S. Gnanakaran 1 , Tanmoy Bhattacharya 1 , 2 , Marcus Daniels 1 , Brandon F. Keele 3 , 4 , Peter T. Hraber 1 , Alan S. Lapedes 1 , Tongye Shen 1 , 5 , Brian Gaschen 1 , Mohan Krishnamoorthy 1 , Hui Li 4 , Julie M. Decker 4 , Jesus F. Salazar-Gonzalez 4 , Shuyi Wang 4 , Chunlai Jiang 6 , 7 , Feng Gao 7 , Ronald Swanstrom 8 , Jeffrey A. Anderson 8 , Li-Hua Ping 8 , Myron S. Cohen 8 , Martin Markowitz 9 , Paul A. Goepfert 4 , Michael S. Saag 4 , Joseph J. Eron 8 , Charles B. Hicks 7 , William A. Blattner 10 , Georgia D. Tomaras 7 , Mohammed Asmal 11 , Norman L. Letvin 11 , 12 , Peter B. Gilbert 13 , Allan C. DeCamp 13 , Craig A. Magaret 13 , William R. Schief 14 , Yih-En Andrew Ban 14 , 15 , Ming Zhang 1 , 16 , Kelly A. Soderberg 7 , Joseph G. Sodroski 17 , Barton F. Haynes 7 , George M. Shaw 4 , Beatrice H. Hahn 4 , Bette Korber 1 , 2 , *
29 September 2011
Here we have identified HIV-1 B clade Envelope (Env) amino acid signatures from early in infection that may be favored at transmission, as well as patterns of recurrent mutation in chronic infection that may reflect common pathways of immune evasion. To accomplish this, we compared thousands of sequences derived by single genome amplification from several hundred individuals that were sampled either early in infection or were chronically infected. Samples were divided at the outset into hypothesis-forming and validation sets, and we used phylogenetically corrected statistical strategies to identify signatures, systematically scanning all of Env. Signatures included single amino acids, glycosylation motifs, and multi-site patterns based on functional or structural groupings of amino acids. We identified signatures near the CCR5 co-receptor-binding region, near the CD4 binding site, and in the signal peptide and cytoplasmic domain, which may influence Env expression and processing. Two signatures patterns associated with transmission were particularly interesting. The first was the most statistically robust signature, located in position 12 in the signal peptide. The second was the loss of an N-linked glycosylation site at positions 413–415; the presence of this site has been recently found to be associated with escape from potent and broad neutralizing antibodies, consistent with enabling a common pathway for immune escape during chronic infection. Its recurrent loss in early infection suggests it may impact fitness at the time of transmission or during early viral expansion. The signature patterns we identified implicate Env expression levels in selection at viral transmission or in early expansion, and suggest that immune evasion patterns that recur in many individuals during chronic infection when antibodies are present can be selected against when the infection is being established prior to the adaptive immune response.
A single virus most often establishes HIV-1 infection. As a consequence, virus sampled early in infection is usually very homogeneous. A few months into the infection, the virus begins to accumulate mutations as it evolves to evade HIV-specific immune responses mounted by the infected host. During chronic infection, the viral population diversifies, reflecting the history of mutations that arose within that infected individual. We hypothesized that particular amino acids might confer a selective advantage during transmission or early infection, and others might recur during chronic infection because they provide common and effective strategies of immune escape. We compared a large number of viral sequences from several hundred infected people sampled soon after transmission or during chronic infection to identify such infection-status “signature” patterns. A particularly robust signature was identified in the signal peptide of Envelope, a region that regulates its expression. Other signatures were found in regions of Envelope that interact with its cellular receptors, or are implicated in immune escape.