Lentiviral dual infection occurs with simian immunodeficiency virus (SIV) and HIV-2 in macaques, HIV-1 in chimpanzees, and feline immunodeficiency virus in cats,1-5 suggesting that HIV-1 dual infection should not be unexpected in humans. The best circumstantial evidence for HIV dual infection is that 10% of HIV infections worldwide involve recombinant viruses.6 Ramos et al reported the first confirmed case of HIV dual infection in humans in 2002.7 There has also been one report of HIV triple infection,8 and a report of infection with HIV-2.9 The initial reports involved people who were dually infected with a virus from a clade different from their initial infecting virus (interclade).7, 10 Because HIV-1 clades can be differentiated genetically, interclade superinfections can be readily detected by molecular methods; immune responses to the initial infection might be less likely to protect against such a divergent superinfecting virus. Subsequently, however, superinfection with the same clade (intraclade) was reported by my group and others.11, 12
|What is the Difference Between HIV Coinfection and Superinfection? ||Top of page|
Similar to other persistent viral infections, such as cytomegalovirus, Epstein-Barr virus, and hepatitis C virus, infection of an individual with a second viral strain (dual infection)13-15 may also occur in HIV infection. Dual infection, which can be classified as either coinfection or superinfection, occurs when an individual is infected with strains derived from two different individuals.
Dual infection can be classified as either coinfection or superinfection:
- Coinfection is infection with two separate strains either simultaneously or within a brief period of time before infection with the first strain is established.
- Superinfection is sequential infection with a heterologous strain after an immune response has been established to the initial strain.16 The term "superinfection" does not mean that the second infection is stronger or more virulent; it is meant to distinguish dual infection from instances of re-infection after the first virus has cleared, as occurs with most respiratory viruses,17 but not with HIV.
The first investigators of chronically infected individuals were unable to detect HIV superinfection in more than 107218 and 21519 person-years of observation, but these were retrospective studies of cohorts of individuals, most of whom were receiving antiretroviral therapy. Early reports of superinfection occurred in the setting of primary infection.7, 8, 20-25 Our group evaluated the incidence of HIV-1 superinfection in a small cohort of individuals with primary infection and found a rate of 5% per year.23 A study in the Swiss HIV Cohort found a similar rate among individuals with primary HIV infection.24
More recently, HIV superinfection has been documented during chronic infection,26-29 so the hypothesis that a patient’s susceptibility to superinfection is limited to the window-period of primary infection may have been biased by the fact that the primary HIV infection cohorts have been more extensively investigated relative to the genetic evolution of HIV16 than have those with chronic infection. Therefore, the rate of dual infection among chronically infected individuals remains largely unknown.
Because the clinical consequences of superinfection are weakly characterized, there have been frequent debates concerning how to best counsel patients already infected with HIV about ongoing safer sex and injection drug use practices.16, 30-32 Most reported cases of dual infection have shown a decrease in CD4+ counts, an increase in viral load, and a change in drug resistance pattern.10, 11, 21, 22, 27, 33-35 My group at UCSD described an ominous instance of superinfection in which the person was initially infected by a drug-sensitive or wild-type strain of HIV-1 and then superinfected by a drug-resistant strain—a phenomenon the UCSD group referred to as DRATS: drug resistance acquired through superinfection.34 This evidence supports the notion that superinfection increases disease progression. However, it is unclear whether or not all superinfections do so.36 Perhaps previous instances of superinfection were identified because the superinfecting virus emerged as the predominant strain, induced a change in disease status, or changed the genotypic resistance pattern.16, 37 Future studies are needed to identify instances of superinfection in which the second virus does not become the predominant strain. These studies, which make use of next generation sequencing38 or heteroduplex mobility assays,39 may help to clarify how and how often HIV-1 dual infection (both co- and super-infection) influences disease progression.
Once the risks of superinfection are better delineated, HIV-infected individuals will be better able to make informed decisions about the risks associated with superinfection exposures with other HIV-infected individuals, although it seems that risk reduction after HIV seroconversion has been associated with a decrease in incidence of superinfection in the Netherlands.40
|How Has HIV Dual Infection Shaped the Global Epidemic?||Top of page|
The genetic diversity of HIV worldwide is considerable41 and is a potential problem in the development of a preventive vaccine.42-44 A large part of this diversity occurs because HIV can undergo recombination (Figure 1), which can only occur when two distinct viral variants infect the same cell.6, 29, 30, 41, 45-48
|Figure 1. HIV-1 Dual-Infection and Recombination Model
A single cell is infected sequentially or simultaneously by two different viruses establishing two integrated proviruses.
Some newly formed virus particles contain one strand of RNA from each provirus and infect new cells.
During reverse transcription, viral Reverse Transcriptase (RT) switches back and forth between the two different RNA strands to synthesize proviral DNA containing genetic information from each of the superinfecting viruses.
Virus from these newly infected cells are genetic hybrids related to each of the initial superinfecting viruses. The hybrid virus can spread by infecting new cells and may escape drug or immune suppression.
|Images and virus models created by Louis E. Henderson, Ph.D.|
There are more than 16 "circulating recombinant forms" (CRFs) of HIV-1 worldwide, and many more "unique recombinant forms." 6, 49-51 Recent molecular epidemiology studies have identified that CRFs are responsible for 18% of infections worldwide,52 and mathematical models have demonstrated that HIV-1 superinfection could account for the prevalence of CRFs worldwide.53 This is substantial evidence that dual infection is not a rare event.16
While HIV superinfection may not precisely reflect initial infection after vaccination, perhaps developers of HIV vaccines should consider instances in which the immune response to the initial infection was unable to protect against the second viral challenge.16, 44, 54 Specifically, a better understanding of the roles of cytotoxic T-cell and neutralizing-antibody responses in controlling or preventing secondary infections or superinfections could help in the design of therapeutic and preventive vaccines.55, 56
Initial investigations into the cytotoxic T-cell responses before and after HIV superinfection found that the individual’s immune response had good control of the initial virus, with low viral loads and high CD4+ counts. However, after superinfection, there was a poor cytotoxic response to the superinfecting virus, and an associated rise in viral load, and decrease in CD4+ counts.7, 12, 57 In these cases, the superinfecting virus did not share apparently important epitopes with the first virus, which could explain how the superinfecting virus became the predominant strain. These data may not support the development of a vaccine based on cytotoxic T-cell responses, and may explain why Merck’s V520 HIV vaccine did not offer substantial protection.58 On the other hand, initial case control investigations into neutralizing antibodies among small cohorts of highly exposed individuals found that those with higher levels of cross-reactive neutralizing antibodies did not become superinfected, while individuals with low levels of neutralizing antibodies did.59 Although these observations were not replicated among individuals superinfected by HIV-1 clades that were different than their initial infection.54 Further studies are required in larger prospective cohorts to delineate the true role of neutralizing antibody in protection against superinfection, and how cross-reactive this neutralizing antibody response must be to offer a realistic level of protection against an initially infecting strain, as in the setting of a preventive vaccine, or against a superinfecting strain. This may be extremely difficult considering the genetic diversity of HIV-1 worldwide.42
A growing body of data suggests that HIV-1 superinfection happens and that it may happen rather frequently; this situation offers challenges for vaccine development. Additional data suggest that HIV superinfection has identifiable clinical consequences, requiring innovative treatment and prevention strategies for our patients who already have HIV and are at continued risk of superinfection. Further research is needed to better understand these aspects of HIV superinfection.
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