Analyses of inter- and intra-patient variation in the V3 loop of the HIV-1 envelope protein

The third hypervariable domain of the HIV-1 gp120 envelope protein (V3) has been the focus of intensive sequencing efforts. To date, nearly one thousand V3 loop sequences have been stored in the HIV sequence database. Studies have revealed that the V3 loop elicits potent type-specific immune responses, and that it plays a significant role in cell tropism and fusion . The immunogenic tip of the loop can serve as a type-specific neutralizing antibody epitope, as well as a cytotoxic T-cell epitope. A helper T-cell epitope that lies within the amino terminal half of the V3 loop has also been characterized. Despite the richness of the immunologic response to this region, its potential for variation makes it an elusive target for vaccine design. Analyses of sibling sequence sets (sets of viral sequences derived from one person) show that multiple forms of the immunogenic tip of the loop are found within most HIV-1 infected individuals. Viral V3 sequences obtained from epidemiologically unlinked individuals from North America and Europe show extensive variation. However, some amino acid positions distributed throughout the V3 loop are highly conserved, and there is also conservation of the charge class of amino acid able to occupy certain positions relative to the tip of the loop. By contrast, the sequences obtained from many countries throughout the African continent reveal that V3 is a remarkably fluid region with few absolute constraints on the nature of the amino acids that can occupy most positions in the loop. The high degree of heterogeneity in this region is particularly striking in view of its contribution to biologically important viral functions

jpHMM: Improving the reliability of recombination prediction in HIV-1

Previously, we developed jumping profile hidden Markov model (jpHMM), a new method to detect recombinations in HIV-1 genomes. The jpHMM predicts recombination breakpoints in a query sequence and assigns to each position of the sequence one of the major HIV-1 subtypes. Since incorrect subtype assignment or recombination prediction may lead to wrong conclusions in epidemiological or vaccine research, information about the reliability of the predicted parental subtypes and breakpoint positions is valuable. For this reason, we extended the output of jpHMM to include such information in terms of ‘uncertainty’ regions in the recombination prediction and an interval estimate of the breakpoint. Both types of information are computed based on the posterior probabilities of the subtypes at each query sequence position. Our results show that this extension strongly improves the reliability of the jpHMM recombination prediction. The jpHMM is available online at http://jphmm.gobics.de/

HIV Types, Groups, Subtypes and Recombinant Forms: Errors in Replication, Selection Pressure and Quasispecies

HIV-1 is a chimpanzee virus which was transmitted to humans by several zoonotic events resulting in infection with HIV-1 groups M P, and in parallel transmission events from sooty mangabey monkey viruses leading to infections with HIV-2 groups A H. Both viruses have circulated in the human population for about 80 years. In the infected patient, HIV mutates, and by elimination of some of the viruses by the action of the immune system individual quasispecies are formed. Along with the selection of the fittest viruses, mutation and recombination after superinfection with HIV from different groups or subtypes have resulted in the diversity of their patterns of geographic distribution. Despite the high variability observed, some essential parts of the HIV genome are highly conserved. Viral diversity is further facilitated in some parts of the HIV genome by drug selection pressure and may also be enhanced by different genetic factors, including HLA in patients from different regions of the world. Viral and human genetic factors influence pathogenesis. Viral genetic factors are proteins such as Tat, Vif and Rev. Human genetic factors associated with a better clinical outcome are proteins such as APOBEC, langerin, tetherin and chemokine receptor 5 (CCR5) and HLA B27, B57, DRB1{*}1303, KIR and PARD3B. Copyright (C) 2012 S. Karger AG, Base

Genital Tract Sequestration of SIV following Acute Infection

We characterized the evolution of simian immunodeficiency virus (SIV) in the male genital tract by examining blood- and semen-associated virus from experimentally and sham vaccinated rhesus monkeys during primary infection. At the time of peak virus replication, SIV sequences were intermixed between the blood and semen supporting a scenario of high-level virus "spillover" into the male genital tract. However, at the time of virus set point, compartmentalization was apparent in 4 of 7 evaluated monkeys, likely as a consequence of restricted virus gene flow between anatomic compartments after the resolution of primary viremia. These findings suggest that SIV replication in the male genital tract evolves to compartmentalization after peak viremia resolves