • HIV/AIDS
genetic distance from the other subtypes. By definition, viruses
from the same subtype should resemble each other and not
viruses of any other subtype across the entire genome. By use
of this current classification scheme, 9 HIV-1 subtypes (A, B,
C, D, F, G, H, J, and K) have been identified. Intersubtype
variation may approach 30% for envelope gene sequences.
Other HIV genetic loci may be used to determine HIV-1 subtypes, although the degree of variation differs according to the
genomic region analyzed.
Surveillance and monitoring studies have demonstrated that
HIV-1 subtypes are not randomly distributed around the globe.
For instance, subtype B is the predominant HIV-1 subtype in
North America, Western Europe, and Australia, whereas subtype C is the predominant HIV-1 subtype in southern Africa
and India. Currently, subtype C is the most commonly found
HIV-1 subtype worldwide, accounting for 150% of all HIV
infections [1]. Some researchers have suggested that viral variability may partially explain the different epidemic patterns
seen in different regions of the world [2]. The virologic and
clinical consequences of HIV subtype variation have been the
focus of considerable research interest (reviewed in [1]). An
increasing body of evidence suggests that HIV-1 subtypes may
differ with respect to virus load levels [3, 4], disease progression
[5], chemokine coreceptor use [6, 7], vertical transmission rates
[8], and transcriptional activation levels [9, 10]. Similarly, HIV
variation may affect the accuracy of the diagnostic tests and
assays used to quantify HIV (reviewed in [11]). Others have
suggested that HIV subtype is also relevant to clinical management of infection [12] and vaccine design [13].
POTENTIAL IMPLICATIONS
OF HIV RECOMBINATION
Because of its diploid nature, HIV may increase its potential
evolutionary success through recombination. Recombination
may occur when a cell becomes infected with ⭓2 genetically
distinct HIV virions, an event also known as superinfection
(figure 1). During the process of reverse transcription, the viral
RT can switch from one viral RNA template to another, thereby
generating progeny that are mosaics of the parent viruses. The
new recombinant virus thus contains sequences derived from
multiple parental genomes (figure 2). An in vitro study has
demonstrated that recombination between 2 distinct retroviral
strains can occur within 2 weeks of infection [14]. Other in
vitro experiments have demonstrated that HIV-1 undergoes 2–3
recombination events per genome per replication cycle [15].
HIV-1 genomes with mosaic structures are classified as “circulating recombinant forms” if they can be grouped phylogenetically with distinct subtypes in different genomic regions
and if they are identified in ⭓3 individuals with no direct
epidemiologic linkage. For instance, HIV-1 circulating recombinant form 01-AE (previously referred to as “subtype E”) is
the virus subtype predominantly responsible for the HIV epidemic in Southeast Asia. Other circulating recombinant forms
have been identified in Russia, Greece, China, and several African countries [11]. In addition to these circulating recom-
Figure 1.
binant forms, unique recombinant viruses have been described
in many countries with at least 2 circulating HIV-1 subtypes.
Recombination between HIV-1 groups M and O has also been
documented [16], and such strains can even become the predominant virus in an individual’s virus population [17]. To
date, recombination between HIV-1 and HIV-2 has not been
reported, despite their coexistence in several countries in West
Africa. Examples of recombinant simian immunodeficiency viruses do exist [18, 19], suggesting that recombination within
retroviral genomes is a common occurrence, although certain
genetic barriers may exist.
Preliminary data estimate the number of HIV infections due
to recombinant viruses worldwide at 10% [20]. More-recent
population-based studies suggest that recombinant viruses may
account for ⭓20% of all HIV infections in some countries [3].
However, even this figure is likely an underestimate of the true
extent of recombination, because many mosaic viruses may be
overlooked if only a limited portion of the viral genome is
analyzed. As more genetic sequence data are generated, as more
sophisticated population-based sampling of virus isolates is performed, and as more individuals become coinfected with multiple strains of HIV, the overall prevalence of recombinant viruses is likely to increase. The high proportion of cases of HIV
in the world that are attributable to recombinant viruses, in
addition to the high likelihood of recombination events in each
replication cycle demonstrate that this mechanism is an efficient
and rapid method by which HIV can evolve. For instance,
retroviral recombination may allow for the simultaneous introduction of a large number of genetic changes. Such changes
can alter cell tropism, viral pathogenicity, antiretroviral drug
susceptibility, the diagnostic accuracy of current serologic and
molecular biology assays, and disease progression (figure 3).
