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. 2008 May 27;105(21):7552-7.
doi: 10.1073/pnas.0802203105. Epub 2008 May 19.

Identification and characterization of transmitted and early founder virus envelopes in primary HIV-1 infection

Brandon F Keele  1 , Elena E Giorgi, Jesus F Salazar-Gonzalez, Julie M Decker, Kimmy T Pham, Maria G Salazar, Chuanxi Sun, Truman Grayson, Shuyi Wang, Hui Li, Xiping Wei, Chunlai Jiang, Jennifer L Kirchherr, Feng Gao, Jeffery A Anderson, Li-Hua Ping, Ronald Swanstrom, Georgia D Tomaras, William A Blattner, Paul A Goepfert, J Michael Kilby, Michael S Saag, Eric L Delwart, Michael P Busch, Myron S Cohen, David C Montefiori, Barton F Haynes, Brian Gaschen, Gayathri S Athreya, Ha Y Lee, Natasha Wood, Cathal Seoighe, Alan S Perelson, Tanmoy Bhattacharya, Bette T Korber, Beatrice H Hahn, George M Shaw
Affiliations

Identification and characterization of transmitted and early founder virus envelopes in primary HIV-1 infection

Brandon F Keele et al. Proc Natl Acad Sci U S A. .

Abstract

The precise identification of the HIV-1 envelope glycoprotein (Env) responsible for productive clinical infection could be instrumental in elucidating the molecular basis of HIV-1 transmission and in designing effective vaccines. Here, we developed a mathematical model of random viral evolution and, together with phylogenetic tree construction, used it to analyze 3,449 complete env sequences derived by single genome amplification from 102 subjects with acute HIV-1 (clade B) infection. Viral env genes evolving from individual transmitted or founder viruses generally exhibited a Poisson distribution of mutations and star-like phylogeny, which coalesced to an inferred consensus sequence at or near the estimated time of virus transmission. Overall, 78 of 102 subjects had evidence of productive clinical infection by a single virus, and 24 others had evidence of productive clinical infection by a minimum of two to five viruses. Phenotypic analysis of transmitted or early founder Envs revealed a consistent pattern of CCR5 dependence, masking of coreceptor binding regions, and equivalent or modestly enhanced resistance to the fusion inhibitor T1249 and broadly neutralizing antibodies compared with Envs from chronically infected subjects. Low multiplicity infection and limited viral evolution preceding peak viremia suggest a finite window of potential vulnerability of HIV-1 to vaccine-elicited immune responses, although phenotypic properties of transmitted Envs pose a formidable defense.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
HIV-1 env diversity in relation to Fiebig stage. (A) Fiebig stages (28) are defined by HIV-1 clinical laboratory test results. Blue symbols depict a Monte Carlo simulation of env sequence identity (%) after transmission (SI Text). Black symbols depict percentage identities in env sequences measured sequentially in 10 subjects, each represented by a different symbol. (B) Frequency distribution of within-patient maximum env diversities in all 102 subjects (Inset) and among the 21 subjects with more heterogeneous sequences. The vertical dashed line in the Inset represents the model prediction of maximum achievable env diversity (0.60%; 95% C.I. = 0.54–0.68%) by 100 days after transmission. Colored areas above each Fiebig stage represent model estimates of maximum env diversity (hatched area = 95% C.I.) and corresponding minimum days since a MRCA sequence. (C) Frequency distribution of within-patient mean env diversity and estimated days since MRCA in relation to Fiebig stage for 81 subjects with more homogeneous env sequences. Red dots in B and C and red bars in the Inset in B indicate subjects shown by phylogenetic analysis of env sequences to have been infected by two or more viruses.
Fig. 2.
Fig. 2.
NJ, Highlighter, and HD analyses of env diversity. (A) Subject 1006. NJ and Highlighter show infection by a single virus with HD frequencies, conforming precisely to model predictions of a single virus infection (red line). (B) Subject 6247. (C) Subject CAAN5342. NJ and Highlighter show infection by two closely (B) or distantly (C) related viruses (clades 1 and 2) with HD frequencies that do not conform to model predictions of a single virus infection (red line). Subject CAAN5342 has multiple sequences representing interlineage env recombination after transmission.
Fig. 3.
Fig. 3.
Effect of APOBEC3G/F-mediated G-to-A hypermutation on HD frequency distribution. HD (x axis) is plotted versus frequency (y axis) as in Fig. 2. G-to-A hypermutations primarily in one sequence (A) or distributed in multiple sequences (B). Hypermutated sequences do not conform to model predictions for HD frequency distribution (red lines) but do conform if APOBEC3G/F related G-to-A mutations are eliminated.
Fig. 4.
Fig. 4.
NJ and Highlighter analysis of sequential env sequences from subject 1058. Sequences depicted by yellow, orange, and brown bars correspond to sample dates March 8, 1998 (Fiebig stage I), March 11, 1998 (Fiebig stage II), and March 18, 1998 (Fiebig stage IV) (Dataset S5). At these time points, plasma vRNA levels were 2,737 copies per ml, 26,162 copies per ml, and 550,000 copies per ml, respectively. The proportion of identical sequences corresponding to the transmitted or early founder env decreased from 89% to 59% to 45%, consistent with model projections illustrated by the blue symbols in Fig. 1A.
Fig. 5.
Fig. 5.
Neutralization sensitivity of transmitted Envs compared with chronic Envs. Red dots represent the IC50 of the transmitted viral Envs, and yellow bars represent the interquartile range, with the median value indicated as the gap between the bars. Black dots and gray bars represent chronic Envs. The dots clustered above the thin black lines are Envs that were not neutralized at the highest concentration of ligand tested. Results for anti-Env mAbs (A), sCD4 and HIVIG (B), and the fusion inhibitor T1249 (C) are depicted. Uncorrected P values at the base of the figure were calculated by using a Wilcoxon rank-sum statistic comparing transmitted and chronic Envs. A total of 20 comparisons were made (Dataset S7); hence, to be significant after consideration of multiple tests, a significance level of 0.0025 was required. P values of <0.0025 are in red.
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