Correlates of spontaneous viral control among long-term survivors of perinatal HIV-1 infection expressing human leukocyte antigen-B57

Abstract

Objective We sought to identify immunologic and virologic correlates of spontaneous viral control among long-term survivors of perinatal HIV infection expressing the protective HLA-B57 allele. Design The frequency, epitope specificity, and functional attributes of HIV-specific T cells and sequence variation within B57-restricted epitopes were compared between “spontaneous controllers” who maintained normal CD4 percentages and viral loads <3000 copies/ml without antiretroviral therapy, and “treated progressors” who had initiated HAART. Methods Recognition of HIV optimal epitopes was assessed by IFNγ Elispot. Functional characterization of CD8 cells targeting B57 epitopes was performed by staining for cytokine production (intracellular IFNγ, IL-2, TNFα) and degranulation. Sequencing of autologous RNA was performed to determine the prevalence of viral escape mutations within B57-restricted epitopes and associated compensatory mutations. Results HLA-B57 remained immunodominant during chronic infection in both controllers and progressors, but controllers recognized fewer epitopes and targeted epitopes within Gag and RT only, whereas progressors demonstrated a broader response targeting additional proteins. No individual epitope was targeted more frequently by spontaneous controllers. CD8 cytokine production patterns were heterogeneous among individuals and even among different epitopes in the same individual, and did not correlate with spontaneous viral control. Extensive sequence variation within B57 epitopes was observed in both groups, but only progressors displayed additional capsid mutations that are known to offset the viral fitness cost of B57-driven immune escape. Conclusions Among HLA-B57+ long-term survivors, spontaneous control of viremia is not associated with a qualitatively or quantitatively superior T cell response, but with uncompensated fitness-attenuating mutations in the viral capsid.

The Hypervariable HIV-1 Capsid Protein Residues Comprise HLA-Driven CD8 + T-Cell Escape Mutations and Covarying HLA-Independent Polymorphisms

“…Furthermore, accumulation of HLA-B-associated Gag escape mutations is linked with lowered viral loads (25). However, escape mutations that reduce viral fitness drive the selection of variants that compensate for reduced function (5,10,14,28,30,35). These compensatory mutations can occur in the same epitope (10,31) or at sites both proximal and distal to the epitope (5,22,24,31).…”

Both HLA-B*57 and Plasma HIV RNA Levels Contribute to the HIV-Specific CD8 + T Cell Response in HIV Controllers

“…However, only a minority of HLA-B*57 ϩ or HLA-B*27 ϩ patients become HIC when infected, even though plasma HIV RNA levels are lower in these patients than in those who do not bear protective HLA alleles (18)(19)(20). In addition, 15% to 70% of HIC in the different cohorts are not HLA-B*57 ϩ (14,(21)(22)(23), and in the Agence Nationale de Recherche sur le SIDA (ANRS), French National Agency for Research on AIDS, cohort of controllers, 43% of HIC patients are HLA-B*57…”

Combination of Immune and Viral Factors Distinguishes Low-Risk versus High-Risk HIV-1 Disease Progression in HLA-B*5701 Subjects

“…HLA-B*5701 subjects with a baseline of Ͼ750 CD4 ϩ T cells/ mm 3 (LRPs) were characterized by the gradual emergence of variants during sequential population bottlenecks (18,53,75) along restricted pathways. No mutants were detected in the QW9 epitope, possibly due to strong purifying selection, while mutations in ISW9, TW10, and CypA appeared to be driven by genetic drift rather than positive selection.…”

“…A few studies have investigated viral diversity in HLA-B*5701 individuals in the context of epitope-specific CD8 ϩ T cell responses (3,38,49,59,75). Most studies have focused on correlates of protection by analyzing immunological profiles of LTNPs/ECs, where viral evolution is difficult to detect.…”