Recombination is particularly relevant in light of data that sug-
Superinfection of the same cell with 2 genetically distinct strains of HIV is a necessary step for virus recombination to occur
HIV/AIDS • CID 2002:34 (15 April) • 1109
Figure 2. During HIV recombination, the viral reverse transcriptase (RT) enzyme can pass from one virus template to another, creating a new
infectious virion that is a mosaic, or chimera, of the parental virions.
gest that it can lead to multidrug resistance [21, 22] as well as
heightened levels of phenotypic zidovudine resistance via linkage of RT mutations [23].
HIV SUPERINFECTION
The first step for retroviral recombination is the infection of a
cell by 2 genetically distinct viruses, which may be of the same
subtype (producing intrasubtype recombination) or of different
subtypes (producing intersubtype recombination) (figure 1).
Superinfection may result from the simultaneous passage of
multiple viruses during a single transmission event or from the
sequential passage of viruses during multiple transmission
events. The existence of recombinant viruses is de facto evidence that superinfection has occurred. However, the proportion of all HIV infections that can be classified as superinfections within a population over any time interval is unknown.
There are several reasons for this paucity of scientific data.
First, superinfection and recombination presumably do not occur within all individuals living with HIV infection. Second,
superinfection and recombination are most easily identified and
characterized if they involve viruses of different subtypes.
Hence, it is probable that estimating recombinant events on
the basis of the prevalence of intersubtype recombinants significantly underestimates the true frequency of all recombinant
events. Although superinfection with viruses of the same subtype and recombination among viruses belonging to the same
subtype can and do occur, current laboratory methods make
reliable identification of intrasubtype recombinant viruses and
intrasubtype superinfections cumbersome. For instance, phylogenetic analyses may have more difficulty in accurately dis1110 • CID 2002:34 (15 April) • HIV/AIDS
tinguishing among closely related HIV gene sequences than
among distantly related sequences.
Third, most HIV infections in Europe and the Americas, the
areas with the most advanced laboratory techniques and the
greatest financial resources, are due to HIV-1 subtype B [24].
Consequently, intersubtype recombination may be rare in these
regions, and intrasubtype recombination would be difficult to
identify for technical reasons. Despite these limitations, the
global distribution of HIV subtypes is changing with increased
travel and immigration [25], and increased monitoring of HIV
diversity is necessary. Recent studies have identified increasing
numbers of people infected with strains other than HIV-1 subtype B in the United States and other developed countries [26,
27]. Unfortunately, the biological consequences of recombination and superinfection have not been fully elucidated. To
date, no studies have definitively determined how naturally
occurring recombinant viruses affect important viral phenotypes, such as cell tropism, drug resistance, replication kinetics,
and disease progression. Furthermore, viral fitness is likely the
result of multiple overlapping viral genomic loci and host genetic factors that have yet to be fully elucidated.
Laboratory and animal studies of superinfection. In vitro
studies first documented that superinfection with multiple
strains of HIV could occur [28]. These experiments showed
that chronically infected cells could be superinfected with another HIV strain and that the magnitude of superinfection
increases with time [29]. Subsequently, Gratton et al. [30] demonstrated that, despite a low overall frequency of HIV-infected
cells in the lymphoid tissue of persons living with HIV infection,
cells that were HIV positive were often multiply infected. The
authors estimated that 6%–18% of the viruses within multiply
Figure 3. Recombination between 2 HIV virions with differing drug resistance profiles can generate a new infectious recombinant virus resistant
to both drugs.
infected cells were recombinant strains. Superinfection with
multiple strains of HIV has also been documented in animals
[31, 32]. Interestingly, one of these studies suggested that there
is a finite period of susceptibility during which superinfection
can occur [32], whereas the other documented superinfection
and the generation of recombinant viruses in an infected chimpanzee reexposed to HIV 15 months after the initial infection
[31]. In addition, animals protected from superinfection lived
longer than did those susceptible to superinfection [32]. These
data, if found to hold true in humans as well, suggest that
persons living with HIV infection who subsequently become
superinfected with HIV may progress to disease more rapidly
than do individuals who do not become superinfected.
