CTL escape and increased viremia irrespective of HIV-specific CD4+ T-helper responses in two HIV-infected individuals

140

169

Control of human immunodeficiency virus type 1 (HIV-1) by HLA-B27-positive subjects has been linked to an immunodominant CD8؉ cytotoxic T-lymphocyte (CTL) response targeting the conserved KK10 epitope (KRWIILGLNK 263-272 ) in p24/Gag. Viral escape in KK10 typically occurs through development of an R 264 K substitution in conjunction with the upstream compensatory mutation S 173 A, and the difficulty of the virus to escape from the immune response against the KK10 epitope until late in infection has been associated with slower clinical progression. Rare alternative escape mutations at R 264 have been observed, but factors dictating the preferential selection of R 264 K remain unclear. Here we illustrate that while all observed R 264 mutations (K, G, Q, and T) reduced peptide binding to HLA-B27 and impaired viral replication, the replicative defects of the alternative mutants were actually less pronounced than those for R 264 K. Importantly, however, none of these mutants replicated as well as an R 264 K variant containing the compensatory mutation S 173 A. In assessing the combined effects of viral replication and CTL escape using an in vitro coculture assay, we further observed that the compensated R 264 K mutant also displayed the highest replication capacity in the presence of KK10-specific CTLs. Comparisons of codon usage for the respective variants indicated that generation of the R 264 K mutation may also be favored due to a G-to-A bias in nucleotide substitutions during HIV-1 replication. Together, these data suggest that the preference for R 264 K is due primarily to the ability of the S 173 Acompensated virus to replicate better than alternative variants in the presence of CTLs, suggesting that viral fitness is a key contributor for the selection of immune escape variants.

Section: Discussionmentioning

confidence: 99%

Structural and Functional Constraints Limit Options for Cytotoxic T-Lymphocyte Escape in the Immunodominant HLA-B27-Restricted Epitope in Human Immunodeficiency Virus Type 1 Capsid

Schneidewind

Brockman

Sidney

et al. 2008

140

169

“…Patients were included in the study only if their CD4 counts were above 300 cells per mm 3 at the time of enrollment and if they had been on continuous antiretroviral therapy (ART) with a plasma viral load of less than 50 copies per ml for at least 6 months. Although these patients were followed for an average of 14 months, for the present study, only data from a sample taken toward the end of the study (i.e., while the patients remained off treatment) were (18,19,24,28,37). For each mutation, the average time between infection and escape in HLA-matched hosts (the reciprocal of the escape rate) and the average time between infection and reversion in HLAmismatched hosts are provided.…”

Section: Methodsmentioning

confidence: 99%

“…Mutations at each of these sites have previously been shown to confer escape in vitro (18,19,24,28,37). The rates at which they escape in HLA-matched hosts and revert in HLA-mismatched hosts, as measured from a longitudinal cohort of 189 acute seroconverters, are presented in Table 1.…”

mentioning

confidence: 99%

Cytotoxic T-Lymphocyte Escape Mutations Identified by HLA Association Favor Those Which Escape and Revert Rapidly

