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Journal of Virology, May 2005, p. 6523-6527, Vol. 79, No. 10
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.10.6523-6527.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Characterization of Human Immunodeficiency Virus Type 1 (HIV-1) Envelope Variation and Neutralizing Antibody Responses during Transmission of HIV-1 Subtype B

Simon D. W. Frost,^1* Yang Liu,² Sergei L. Kosakovsky Pond,¹ Colombe Chappey,² Terri Wrin,² Christos J. Petropoulos,² Susan J. Little,¹ and Douglas D. Richman^1,3

University of California,¹ Veterans Affairs San Diego Healthcare System, San Diego,³ ViroLogic, Inc., South San Francisco, California²

Received 8 October 2004/ Accepted 19 February 2005

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We analyzed neutralization sensitivity and genetic variation of transmitted subtype B human immunodeficiency virus type 1 (HIV-1) in eight recently infected men who have sex with men and the virus from the six subjects who infected them. In contrast to reports of heterosexual transmission of subtype C HIV-1, in which the transmitted virus appears to be more neutralization sensitive, we demonstrate that in our study population, relatively few phenotypic changes in neutralization sensitivity or genotypic changes in envelope occurred during transmission of subtype B HIV-1. We suggest that limited genetic variation within the infecting host reduces the likelihood of selective transmission of neutralization-sensitive HIV.

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Human immunodeficiency virus (HIV) can rapidly escape from autologous neutralizing antibody responses (1, 5, 7). Evolution of N-linked glycosylation sites (NGS), which anchor a "glycan shield" of carbohydrates to the envelope (7), and variable loops that bind antibodies, may contribute to escape from neutralizing antibodies. However, both NGS and variable loops may be associated with a replicative cost, such that there is a tradeoff for the virus between immune escape and replication rate within the host. Consistent with this hypothesis, Derdeyn et al. (3) reported that subtype C HIV type 1 (HIV-1) envelope demonstrated a more compact, neutralization-sensitive form with fewer NGS upon heterosexual transmission of HIV in a study of eight epidemiologically linked pairs. It is unclear whether these results are generalizable to other subtypes or other modes of transmission.

(This work was presented in part at the 11th Conference on Retroviruses and Opportunistic Infections, San Francisco, CA, 8 to 11 February 2004, abstr. 384.)

We studied eight sexual transmissions of subtype B HIV-1 in six epidemiologically linked sets of men who have sex with men, four pairs and two triplets in which one individual infected two others. Samples from recently infected recipients were obtained within a median of 30 days (range, 21 to 85 days) after the estimated date of infection. Samples from the source subjects were obtained between 94 days before and 32 days after screening of the recipient. Four transmissions were from recently infected source subjects, and four transmissions were from chronically infected source subjects (Table 1 and Supplementary Material at http://www.hivevolution.org). Phylogenetic analysis of sequences derived from envelope pools (not shown) and from molecular clones (Fig. 1 and Supplementary Material at http://www.hivevolution.org) confirmed the epidemiological clustering of these individuals.

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TABLE 1. Pattern of genetic evolution between source and recipient in epidemiologically linked transmission groups

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FIG. 1. Maximum-likelihood phylogenies of transmission clusters associated with chronic sources (top) and recently infected sources (bottom). Source sequences are labeled by triangles, and recipient sequences are labeled by circles. The scale bar represents genetic distance (1 = 100% divergence).

Sequence comparison of molecular clones revealed that sequences in the source and recipients clustered separately for all transmissions (Fig. 1), although the bootstrap support for clustering was low (48%) for the 0206 to 0201 transmission, due to the extremely low divergence (0.04%) between viral sequences isolated from these individuals. Genetic diversity was higher in the chronic sources than in the recent sources (means of 1.6% versus 0.27%, Wilcoxon test, P = 0.05; Table 1); however, the evolutionary divergence between source and recipient was low (mean = 0.41%). Although there was evidence of positive selection on env, as measured by an elevated nonsynonymous to synonymous substitution rate ratio (dN/dS of >1) in some branches of the phylogenetic tree, there was no consistent evidence of positive selection between the viruses present in the source and those present in the recipient (Table 1).

Neutralizing antibody responses to the transmitted viruses were measured using a recombinant virus assay (5) that can evaluate both envelope populations (pools) and envelope molecular clones (median, 12 per individual; range, 11 to 15). Neutralizing antibody titers against virus envelope populations and clones were determined for matching source and recipient plasma samples. Based on the neutralization of virus envelope pools (results not shown) and clones (Fig. 2) by matched source plasma samples, only two of eight transmissions, both from chronically infected sources, were associated with increased neutralization sensitivity (more than twofold) in the recipient. As titers of neutralizing antibodies may be low in the matched source plasma samples, we also measured the neutralization of source and recipient virus using plasma from an individual who exhibited broad cross-reactivity and high titers to a panel of viruses (for example, 50% inhibitory concentrations of >100-fold dilution for HIV-1 JRCSF and >1,000-fold dilution for HIV-1 NL4-3). Neutralization titers were low (<100) except in the two transmissions identified using source plasma as being associated with a change in neutralization sensitivity (a change in titer from 35 to 169 in pair 0465/0449 and a change in titer from 74 to 290 in pair 0564/0557). In source patient 0465, the neutralization-sensitive viruses clustered together (Mantel test between genetic distance and difference in neutralization sensitivity, r = 0.55, P = 0.007), whereas in source patient 0564, the neutralization-sensitive viruses were scattered throughout the tree (Mantel test, r = 0.03, P = 0.4), indicating multiple, independent evolution of neutralizing antibody sensitivity in this patient. These results confirm the overall lack of evolution of neutralization sensitivity in our study subjects, with the exception of transmissions from two chronically infected patients whose virus exhibited high genetic diversity.

