The findings in the SHIV and SIV studies summarized here are the first clear demonstration that there is selection, or exclusion, of specific genotypes during vaginal transmission. Previous studies demonstrated that a limited number of genotypes, as characterized by the nucleotide sequence in specific regions of the envelope gene, are found in humans recently infected with HIV-1. In one study, it was shown that two individuals, infected by heterosexual contact, had viral variants with a gp120 sequence that was found in only a minor fraction of the proviral population in the blood of the transmitter.2
A more recent study by the same group characterized viral variants in a single transmitter–recipient heterosexual pair and concluded that whereas the V3 loop sequences in the major variant of the donor and recipient were similarly, the sequence of the V1–V2 env sequences in the recipient were found only in a minor variant of the donor.9
The authors speculate that this was because these variants had a selective advantage in penetrating the mucosal barrier during sexual contact. A study involving a relatively large number of acute seroconverters found that, when the nucleotide sequences of viruses in each individual were compared, there was little sequence heterogeneity in two normally hyper-variable regions of the env
However, this result was not limited to individuals that had been infected by sexual contact but was also found in individuals infected parenterally.1
This finding does not support the hypothesis that viruses with certain envelope nucleotide sequences are transmitted by sexual contact because they can more efficiently penetrate the vaginal mucosa, but rather supports the idea that only a limited number of the viral genetic variants in a donor have the fitness to initiate an infection in a naive recipient, regardless of the route of transmission. Interestingly, in these studies the sequence homogeneity of the envelope did not extend to the gag
Thus the acute seroconverters were apparently infected with multiple virus variants that were homogeneous in envelope nucleotide sequence but heterogeneous in gag
With regard to preferential sexual transmission of viruses with a particular phenotype, numerous studies have demonstrated that individuals acutely infected with HIV-1 have a viral variant that can grow in primary macrophages but not in T cell lines and does not cause syncytia in MT-2 cells. It has been widely presumed that these viral variants with a macrophage-tropic/non-syncytium-inducing (NSI) viral phenotype are selectively transmitted by sexual contact. This notion has been championed to explain the finding of limited genetic heterogeneity of HIV envelope in individuals infected by sexual contact. Thus a virus with a envelope sequence that allows it to replicate in macrophages would be more likely to be transmitted by sexual contact because the virus could infect the most likely target cells in the genital mucosa. However, as with envelope nucleotide homogeneity, this apparent restriction of viral phenotype in acutely infected people occurs regardless of the route of transmission. In addition, one study of a relatively large number of acute seroconverters infected by sexual contact found that the virus that was transmitted to the donor had the same phenotype as the major viral variant in the donor.10
In this study, all of the HIV-1 isolates from 21 individuals with primary HIV-1 infection replicated in monocyte-derived macrophage cultures. Seven of these isolates also replicated in T cell lines and were thus dual tropic. Studies on 10 pairs of individuals consisting of the index case and seroconverting sexual partner showed that, when the viral phenoypes in the two individuals forming a transmission pair were compared, the phenotype of the HIV-1 was the same in both individuals in 9 of the 10 transmission pairs. Further, both of the individuals in five of the pairs were infected with a syncytium-inducing (SI) variant. Thus, this study found that there was no selection for macrophage-tropic/NSI viruses during sexual transmission.10
As the authors of this study10
point out, there are a number of case reports and smaller studies in which index cases with T cell-tropic/SI variants infected a sexual partner.2,11–14
In approximately half of these transmission events, the seroconverting partner became infected with a T cell-tropic/SI variant.
The significance of macrophage-tropic versus T cell-tropic HIV-1 phenotypes has been called into question. In a carefully controlled in vitro
study, six of eight macrophage-tropic HIV-1 isolates or clones were able to infect one or more T cell lines productively, producing high titers of viral p24 antigen and infectious progeny virus.14
This demonstrates that most “macrophage-tropic” HIV isolates are actually dual tropic. It has long been recognized that essentially all “macrophage-tropic” HIV-isolates replicate in primary T cells. The differences in the results of the studies reported above may have resulted from differences in culture techniques, but there also have been differences in the way the same results have been interpreted by different groups. Fundamentally, it is difficult, perhaps impossible, to extend any in vitro
finding to the in vivo
situation. When all the published data are reviewed, it seems clear that there is no restriction on the sexual transmission of HIV-1 variants that can replicate in T cell lines but not macrophages in vitro
. The results of the in vivo
SIV and SHIV studies described here support that conclusion.
We have demonstrated that only some viral genotypes can produce a systemic infection after vaginal inoculation. This supports the conclusion that there is selection for viral genotypes during sexual transmission of HIV. However, the common phenotype, if any, of the selected genotypes is not apparent from in vitro studies of viral phenotype. We did find that all the viruses that were capable of transmission by vaginal inoculation had a common in vivo phenotype. After intravenous inoculation of rhesus macaques, all the transmitting viruses produced plasma antigenemia and high levels of plasma viral RNA. In contrast, although the nontransmitting viruses infect rhesus macaques after intravenous inoculation, the infection that occurs after intravenous inoculation is characterized by a lack of viral antigen in plasma and the low levels of plasma viral RNA. On the basis of these results, it is likely that viruses that are adapted to replicate to high levels in vivo are capable of being transmitted by vaginal inoculation. This principle may also apply to the transmission of HIV in humans.