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Journal of Virology, April 2009, p. 3993-3997, Vol. 83, No. 8
0022-538X/09/$08.00+0     doi:10.1128/JVI.01108-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Transmission and Long-Term Stability of Compensated CD8 Escape Mutations

Arne Schneidewind,^1,2 Zabrina L. Brumme,¹ Chanson J. Brumme,¹ Karen A. Power,¹ Laura L. Reyor,¹ Kristin O'Sullivan,¹ Adrianne Gladden,¹ Ursula Hempel,¹ Thomas Kuntzen,¹ Yaoyu E. Wang,¹ Cesar Oniangue-Ndza,¹ Heiko Jessen,³ Martin Markowitz,⁴ Eric S. Rosenberg,¹ Rafick-Pierre Sékaly,⁵ Anthony D. Kelleher,⁶ Bruce D. Walker,¹ and Todd M. Allen^1*

Partners AIDS Research Center, Massachusetts General Hospital, Boston, Massachusetts,¹ Klinik für Innere Medizin I, Universitätsklinikum Regensburg, Regensburg, Germany,² Jessen-Praxis, Berlin, Germany,³ Aaron Diamond AIDS Research Center, New York, New York,⁴ Université de Montréal, Montreal, Canada,⁵ University of New South Wales, Sydney, Australia⁶

Received 26 May 2008/ Accepted 8 December 2008

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Human immunodeficiency virus effectively evades CD8⁺ T-cell responses through the development of CD8 escape mutations. Recent reports documenting reversion of transmitted mutations and the impact of specific escape mutations upon viral replication suggest that complex forces limit the accumulation of CD8 escape mutations at the population level. However, the presence of compensatory mutations capable of alleviating the impact of CD8 escape mutations on replication capacity may enable their persistence in an HLA-mismatched host. Herein, we illustrate the long-term stability of stereotypic escape mutations in the immunodominant HLA-B27-restricted epitope KK10 in p24/Gag following transmission when accompanied by a specific compensatory mutation.

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The association between expression of certain human leukocyte antigen (HLA) class I alleles and disease progression in human immunodeficiency virus type 1 (HIV-1) infection is well documented, with both HLA-B57 and -B27 overrepresented in cohorts of long-term nonprogressors (20, 28). Furthermore, immunological control of HIV-1 has been linked to preferential targeting of cytotoxic T-lymphocyte (CTL) epitopes in Gag (13, 16, 22, 27, 30, 35). Notably, the epitopes B57-TW10 and B27-KK10, located adjacent to one another in a conserved p24/capsid region, are immunodominantly targeted during acute infection (3, 4, 19, 21). Therefore, control of HIV-1 may be partially attributable to the presence of particular CTL responses targeting epitopes from constrained regions with inherent limitations for sequence evolution in order to effectively evade immune pressures.

There is growing evidence that HIV-1 continuously adapts to CTL selection pressures (9, 29, 34), raising the possibility that some escape mutations eventually accumulate on a population level. Accrual of multiple escape mutations might impair the mounting of critical CD8 responses in subsequently infected subjects, as evidenced in both mother-to-child transmission (18) and adult infection (2). However, the deleterious impact of CD8 escape mutations upon viral replication (7, 12, 17, 26, 31) and their reversion upon transmission (1, 2, 12, 23, 24) suggest that purifying selective forces may also limit the accumulation of escape mutations at the population level. Interestingly, the critical role that secondary compensatory mutations have in tempering the impact of CTL escape mutations on viral replication (7, 12, 31) suggests that they could have a stabilizing effect.

Viral escape in B27-KK10 (KRWIILGLNK_263-272) typically occurs through an L₂₆₈M mutation early after infection (10, 19, 21, 31). This mutation confers partial escape from the CD8 response, with little impact on replication capacity (25, 31). Development of de novo responses against the L₂₆₈M variant (25, 32) is likely responsible for selection of the secondary R₂₆₄K escape mutation, resulting in full escape from both wild-type and variant-specific immune pressures (10, 31, 32). The development of R₂₆₄K has been associated with rapid disease progression in B27-positive subjects (5, 14, 19, 21). Alone, R₂₆₄K dramatically impairs viral replication capacity, which is restored to a near-wild-type level in the presence of a strongly linked compensatory mutation, S₁₇₃A (31). The compromised replication capacities of viruses independently harboring R₂₆₄K or S₁₇₃A (11, 31) may explain the delay in viral escape within KK10 and the long-term control of HIV-1 exhibited in HLA-B27-positive individuals.

