Maternal Transmission of Human Immunodeficiency Virus Escape Mutations Subverts HLA-B57 Immunodominance but Facilitates Viral Control in the Haploidentical Infant

Human immunodeficiency virus (HIV)-infected infants in the developing world typically progress to AIDS or death within the first 2 years of life. However, a minority progress relatively slowly. This study addresses the potential contribution of viral factors to HIV disease progression in eight infants selected from a wellcharacterized cohort of C clade HIV-infected infants, monitored prospectively from birth in Durban, South Africa. Three infants were defined as "progressors," and five were defined as "slow progressors." We observed that slow-progressor infants carry HIV isolates with significantly lower replicative capacity compared to virus from progressors. Furthermore, our data suggest a link between the attenuated viral phenotype and HLA-B* 57/5801 epitope-specific Gag mutational patterns of the transmitted virus and not to coreceptor usage or to the presence of Nef deletions or insertions. These data underline the importance of virus-host interactions and highlight the contribution of viral attenuation through Gag-specific CD8 ؉ T-cell escape mutations, among other factors, in the control of pediatric HIV infection.

Section: Clinical Evolution and Virus Isolationmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 99%

Replicative Capacity of Human Immunodeficiency Virus Type 1 Transmitted from Mother to Child Is Associated with Pediatric Disease Progression Rate

Prado

Prendergast

Thobakgale

et al. 2010

“…Transmission of such isolates already harboring escape mutations may then potentially prevent early immune control. This was demonstrated for HIV-1, where compensated escape mutations were stable upon their transmission (43) and preexisting compensatory mutations facilitated the development of escape mutations associated with rapid disease progression even in the presence of protective HLA class I alleles (44). For HCV, it is unclear if the sequence of the transmitted virus also plays a role in subsequent immune control.…”

Section: Discussionmentioning

confidence: 99%

Escape from a Dominant HLA-B*15-Restricted CD8 ⁺ T Cell Response against Hepatitis C Virus Requires Compensatory Mutations outside the Epitope

Ruhl

Chhatwal

Strathmann

et al. 2012

Self Cite

Antiviral CD8 ؉ T cells are a key component of the adaptive immune system against hepatitis C virus (HCV).For the development of immune therapies, it is essential to understand how CD8 ؉ T cells contribute to clearance of infection and why they fail so often. A mechanism for secondary failure is mutational escape of the virus. However, some substitutions in viral epitopes are associated with fitness costs and often require compensatory mutations. We hypothesized that compensatory mutations may point toward epitopes under particularly strong selection pressure that may be beneficial for vaccine design because of a higher genetic barrier to escape. We previously identified two HLA-B*15-restricted CD8 ؉ epitopes in NS5B (LLRHHNMVY 2450-2458 and SQRQKKVTF 2466-2474 ), based on sequence analysis of a large HCV genotype 1b outbreak. Both epitopes are targeted in about 70% of HLA-B*15-positive individuals exposed to HCV. Reproducible selection of escape mutations was confirmed in an independent multicenter cohort in the present study. Interestingly, mutations were also selected in the epitope flanking region, suggesting that compensatory evolution may play a role. Covariation analysis of sequences from the database confirmed a significant association between escape mutations inside one of the epitopes (H2454R and M2456L) and substitutions in the epitope flanking region (S2439T and K2440Q). Functional analysis with the subgenomic replicon Con1 confirmed that the primary escape mutations impaired viral replication, while fitness was restored by the additional substitutions in the epitope flanking region. We concluded that selection of escape mutations inside an HLA-B*15 epitope requires secondary substitutions in the epitope flanking region that compensate for fitness costs.A ntiviral CD8 ϩ T cells are one of the key components of the adaptive immune system against hepatitis C virus (HCV). During acute infection, HCV-specific CD8 ϩ T cells are activated in the majority of patients (24, 38). Nevertheless, viral persistence is observed in 50 to 80% of patients. These patients with chronic HCV infection are at risk of progressive liver disease and liver cancer. For the development of immune therapies against HCV, it is essential to understand how CD8 ϩ T cells contribute to clearance of infection and why they fail so often. Different mechanisms for CD8 ϩ T cell failure have been described. The proposed mechanisms include primary failure by lack or impairment of priming of specific CD8 ϩ T cells upon HCV infection, as well as secondary failure after the initial priming (reviewed in reference 40). Studies of patients with acute HCV infection suggest that CD8 ϩ T cells are activated in most patients, irrespective of the outcome of infection (6), which supports an important role for secondary failure of HCV-specific CD8 ϩ T cells.Upon transition from acute to chronic HCV infection, the frequency of specific CD8 ϩ T cells declines (6). Moreover, CD8 ϩ T cells from patients with chronic HCV infection produce fewer cytokines and p...

“…Moreover, a recent study of children born to B57 ϩ mothers revealed reduced viral loads in the B57 ϩ children despite the transmission of B57 CTL escape mutants (54). In addition, there is a report of an inverse relationship between plasma viral load and the number of genotypic resistance mutations during primary infection (14).…”

Section: Discussionmentioning

confidence: 99%

Impaired Replication Capacity of Acute/Early Viruses in Persons Who Become HIV Controllers

Miura

Brumme

Brockman

et al. 2010

Self Cite

121

129

were shown to exhibit impaired replication capacities, in part associated with escape mutations from cytotoxic-T-lymphocyte (CTL) responses. In contrast, little is known about viruses during acute/early infection in individuals who subsequently become HIV controllers. Here, we examine the viral replication capacities, HLA types, and virus sequences from 18 HIV-1 controllers identified during primary infection. gag-protease chimeric viruses constructed using the earliest postinfection samples displayed significantly lower replication capacities than isolates from persons who failed to control viremia (P ‫؍‬ 0.0003). Protective HLA class I alleles were not enriched in these early HIV controllers, but viral sequencing revealed a significantly higher prevalence of drug resistance mutations associated with impaired viral fitness in controllers than in noncontrollers (6/15 [40.0%] versus 10/80 [12.5%], P ‫؍‬ 0.018). Moreover, of two HLA-B57-positive (B57 ؉ ) controllers identified, both harbored, at the earliest time point tested, signature escape mutations within Gag that likewise impair viral replication capacity. Only five controllers did not express "protective" alleles or harbor viruses with drug resistance mutations; intriguingly, two of them displayed typical B57 signature mutations (T242N), suggesting the acquisition of attenuated viruses from B57 ؉ donors. These data indicate that acute/early stage viruses from persons who become controllers have evidence of reduced replication capacity during the initial stages of infection which is likely associated with transmitted or acquired CTL escape mutations or transmitted drug resistance mutations. These data suggest that viral dynamics during acute infection have a major impact on HIV disease outcome.