Fryer

Frater

Duda

et al. 2012

dIdentifying human immunodeficiency virus (HIV) immune escape mutations has implications for understanding the impact of host immunity on pathogen evolution and guiding the choice of vaccine antigens. One means of identifying cytotoxic-T-lymphocyte (CTL) escape mutations is to search for statistical associations between mutations and host human leukocyte antigen (HLA) class I alleles at the population level. The impact of evolutionary rates on the strength of such associations is not well defined. Here, we address this topic using a mathematical model of within-host evolution and between-host transmission of CTL escape mutants that predicts the prevalence of escape mutants at the population level. We ask how the rates at which an escape mutation emerges in a host who bears the restricting HLA and reverts when transmitted to a host who does not bear the HLA affect the strength of an association. We consider the impact of these factors when using a standard statistical method to test for an association and when using an adaptation of that method that corrects for phylogenetic relationships. We show that with both methods, the average sample size required to identify an escape mutation is smaller if the mutation escapes and reverts quickly. Thus, escape mutations identified as HLA associated systematically favor those that escape and revert rapidly. We also present expressions that can be used to infer escape and reversion rates from cross-sectional escape prevalence data.T he human leukocyte antigen (HLA)-restricted cytotoxic T-lymphocyte (CTL) immune response is thought to make a significant contribution to the control of human immunodeficiency virus (HIV) (4,5,13,27). A deeper understanding of the CTL response is important to the development of an HIV vaccine. One way to study the CTL response is by investigating the way in which HIV is evolving escape mutants-viral strains that evade recognition by CTLs. Evidence to support the evolution of CTL escape mutants has been observed both within individuals (4,21,28,36,39) and at the population level (3,9,17,23,25,33,38). At the population level, evidence has been found in the form of statistical associations between certain HLA class I alleles-the human genetic determinants of CTL responses-and certain mutations away from the sample/subtype consensus in the HIV genome (3, 9, 33). The patterns emerge because of heterogeneity in HLA alleles among the population. Individuals who share HLA alleles tend to target the same viral antigens (called CTL epitopes) and therefore drive the same escape mutations. Escape mutations have been shown to revert to the wild-type form (e.g., back to the subtype consensus) following transmission to hosts who do not bear the selecting HLA (28, 29). The combination of these two factors-escape in "HLA-matched" hosts and reversion in "HLAmismatched" hosts-means that although viral mutants can be transmitted between individuals, any particular escape mutation should be more prevalent in HLA-matched than in HLA-mismatched hosts. Simple statistic...

“…With the increased feasibility of screening for genome-wide CTL responses (1,5,9,22,26,59,67) and sequencing of HIV-1 (58,60), numerous studies have undertaken comprehensive analyses to examine the interplay between host CTL responses and the evolution of HIV-1 (2,10,16,21,30,31,36,39,53,65). In particular, two studies investigated HIV-1 sequence variations across the entire genome and revealed a strong influence of CTL-driven immune responses on HIV-1 evolution both within the first month and many years after infection (2,10).…”

mentioning

confidence: 99%

Rapid Reversion of Sequence Polymorphisms Dominates Early Human Immunodeficiency Virus Type 1 Evolution

Gladden

Altfeld

et al. 2007

145

147

The error-prone replication of human immunodeficiency virus type 1 (HIV-1) enables it to continuously evade host CD8 ؉ T-cell responses. The observed transmission, and potential accumulation, of CD8 ؉ T-cell escape mutations in the population may suggest a gradual adaptation of HIV-1 to immune pressures. Recent reports, however, have highlighted the propensity of some escape mutations to revert upon transmission to a new host in order to restore efficient replication capacity. To more specifically address the role of reversions in early HIV-1 evolution, we examined sequence polymorphisms arising across the HIV-1 genome in seven subjects followed longitudinally 1 year from primary infection. As expected, numerous nonsynonymous mutations were associated with described CD8 ؉ T-cell epitopes, supporting a prominent role for cellular immune responses in driving early HIV-1 evolution. Strikingly, however, a substantial proportion of substitutions (42%) reverted toward the clade B consensus sequence, with nearly one-quarter of them located within defined CD8 epitopes not restricted by the contemporary host's HLA. More importantly, these reversions arose significantly faster than forward mutations, with the most rapidly reverting mutations preferentially arising within structurally conserved residues. These data suggest that many transmitted mutations likely incur a fitness cost that is recovered through retrieval of an optimal, or ancestral, form of the virus. The propensity of mutations to revert may limit the accumulation of immune pressure-driven mutations in the population, thus preserving critical CD8؉ T-cell epitopes as vaccine targets, and argue against an unremitting adaptation of HIV-1 to host immune pressures.