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Human Immunodeficiency Virus Superinfection and Recombination: Current State of Knowledge and Potential Clinical Consequences

  1. Jason T. Blackard1⇓,
  2. Daniel E. Cohen1, and
  3. Kenneth H. Mayer2
  1. 1Research and Evaluation Department, Fenway Community Health, Boston, Massachusetts
  2. 2Miriam Hospital, Brown University, Providence, Rhode Island
  1. Reprints or correspondence: Dr. Jason T. Blackard, Research and Evaluation Dept., Fenway Community Health, 16 Haviland St., Boston, MA 02115 (jblackard{at}fenwayhealth.org).
 
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Abstract

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 high-risk 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 (HIV-2). Moreover, as a result of its extensive genetic variation, HIV-1 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 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 >50% 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].

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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].

Figure 1
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Figure 1

Superinfection of the same cell with 2 genetically distinct strains of HIV is a necessary step for virus recombination to occur

Figure 2
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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.

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 recombinant 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 suggest that it can lead to multidrug resistance [21, 22] as well as heightened levels of phenotypic zidovudine resistance via linkage of RT mutations [23].

Figure 3
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Figure 3

Recombination between 2 HIV virions with differing drug resistance profiles can generate a new infectious recombinant virus resistant to both drugs.

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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 distinguishing 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 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 infection-competition 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 HIV-2 [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 HIV-1 levels are affected by concomitant HIV-2 infection [36, 37]. Although HIV-2 may partially protect against subsequent HIV-1 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-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.

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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 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.

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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 >8 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.

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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.

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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.

  • Received November 20, 2001.
  • Revision received December 19, 2001.
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  1. Clin Infect Dis. (2002) 34 (8): 1108-1114. doi: 10.1086/339547
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