Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Clinical Trial
. 2011 Sep;7(9):e1002209.
doi: 10.1371/journal.ppat.1002209. Epub 2011 Sep 29.

Recurrent signature patterns in HIV-1 B clade envelope glycoproteins associated with either early or chronic infections

S Gnanakaran  1 , Tanmoy Bhattacharya, Marcus Daniels, Brandon F Keele, Peter T Hraber, Alan S Lapedes, Tongye Shen, Brian Gaschen, Mohan Krishnamoorthy, Hui Li, Julie M Decker, Jesus F Salazar-Gonzalez, Shuyi Wang, Chunlai Jiang, Feng Gao, Ronald Swanstrom, Jeffrey A Anderson, Li-Hua Ping, Myron S Cohen, Martin Markowitz, Paul A Goepfert, Michael S Saag, Joseph J Eron, Charles B Hicks, William A Blattner, Georgia D Tomaras, Mohammed Asmal, Norman L Letvin, Peter B Gilbert, Allan C Decamp, Craig A Magaret, William R Schief, Yih-En Andrew Ban, Ming Zhang, Kelly A Soderberg, Joseph G Sodroski, Barton F Haynes, George M Shaw, Beatrice H Hahn, Bette Korber
Affiliations
Clinical Trial

Recurrent signature patterns in HIV-1 B clade envelope glycoproteins associated with either early or chronic infections

S Gnanakaran et al. PLoS Pathog. 2011 Sep.

Abstract

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.

PubMed Disclaimer

Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Mapping of signature sites (red) on the three-dimensional structure of gp120 (silver).
A ribbon structure of the HIV-1 gp120 core +V3 in the CD4-bound conformation is shown in white. (A) Key residues involved in co-receptor and antibody (2G12, b12, b13 and F105) binding that are proximal to the position 415 are shown. Residues 295 and 332, that contribute to the 2G12 epitope, and residue 444, that is important for co-receptor binding, are shown as blue balls. A motif spanning the region 417 to 421 (cyan color) that is proximal to position 415 and contains residues that take part in binding to coreceptor (419), b12 (417–419), b13 (419–421) and F105 (421). CD4 (orange) is shown for better visualization of receptor binding site region. (B) Locations of signature patterns involving glycan motifs (N-notP-[ST]). (C) Spatial locations of signature sites within a set of functional sites (blue) associated with CCR5 binding. The 17b antibody Fab is included to mark the region in gp120 that takes part in CCR5 binding. Signature sites are labeled with HXB2 reference numbers.
Figure 2
Figure 2. p- and q-values found in shuffling experiments in which the entire sequence signature strategy was repeated 10 times after randomizing the early and chronic designation of each subject.
The black x's represent the distribution of p- and q-values in the real data, while the colored circles represent the findings for incremental inclusion of Fiebig stages 2–6 in shuffled data. The lower quadrant of part of the graph is almost exclusively occupied by the real data, indicating a signature dependent on early versus chronic status; p-values of less than 10−6 were rare in the randomized data, and value less than 10−8 were exclusively found among real data classifications.
Figure 3
Figure 3. Three statistically significant structures-based regional clusters in gp120 (white) associated with changes in polarity.
These regional clusters occur near the CD4-binding site (orange) shown in (A). The CD4-bound conformation of the HIV-1 gp120 core+V3 is shown, from the perspective seen by CD4. The three clusters (B–D) are shown in red. The residues that form these sets are shown in panel (E). All maps are based on HXB2 numbering.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Haynes BF, Shattock RJ. Critical issues in mucosal immunity for HIV-1 vaccine development. J Allergy Clin Immunol. 2008;122:3–9. - PMC - PubMed
    1. Rerks-Ngarm S, Pitisuttithum P, Nitayaphan S, Kaewkungwal J, Chiu J, et al. Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand. N Engl J Med. 2009;361:2209–2220. - PubMed
    1. Korber B, Gnanakaran S. The implications of patterns in HIV diversity for neutralizing antibody induction and susceptibility. Curr Opin HIV AIDS. 2009;4:408–417. - PMC - PubMed
    1. Barouch DH, Korber B. HIV-1 vaccine development after STEP. Annu Rev Med. 2010;61:153–167. - PMC - PubMed
    1. Gaschen B, Taylor J, Yusim K, Foley B, Gao F, et al. Diversity considerations in HIV-1 vaccine selection. Science. 2002;296:2354–2360. - PubMed

Publication types

MeSH terms