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FIG. 2. Comparison between source and recipient subjects, in terms of neutralizing antibody titers using source subject plasma (matched by transmission cluster), for infections from chronic and recently infected sources. Neutralizing antibody titers are expressed as the reciprocal of the dilution of donor plasma required to reduce the viral replication rate to 50% relative to a negative control. Boxes represent the median and interquartile ranges; whiskers extend to 1.5 times the interquartile range or the most extreme data point, whichever is closer.

In the study population as a whole, there was no trend toward an increase or decrease in the length of gp160 or in the number of potential NGS (Fig. 3). In one of the two transmissions (0564/0557) that were associated with an increase in neutralization sensitivity, the number of potential NGS decreased from a mean of 32.4 (range, 31 to 34; n = 14 sequences) to a mean of 29.8 (range, 29 to 30; n = 15 sequences), while the length of gp160 decreased from a mean of 869.7 (range, 867 to 871) to a mean of 859.8 (range, 858 to 865). However, in the other transmission associated with an increase in neutralization sensitivity (0465/0449), the number of potential NGS remained relatively constant and the envelope was longer in the recipient than in the source partner.

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FIG. 3. Comparison between source and recipient subjects, in terms of envelope length (in amino acid residues) and potential N-linked glycosylation sites (PNGS). Boxes represent the median and interquartile ranges; whiskers extend to 1.5 times the interquartile range or the most extreme data point, whichever is closer. We also restricted analysis to the V1-V4 region, as studied by Derdeyn et al. (3); the results were comparable.

Our results show that transmission of subtype B HIV-1 among men who have sex with men may not be generally associated with a more compact, neutralization-sensitive form of the virus. It is unclear whether this difference may arise due to the mode of transmission or due to subtype-specific virological factors. In the two cases where transmission was associated with an increase in neutralization sensitivity, the source harbored a more heterogeneous viral population (>1% diversity). The source partners reported by Derdeyn et al. (3), most of whom were chronically infected with subtype C, exhibited far greater variation in the viral envelope length, number of potential NGS, and genetic variation than the source partners reported in this study. All six source partners reported in this study exhibited <5% genetic diversity in the V1-V4 region of env, and four of six exhibited less than 1% diversity. In our study, only virus isolated from chronically infected individuals exhibited length variation in V1-V4 (Table 1). In contrast, all eight source partners in the study of Derdeyn et al. (3) exhibited >2% diversity and five of eight exhibited >5% diversity in the same region of env, and there was significantly more length variation in V1-V4 in the source partners studied by Derdeyn et al. (3) (maximum difference in length ranged from 6 to 37) than in the source partners in our study (maximum difference in length ranged from 0 to 9; Wilcoxon test, P = 0.0013). However, similar to the pattern of selection in our study population, there was no consistent evidence for positive selection pressure driving the divergence between source and recipient partners studied by Derdeyn et al. (3); elevated dN/dS between the viruses in the source and those in the recipient was detected in only two of the eight pairs, 13 (dN/dS between patients = 6.82, dN/dS within patients = 0.57, P = 0.03) and 135 (dN/dS between patients = 6.77, dN/dS between patients = 1.24). Hence, the differences between subtypes reported here and by Chohan et al. (2) may reflect different levels of genetic variation within patients, with a simultaneous influence on the potential for the transmission of rare, divergent viruses rather than reflecting the mode of transmission.

Many factors may contribute to the level of within-patient genetic variation in envelope, including time since infection (6). We have also studied a heterosexual transmission of subtype AG, which has a subtype A-like envelope, in which an acutely infected man infected his female partner. No difference in neutralization sensitivity between source (neutralizing antibody titer = 148; 4/11 clones with titers of >100) and recipient (neutralizing antibody titer = 106; 2/10 clones with titers of >100) was found; however, genetic diversity in the source was extremely low (0.3%), consistent with the acute infection stage. Given that primary infection may play an important role in the transmission of HIV, due to the extremely high viral loads (4), the opportunity for viruses to evolve sensitivity to neutralizing antibody during transmission at a population level may be limited by the lack of genetic variation in many transmitters of HIV-1, especially in regions of low HIV prevalence, where recent infection may play a major role in contributing to HIV incidence. In regions of high HIV prevalence, transmissions from chronically infected individuals may outnumber those from recently infected individuals, leading to changes in neutralization sensitivity during transmission occurring more frequently. We emphasize that our results are suggestive, pending larger studies. Clonal analysis of HIV in epidemiologically linked pairs in areas where significant levels of heterosexual transmission of subtype B occur, like South America and the Caribbean, should help to clarify the relative roles of the mode of transmission, HIV-1 subtype, and within-patient diversity in selection of viral variants during transmission.

Nucleotide sequence accession numbers. The sequences presented in this study have been deposited in GenBank.

 
This work was supported by grants AI 27670, AI 38858, AI 43638, AI47745, and AI57167; the UCSD Center for AIDS Research (AI 36214); grant AI 29164 from the National Institutes of Health; and the Research Center for AIDS and HIV Infection of the Veterans Affairs San Diego Healthcare System. The development of HIV envelope assay and sequence analysis systems is supported in part by NIH Small Business Innovative Research Grants to ViroLogic (AI48990 and AI57068).

We thank Bette Korber for providing us with additional details of the sequence analyses performed by Derdeyn et al. (3).

 
* Corresponding author. Mailing address: UCSD Antiviral Research Center, 150 W. Washington St., Suite 100, San Diego, CA 92103. Phone: (619) 543-8080. Fax: (619) 298-0177. E-mail: sdfrost{at}ucsd.edu.

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Journal of Virology, May 2005, p. 6523-6527, Vol. 79, No. 10
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.10.6523-6527.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

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