Although these in vitro and animal studies are interesting
and suggest that superinfection may have important clinical
ramifications, they do not provide absolute proof that superinfection commonly occurs naturally in humans or that it affects the course of HIV infection. Recently, a dual infectioncompetition assay has been used to examine viral fitness in
relation to disease progression [33]. It may prove to be a useful
laboratory technique for addressing the biologic consequences
of superinfection.
HIV superinfection in vivo. Superinfection can be documented by finding evidence of ⭓2 distinct HIV genetic sequences within the same person. The superinfecting viruses, in
theory, could belong to distinct types, groupings, or subtypes
of HIV, or could even belong to the same HIV subtype. Several
studies have documented dual infections with HIV-1 and HIV2 [34, 35]. In dually infected individuals, the influences of HIV-
1 and HIV-2 on one another and on the host have not been
fully established. For instance, it is unclear how plasma HIV1 levels are affected by concomitant HIV-2 infection [36, 37].
Although HIV-2 may partially protect against subsequent HIV1 infection [38], this protection is not absolute. The exact mechanisms of this protection are unclear, although HIV-2–mediated
interference in HIV-1 replication has been suggested as a mechanism [39]. These data suggest that, although superinfection is
possible, the superinfection of a person with a second strain
of HIV may be influenced by the presence of the first strain
of HIV. Additionally, the extent to which HIV-specific immunity in previously infected individuals may or may not protect against superinfection is not known.
At least 1 study has documented human HIV superinfection
[40] and recombination [16] involving both group M and
group O viruses. Evidence of coinfection with viruses belonging
to different HIV-1 subtypes has been reported from several
countries, including Uganda [41], Brazil [42], Spain [43], Kenya [44], and Denmark [45], where multiple HIV subtypes are
known to be circulating. Cases of superinfection with HIV
isolates of the same subtype have been reported as well [46–50].
Zhu et al. [48] demonstrated multiple strains of HIV in the
blood of a patient who recently seroconverted, in whom recombinant viruses were also found. It is unclear from this
particular case whether the presence of multiple, distinct HIV
strains was due to superinfection with a second strain of HIV
after the initial infection, or whether simultaneous infection
with multiple strains of HIV occurred during a single transmission event. A similar report by Diaz et al. [49] described
HIV/AIDS • CID 2002:34 (15 April) • 1111
HIV-1 superinfection in a transfusion recipient exposed to 2
different HIV-1–seropositive donors. The presence, in the recipient, of 2 distinct virus populations that were each closely
related to distinct transfusion donors established this as a definitive case of HIV-1 superinfection. Recombination between
these 2 virus populations also occurred.
To our knowledge, no studies addressing the prevalence of
superinfection in HIV-infected populations have been published, to date. From the limited number of case histories described in the literature, it is difficult to draw conclusions about
the implications of superinfection with regard to virus load
levels during infection, replication kinetics, antiretroviral drug
susceptibility, and disease progression. A case report has suggested that HIV superinfection may favor viral synergism [51].
An injection drug user was dually infected with 2 genetically
and phenotypically distinct strains of HIV-1 subtype B. Sequencing of multiple gp120 clones from uncultured peripheral
blood mononuclear cells (PBMC) showed the predominance
of group 2 viruses in vivo. However, group 2 viruses alone
could not productively infect PBMC. Only addition of group
1 viruses (i.e., superinfection) caused high replication of group
2 viruses in cultured PBMC. The authors concluded that these
data provide direct evidence in favor of superinfection and
subsequent recombinant events likely to have altered growth
kinetics.
RECENT BEHAVIORAL TRENDS:
IMPLICATIONS FOR HIV SUPERINFECTION
AND RECOMBINATION
Intense prevention and education efforts have been designed
to keep at-risk individuals from acquiring HIV infection, but
not enough attention has been paid to ongoing risk-taking by
individuals who are already infected. Unfortunately, growing
evidence suggests that unprotected intercourse continues to
occur at high rates among both HIV-seropositive [52, 53] and
HIV-seronegative people in the developed world, particularly
among men who have sex with men [54, 55]. Moreover, reports
from several large cities of increases in the prevalences of sexually transmitted diseases raise concerns that a resurgence in
the incidence of HIV infection may be on the horizon. This
increase in risk-taking behavior may be due, in part, to the
decrease in the number of AIDS cases and AIDS-related deaths
[56, 57] during the past 5 years, as well as people’s confidence
that new HIV treatments are highly effective, which may have
decreased some individuals’ concerns regarding HIV transmission. Many persons living with HIV infection may no longer
perceive a significant risk associated with unprotected anal intercourse once they have had HIV infection diagnosed. Although the implications of continued unprotected sexual intercourse between seroconcordant HIV-infected partners have
1112 • CID 2002:34 (15 April) • HIV/AIDS
not been explored, these reports of greater risk-taking and increased prevalences of sexually transmitted diseases among infected and at-risk individuals suggest that the prevalence of
recombinant HIV and superinfection is likely to increase and
alter the natural history of chronic HIV infection.
