HIV Superinfection vs Dual Initial Infection: What Clinicians and Patients Should Know

Julia L. Marcus; J. Jeff McConnell, MA; Robert M. Grant, MD, MPH


June 08, 2005


HIV-1-infected patients and their clinicians have been asking questions about superinfection -- reinfection with a second strain of HIV after the first infection has been established through seroconversion -- since the early years of the HIV/AIDS epidemic: Does superinfection happen? What is the risk of being superinfected? What will happen to me if I become infected with a second virus? Can I acquire drug resistance through superinfection? Although we continue to ask questions about superinfection -- as well as search for a definitive case -- ongoing research has begun to offer some answers.

The first reported evidence of superinfection came from studies of monkeys in 1987.[1] More recent research suggests that there may be a window of time in which nonhuman primates are susceptible to superinfection. Otten and colleagues[2] found that pig-tailed macaques could be successfully reinfected with a second viral strain up to 4 weeks after initial infection. Attempts to reinfect the macaques were unsuccessful at 8, 12, 14, and 72 weeks after infection. The biological mechanisms that block superinfection after 4 weeks in this animal model are not yet known.

A similar pattern suggesting a "window of susceptibility" has been described in superinfection research in humans. Sixteen cases of apparent superinfection in HIV-1-infected persons have been reported, all since 2002. In 15 of these cases, the second virus appeared within the first 3 years of HIV infection.[3,4,5,6,7,8,9,10] In 1 case, the second virus may have appeared after 3 years of infection, but the timing of this event is unknown due to minimal follow-up.[11] See Table 1 for a comprehensive list of reported cases.

In order to definitively distinguish between infection with 2 or more strains at the time of initial infection vs "superinfection" at a point after the initial infection is established, several demanding criteria must be met. Current superinfection research faces several epidemiologic and virologic limitations that call into question the very use of the term "superinfection" to describe what we have seen so far. At this point, there have been no reported cases of superinfection in which a source partner for the second virus was identified. Until a source partner for superinfection is found, and the timing of exposure confirmed, we cannot be absolutely sure that the second virus was acquired after seroconversion; a patient with a dual infection may express the 2 viruses sequentially, thus appearing to be superinfected. Additionally, technical limitations mean that it cannot be virologically proven that the second virus was not present at baseline. In our own study,[10] described in greater detail below, we were unable to detect the divergent virus at baseline using heteroduplex tracking assays (HTA) to detect minor viral variants, but these methods cannot detect minor variants that are present in less than 1.5% to 3.0% of the overall viral population. Many of the other case reports of putative superinfection have not been confirmed using sensitive assays to detect dual infection at baseline. Using HTA, we were also unable to detect the first virus at follow-up even though we assume that it is still present in the body. For these reasons, we prefer to label most "superinfection" cases described thus far as sequentially expressed dual infections (SEDI). Sequential expression of viruses in individuals may reflect sequential acquisition (superinfection) or nearly concomitant dual infection with sequential expression of viruses due to dynamic immune responses.

In our study, we drew a sample of 104 recently infected patients from The Options Project, the San Francisco site for The Acute Infection and Early Disease Research Program (AIEDRP).[10] All patients who remained in the study for at least 6 months and who were untreated at the 6-month visit were included. The last follow-up timepoint with HIV RNA of > 100 copies/mL was selected for comparison to a baseline sample. Superinfection screening involved phylogenetic analysis of protease and reverse transcriptase sequences at baseline and follow-up timepoints using bootstrapped, neighbor-joining trees. After 192 person-years of follow-up, we initially observed 8 cases that appeared to involve the sequential appearance of new viruses over the first few years of infection. However, SEDI could only be confirmed in 4 cases after examination of multiple timepoints. In 3 of these cases, there was evidence of exposure to possible superinfection in the form of self-reported unprotected receptive anal intercourse or treatment for sexually transmitted infections. Using analysis of multiple timepoints and sensitive assays to detect multiple viruses at baseline, we have not been able to rule out superinfection in any of these 4 cases. However, this work is not yet completed. Because source partners are not available to confirm the timing of exposure to the second virus, these cases will not provide definitive proof of superinfection.


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