Selection Of Gp120 Protein During Evolution And The Function Of V1 Region

Species-specific strains of simian immunodeficiency virus(SIV) have endemically infected more than 40 species of African nonhuman primates. Multiple cross-species transmissions of SIVcpz from chimpanzees and SIVsmm from sooty mangabeys to humans have resulted in the current epidemics of HIV-1 and HIV-2, respectively. Unlike HIV, SIV infections of natural hosts are typically nonpathogenic, a difference that is believed to be the result of adaptive evolution over thousands of years. In fact, there is evidence to indicate that SIV may have a deep history extending tens of thousands or even millions of years. In contrast, HIV was discovered in the human population less than a century ago, is pathogenic and is evolving quickly.Although a number of studies have examined the evolutionary relationships, origins and genetic diversity of SIV and HIV, the evolutionary patterns, or states, of SIV and HIV remain poorly understood. Given their differences in pathogenicity, prevalence and evolutionary history, HIV and SIV may have different evolutionary patterns. In this study, we built two data sets encompassing the env genes of HIV-1 and closely related SIVs from the LANL HIV sequence database, and investigate the evolutionary mechanisms(selection pressure) underlying variation in SIV and HIV env genes. Our results indicate that SIV has been subjected to less positive selection during its long evolutionary history and is more adaptive to its hosts. While a less adaptive relationship exists between HIV and humans, which may be a result of its relatively short evolutionary time. This indicated that, given enough time, HIV will evolve toward a more adaptive states similar to that of most SIVs.Transmission bottleneck occurs during each HIV transmission event, which allows for only a few viruses to establish new infection, and researchers have been trying to elicit what genetic characters of these transmitted viruses are preferentially selected. And according to the above results, ancient evolutionary patterns exits during the evolution history of SIV and HIV env genes, then we constructed different data sets which comprise closely related HIV and SIV Env sequences. And we first analyzed the amino acids changes of envelope during SIV/HIV deep transmission history. We confirmed that variable region of gp120 protein, especially V1 region was preferentially selected during both the HIV-1/SIV and HIV-2/SIV transmission history. Shorter V1 region was preferred each transmission history we studied. While at the population level, HIV may evolve to expand V1 region gradually to escape immune recognition. We analyzed more available sequences from six subtypes and CRFs which had 15-20 years’ time span. Slight increase(0.5-3.0 amino acids for different subtypes) of V1 length was observed for all the subtypes. Consistent with previous results, this data indicates ongoing genetic drift of V1 region with more amino acids, which was believed to escape from NAb recognition.Given the important role that V1 region may play during transmission and evolution, we next constructed different HIV-1 V1 mutants using different HIV-1 subtypes to elicit its role in envelope function, and we found that V1 region, though highly variable, was indispensable for virus entry and infection in all the subtypes we studied, and further experiments indicated that this is probably because V1 deletion mutants impair the processing of gp160 to mature gp120 and gp41, and influence Env incorporation. These results indicated that V1 region play a critical role in HIV transmission and infection.Our studies first analyzed the positive selection pressure on Env protein of HIV and SIV, which have a clearly transmission history. The results indicate that through a long history of evolution SIV is more adaptive and has suffered less positive selection, while HIV exhibits different evolutionary patterns, with current HIV sequences exhibiting more positive selection than SIV. Then specific changes on gp120 protein was analyzed during the different HIV and SIV transmission history, which indicates that V1 region play a critical role during transmission. Functional studies further confirmed the important role of V1 in transmission and infection, which suggests that V1 region may serve as an attractive target for designing new HIV prevention tools.