Identifying HIV-1 dual infections

Abstract

Transmission of human immunodeficiency virus (HIV) is no exception to the phenomenon that a second, productive infection with another strain of the same virus is feasible. Experiments with RNA viruses have suggested that both coinfections (simultaneous infection with two strains of a virus) and superinfections (second infection after a specific immune response to the first infecting strain has developed) can result in increased fitness of the viral population. Concerns about dual infections with HIV are increasing. First, the frequent detection of superinfections seems to indicate that it will be difficult to develop a prophylactic vaccine. Second, HIV-1 superinfections have been associated with accelerated disease progression, although this is not true for all persons. In fact, superinfections have even been detected in persons controlling their HIV infections without antiretroviral therapy. Third, dual infections can give rise to recombinant viruses, which are increasingly found in the HIV-1 epidemic. Recombinants could have increased fitness over the parental strains, as in vitro models suggest, and could exhibit increased pathogenicity. Multiple drug resistant (MDR) strains could recombine to produce a pan-resistant, transmittable virus. We will describe in this review what is presently known about super- and re-infection among ambient viral infections, as well as the first cases of HIV-1 superinfection, including HIV-1 triple infections. The clinical implications, the impact of the immune system, and the effect of anti-retroviral therapy will be covered, as will as the timing of HIV superinfection. The methods used to detect HIV-1 dual infections will be discussed in detail. To increase the likelihood of detecting a dual HIV-1 infection, pre-selection of patients can be done by serotyping, heteroduplex mobility assays (HMA), counting the degenerate base codes in the HIV-1 genotyping sequence, or surveying unexpected increases in the viral load during follow-up. The actual demonstration of dual infections involves a great deal of additional research to completely characterize the patient's viral quasispecies. The identification of a source partner would of course confirm the authenticity of the second infection.

Figure 1

HIV-1 plasma viral load at different clinical stages. HIV infection is characterized by an acute phase with a high viral load, which decreases as specific immunity develops (solid line). After seroconversion (SC), the chronic phase of the infection starts, lasting several years. The chronic phase of the infection is traditionally followed by the AIDS phase, but is now increasingly replaced by the start of antiretroviral therapy (ART) in many parts of the world. An HIV-1 dual infection during the acute phase is called a co-infection, after seroconversion it is referred to as a superinfection. HIV-1 superinfections often result in an increase, sometimes temporary, of the viral load (dotted line) and an earlier start of therapy. HIV-1 superinfections in most cases are found close to the acute infection, and only rarely occur later than a few years after primary infection.

Figure 2

Degenerate base counts in the RT sequence of in a triple HIV-1 infected patient. The HIV-1 plasma viral load of an individual twice superinfected with HIV-1 is shown here to illustrate the importance of sampling time when assessing HIV-1 dual infections. The patient was infected with two different subtype B strains (indicated in yellow and red), and with CRF01_AE (blue) [24]. Degenerate base counts in the genotyping RT sequence of this patient vary from 0 at the time of the second superinfection, till 85 in the chronic phase of infection with three viral strains.