FUTURE RESEARCH INITIATIVES
Because no studies have investigated HIV superinfection at the
population level, the consequences of superinfection remain
unclear. Several critical questions remain to be answered: (1)
What is the frequency of superinfection in persons living with
HIV? (2) Is superinfection associated more frequently with a
particular mode of transmission or risk group? (3) What are
the long-term consequences of superinfection with regard to
disease progression? An interesting case report does indeed suggest that superinfection may be associated with accelerated disease progression [58]. The subject described in this report had
a nonprogressive HIV infection and undetectable viremia for
18 years before he initiated a sexual relationship with a man
who had advanced HIV disease and an extensive antiretroviral
treatment history. Soon after beginning the relationship, the
subject’s virus load increased and his CD4 T cell count declined,
suggesting that superinfection with a genetically distinct strain
of HIV may have occurred and may have altered disease progression. The accelerated course of disease after superinfection
may have been due to new infection with a more virulent HIV
strain or to lack of immunologic recognition of the new infecting strain. Other consequences of superinfection may be
the generation of recombinant viruses that have increased resistance to antiretroviral drugs [21] or alterations in cell tropism
or pathogenic potential.
Although the consequences of viral recombination for persons living with HIV have not been resolved, an increasing
number of individuals who have recently seroconverted have
become infected with drug-resistant viruses [59, 60], and sexual
transmission of multiple-drug–resistant virus has been documented [61]. There are few data regarding the natural history
of HIV infection in individuals who harbor multiple distinct
forms of HIV or recombinant viruses. Of particular concern
are couples in which both partners are living with HIV infection. To date, there are no data to suggest that seroconcordant
couples should be counseled to use barrier protection to protect
against HIV superinfection per se, although theoretical concerns about the transmission of other sexually transmitted viruses (e.g., cytomegalovirus, herpes simplex virus, and human
herpesvirus type 8) are salient.
We hypothesize that superinfection or recombination within
treatment-experienced seroconcordant couples could have serious consequences for subsequent treatment, particularly if the
strain infecting one partner is drug susceptible, but the strain
infecting the other is drug resistant. This situation sets up a
scenario in which a drug-resistant virus or a more-fit virus
from one partner may cause superinfection in the other, thereby
limiting future treatment options or leading to accelerated disease progression. Several prospective surveillance studies are
under way to evaluate the likelihood of the occurrence of these
events among seroconcordant HIV-infected sexual partners.
CONCLUSIONS
Key areas of research with regard to HIV superinfection remain
to be investigated. These include the following: (1) determination of the effectiveness of the immune response induced by
initial infection with HIV in conferring protection against subsequent superinfection; (2) assessment of the biologic consequences of superinfection and recombination for viral fitness,
drug resistance, virus transmissibility, and natural history and
progression of disease; (3) further monitoring of viral diversity
and development of more-sophisticated techniques for assessing superinfection; and (4) assessment of the relevance of superinfection and recombination to future vaccine design and
development, diagnostic testing, antiretroviral drug susceptibility, and virus load measurement.
It is likely that virus superinfection and recombination will
become increasingly common as more people become infected
with HIV but live longer as a result of more effective treatments.
These phenomena have the potential to significantly affect the
HIV pandemic in the future. It is now the responsibility of the
scientific community to respond by developing sound laboratory-based studies and behavioral interventions that will afford us a better understanding of the clinical significance of
superinfection and recombination.
7.
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Acknowledgments
We thank the dedicated staff of Fenway Community Health
and the countless volunteers who made our work over the years
possible. We thank Matt Iwanowicz for editorial assistance.
22.
23.
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