The ability of S₁₇₃A to restore the replicative capacity of R₂₆₄K suggests that in combination, these mutations may be stable and unlikely to revert. To test this hypothesis, we analyzed the transmission frequencies of the clustered mutations S₁₇₃A, R₂₆₄K, and L₂₆₈M. Bulk Gag sequences from 211 HLA-B*27-negative subjects at the baseline (from a total of 227 individuals, including 16 B*27-positive individuals) with acute/early clade B HIV-1 infections, enrolled in North America, Europe, and Australia, were examined. Sequencing of autologous virus, HLA typing, and data analyses were performed as previously described (1). As shown in Fig. 1A, we identified a total of 45 (21%) HLA-B*27-negative subjects whose viruses harbored B*27-KK10-associated polymorphisms. These included 22 (10%) subjects with viruses bearing L₂₆₈M in the absence of R₂₆₄K and 11 (5%) subjects with viruses encoding all three stereotypic (S₁₇₃A/R₂₆₄K/L₂₆₈M) mutations. Viral sequences from five (2%) subjects displayed S₁₇₃A and R₂₆₄K without L₂₆₈M. Notably, in viruses from five subjects, we observed the presence of R₂₆₄K without S₁₇₃A, with two of these viruses displaying S₁₇₃T, a mutation which does not compensate for the fitness defect of R₂₆₄K (31). Finally, viruses from two individuals exhibited the rare R₂₆₄G escape mutation (21). Taken together, the strong association of mutations at these positions with expression of HLA-B27 (31) suggests that the respective mutations evolved previously in HLA-B27-positive individuals.

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FIG. 1. HLA-B27-associated KK10 mutations in viruses from HLA-mismatched individuals. Gag sequences (amino acids 168 to 278) derived from B*27-negative individuals harboring mutations in the KK10 epitope (boxed) during acute infection are aligned with the clade B consensus sequence. Amino acid positions 173, 264, and 268 are shaded gray. (A) Cross-sectional sequences from 45 viruses. Patient identification numbers, origins, and HLA class I serotypes are shown. (B) Longitudinal sequences from three individuals show fixation of the stereotypic S173A/R264K/L268M mutations for up to 1,473 days. "pp" indicates time postpresentation. The frequencies of the clustered mutations S173A/R264K/L268M in clonal sequences at the last time points for each individual are shown to the right of the sequences. The asterisk in the AC41 row indicates that 2 of the 15 clones showed S173T as well as wild-type R264 and L268 within a sequence backbone, indicative of a phylogenetically unrelated superinfecting viral strain (T. M. Allen, unpublished results).

For three subjects with S₁₇₃A/R₂₆₄K/L₂₆₈M, we had access to longitudinal samples and followed viral sequence evolution for up to 4.5 years, assessing the stability of these mutations. Subject AC-38, reported previously (1), exhibited low levels of viral replication (<5,000 copies/ml) during the first 1.1 years (Fig. 2A). During this time, 23 amino acid substitutions developed across the viral proteome, excluding Env, with 10 located within targeted CD8 epitopes and 8 representing reversions toward the clade B consensus sequence (1). Over the following 2.9 years, viral loads (VL) transiently increased to 60,000 copies/ml, and an additional 29 mutations, including 3 reversions and 15 forward mutations within epitopes restricted by the patient's HLA-I haplotype, evolved. Therefore, viral replication was sufficient to enable substantial levels of escape and reversion. However, none of the S₁₇₃A/R₂₆₄K/L₂₆₈M mutations reverted (Fig. 1B).

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FIG. 2. Clinical courses for three individuals with viruses harboring B27-associated KK10 mutations. VL in numbers of copies/ml (solid line) and CD4+ count in numbers of cells/µl (dashed line) following acute HIV-1 infection are documented for subjects AC-38 (A), AC-41 (B), and AC-141 (C). Circles and arrowheads indicate time points from which Gag sequences were obtained, corresponding to the alignment in Fig. 1B. Gray bars indicate periods of HAART.

Subject AC-41 presented during primary HIV-1 infection with a VL of 252,000 copies/ml, and highly active antiretroviral therapy (HAART) was immediately initiated (Fig. 2B). A structured treatment interruption (STI) started at 4 months postpresentation, with reinitiation of HAART 1 month later due to a VL rebound. VL was again suppressed to <50 copies/ml for the next 27 months, whereupon treatment discontinuation resulted in a subsequent rise in VL to 15,000 copies/ml. Sequencing of gag at the end of the first STI and 12 months after the start of the second STI (days 157 and 1319 postpresentation, respectively) again revealed a lack of reversion of the stereotypic S₁₇₃A/R₂₆₄K/L₂₆₈M mutations (Fig. 1B), despite evolution of 20 mutations in Gag (including 11 in epitopes restricted by the respective HLA-I alleles and 6 reversions).

In the third subject, AC-141, VL varied between 74,000 and 150,000 copies/ml during the first 7 months postpresentation (Fig. 2C). Sequence analyses at days 34, 71, 113, and 216 revealed stability among the S₁₇₃A/R₂₆₄K/L₂₆₈M mutations over the entire period of follow-up (Fig. 1B), while two amino acid substitutions in other regions of Gag again indicated ongoing viral evolution (data not shown).

