In the two largest studies of sequences from acutely transmitted virus to date, the proportion of individuals infected by a single genetic variant in comparison to multiple variants did not conform to a Poisson distribution. The authors concluded from this finding that genetic constriction at transmission was not likely due simply to a very low probability stochastic event , but that active processes were required to produce the observed distribution of multiple versus single virus transmissions. If genetic constriction at transmission results from the active selection of specific viral amino acid sequences, early stages in viral transmission and expansion must favor these GANT61 selected sequences for interactions with specific extracellular receptors or intracellular co-factors. In fact, this has been shown to be true, as there is a strong preference for transmission of CCR5 tropic over CXCR4 tropic strains of virus. A likely candidate HIV protein to harbor such signatures would be the viral envelope, the WY 14643 initial contact point between the virus and both target cells and the extracellular milieu. Previous investigation of small sample sizes of early HIV envelopes has failed to detect conclusive commonalities in mutational patterns between transmitted envelopes from different patients , although more recent studies have shown that viruses with shorter loop lengths and few potential N linked glycosylation sites are enriched among transmitted viruses. A comparison of envelope sequences of acutely infected individuals and chronically infected individuals was recently completed based on a much larger sample size. Consensus envelope amino acid sequences from forty-three acutely infected individuals were compared to forty-eight consensus sequences from chronically infected individuals, using previously described phylogenetically controlled methods. A hold out set of comparable size was reserved to validate signatures defined in the original data. Potential signatures were identified at or near the CCR5 coreceptor binding site and the CD4 binding site, as well as at amino acid positions 413�C415, where transmitted viruses exhibited loss of a potential N-linked glycosylation site that has previously been associated with escape from broadly neutralizing antibodies. The amino acid position that showed the most dramatic and statistically significant difference between acute/early and chronic envelopes in both the initial and validation analysis was amino acid position 12 of the envelope glycoprotein. Position 12 is variable; within the B clade as well as most other clades, a histidine is the most common amino acid at this position.