Recent case reports of human immunodeficiency virus type 1 (HIV-1) superinfection demonstrate that an established infection does not confer complete protection against reinfection with a divergent strain (3
Lentivirus superinfection experiments with nonhuman primate systems using intravenous challenges with high-viral-titer inoculums have shown variable results. One of two chimpanzees could be superinfected with another strain of the same HIV-1 subtype (20
). Superinfection with a heterologous HIV-2 strain was restricted to the first 2 months postinfection in pig-tailed macaques (54
). Six of seven baboons infected with HIV-2 resisted superinfection with heterologous HIV-2 strains (42
), while four coculture-negative HIV-2-infected rhesus macaques could be superinfected with pathogenic simian immunodeficiency virus (SIV) strain SIVmac251 and became persistently viremic (57
). Attenuated strains of SIV could protect rhesus macaque against superinfection (10
), but such protection decreased with more-attenuated vaccine strains (27
) and more-divergent and -pathogenic SIV challenge strains (57
). One of two (57
) and three of three (60
) cynomologous macaques infected with HIV-2 could be superinfected with pathogenic SIVsm but showed reduced rates of disease progression.
The ability of an established lentivirus infection and associated immune responses to protect against superinfection may depend in part on the degree of sequence divergence between the two viruses and the state of immunocompetence of the host. The greater the degree of divergence between the resident and the challenge strains the less the immune responses to the first virus may recognize a later challenge strain. Within the HIV-1 family a wide range of sequence divergence exists. Strains within a single subtype of group M HIV-1 can vary by up to 20% in envelope amino acid sequence, while different group M subtypes vary by up to 35% (21
). Even greater divergence between the different HIV-1 groups (M, N, and O) and between HIV-1 and HIV-2 is seen. In humans, prior infection with HIV-2 does not appear to protect against subsequent infection with HIV-1 (82
). An individual infected with both group M and group O HIV-1 viruses was identified (71
), although it is not known whether the infections were nearly simultaneous or sequential. Indirect evidence for infections with more then one subtype of HIV-1 group M viruses is seen in the large number of distinct intersubtype recombinants, each with a presumably independent origin (8
), and in numerous cases of dual-subtype infections (4
). It is not known with what time intervals such dual infections are acquired.
The ability of HIV-1 to infect seropositive hosts previously infected with different subtypes of group M HIV-1 has been recently reported for two injection drug users (IDUs) and a homosexual man (28
). The two IDUs were untreated and became superinfected with a different HIV-1 subtype 3 to 11 months after their initial infections (61
). The homosexual man was successfully treated for a period of over 2 years with a regimen of highly active antiretroviral therapy (HAART) initiated during primary infection. He became infected with a different subtype of HIV-1 3 to 4 months after discontinuing HAART (28
). These three cases indicate that any protection against HIV superinfection that may have been provided by a preexisting infection was only partial when the challenge strains belonged to a different HIV-1 group M subtype.
Two cases of superinfection with a virus belonging to the same HIV-1 subtype have been reported (3
). A patient who had initiated effective HAART treatment at the time of acute infection was superinfected while undergoing structured treatment interruption, followed by rapidly rising viremia (3
). In the second case an untreated subject infected with a drug-resistant strain was superinfected with a wild-type strain within 4 months of infection (31
). No other cases of same-subtype superinfection have been reported among the numerous longitudinal sequence analysis studies of HIV-1 (15
), although it is conceivable that prior cases were dismissed as PCR contamination (38
). Cases of same-subtype coinfection involving strains from different sources have been reported, but such coinfections occurred either simultaneously (18
), nearly simultaneously (41
), or at unknown intervals (64
As only two clear cases of same-subtype HIV-1 superinfection have been reported to date, it remains possible that some level of protection against superinfection is provided by an established infection. To measure the frequency of same-subtype superinfection in a highly exposed and largely untreated population, we phylogenetically analyzed HIV-1 sequences in longitudinally collected serum from 37 street-recruited active IDUs.