These data suggest that in the presence of S₁₇₃A, the R₂₆₄K and L₂₆₈M escape mutations are transmitted and can remain stable in the absence of selective CTL pressure for several years despite ongoing viral replication and evolution. In contrast, escape mutations in B57-TW10, likewise immunodominantly targeted during acute infection (4), have been documented to revert upon transmission to an HLA-mismatched host (23). This difference might be due to the particular characteristics of escape and compensatory mutations. For the B57-TW10 epitope, the primary T₂₄₂N escape mutation exhibits only a 10-fold impact on viral replication (7), in comparison to the nearly 1,000-fold impact of R₂₆₄K in B27-KK10 (31). Moreover, for B57-TW10, several independent compensatory mutations have been described, each of which only partially restores replication capacity (7). Notably, however, none of these compensatory mutations appears absolutely necessary for development of T₂₄₂N (7), and at least one of the compensatory mutations does not confer a defect on viral replication when present in isolation (15). Therefore, it is likely that T₂₄₂N reverts irrespective of the presence of compensatory mutations. In contrast, R₂₆₄K may be impaired in its ability to revert, due to the critical role of the S₁₇₃A compensatory mutation in its development. Independent reversions at residue A₁₇₃ or K₂₆₄ would substantially reduce viral replication (11, 31), diminishing the probability that sequential reversions would take place. In a recent publication by Brumme et al., mutation T₂₄₂N was documented to revert faster than any other escape mutation in Gag, while no reversion was observed for R₂₆₄K within the first year of infection (8), supportive of our observation that this dominant escape mutation in KK10 usually remains stable also in the absence of HLA-B27-mediated CTL pressure. Most interestingly, reversion of the early L₂₆₈M escape mutation in KK10 happens at a moderate speed in HLA-B*27-negative hosts. In these cases of reversion toward lysine at position 268, the transmitted methionine is never accompanied by S₁₇₃A and/or R₂₆₄K. Thus, the specific characteristics of the compensatory mutation S₁₇₃A not only allow for eventual immune escape from CTL pressure against the epitope KK10 (31) but also appear to fixate the collective set of mutations following transmission and to facilitate their accumulation at the population level.

These observations suggest that there is a possibility for an increasing prevalence of stereotypic KK10 escape mutations on a population level. However, the relatively low S₁₇₃A/R₂₆₄K/L₂₆₈M and overall R₂₆₄K frequencies of approximately 5% and 10%, respectively, in the B*27-negative individuals analyzed here as well as the low prevalences of these mutations in the LANL HIV database (31) do not allow direct testing of this hypothesis. Therefore, it is important to consider an array of factors contributing to the low frequency. First, in Caucasian populations, expression of HLA-B*27 is rather rare, as reflected by our cohort (16/227 [7%]). Second, the R₂₆₄K escape mutation does not generally develop early after infection (14, 19, 21) when the risk of transmission of HIV-1 is particularly high (6, 33). Third, HLA-B27-positive subjects exhibiting higher VL and likely accelerated rates of disease progression following development of R₂₆₄K (14, 19, 21) may be less apt to transmit HIV-1, due to their clinical status. Therefore, the low S₁₇₃A/R₂₆₄K/L₂₆₈M prevalence in our cohort and in the LANL HIV database might well reflect the slow pace with which these variants accumulate on the population level. However, CTL escape mutations associated with more-frequent HLA alleles and selected for more rapidly during acute infection may exhibit a greater capacity to accumulate in the population if they too acquire compensatory mutations or if their overall impact on replication capacity remains negligible.

The potential for CTL escape mutations, especially those residing within critical regions such as Gag (13, 16, 22, 27, 30, 35), to remain stable following transmission may have serious implications for the new host. Particularly, HLA-B27-positive individuals might be imperiled if they become infected with a replicative competent viral variant already harboring KK10 escape mutations, thereby losing their dominant and presumably most effective immune response.

Nucleotide sequence accession numbers. Sequences were submitted to GenBank under accession numbers DQ127542, DQ127543, DQ127546, DQ127547, and FJ667208 to FJ667256.

 
This study was supported by the National Institutes of Health, grant R01-AI054178 (T.M.A.), and a grant from the Bill & Melinda Gates Foundation (B.D.W. and T.M.A.). A.D.K. is supported by a Practitioner grant from the NHMRC of Australia.

 
* Corresponding author. Mailing address: Division of Infectious Diseases, Massachusetts General Hospital, Bldg. 149, 13th St., Rm. 6625, Charlestown, MA 02129. Phone: (617) 726-7846. Fax: (617) 724-8586. E-mail: tallen2{at}partners.org

Published ahead of print on 17 December 2008.

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Journal of Virology, April 2009, p. 3993-3997, Vol. 83, No. 8
0022-538X/09/$08.00+0     doi:10.1128/JVI.01108-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

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