CTL Responses of High Functional Avidity and Broad Variant Cross-Reactivity Are Associated with HIV Control

Abstract

Cytotoxic T lymphocyte (CTL) responses targeting specific HIV proteins, in particular Gag, have been associated with relative control of viral replication in vivo. However, Gag-specific CTL can also be detected in individuals who do not control the virus and it remains thus unclear how Gag-specific CTL may mediate the beneficial effects in some individuals but not in others. Here, we used a 10mer peptide set spanning HIV Gag-p24 to determine immunogen-specific T-cell responses and to assess functional properties including functional avidity and cross-reactivity in 25 HIV-1 controllers and 25 non-controllers without protective HLA class I alleles. Our data challenge the common belief that Gag-specific T cell responses dominate the virus-specific immunity exclusively in HIV-1 controllers as both groups mounted responses of comparable breadths and magnitudes against the p24 sequence. However, responses in controllers reacted to lower antigen concentrations and recognized more epitope variants than responses in non-controllers. These cross-sectional data, largely independent of particular HLA genetics and generated using direct ex-vivo samples thus identify T cell responses of high functional avidity and with broad variant reactivity as potential functional immune correlates of relative HIV control.

Gag and env conserved element CE DNA vaccines elicit broad cytotoxic T cell responses targeting subdominant epitopes of HIV and SIV Able to recognize virus-infected cells in macaques

“…The CE selection included analysis of MHC binding prediction to address immunogenicity in humans, and we found that epitopes from all MHC class I known supertypes were represented in Gag CE. As reported previously, 19 in a group of 50 people, >30 epitopes were recognized using >40 HLA alleles. No similar laboratory studies have been performed for Env, but in silico analysis indicated that the Env CE together represent a predicted 141 MHC Class I and 760 MHC Class II epitopes with an IC50 value < 50 nmol (www.iedb.org).…”

“…During primary infection in humans the reduction of the original viral burst is associated with the emergence of HIV-specific cytotoxic CD8 + T lymphocytes (CTL). 19 , 33 , 34 , 39–53 Their role in controlling viremia was confirmed by systemic CD8 depletion in SIV/SHIV infected macaques, which resulted in a rapid increase in viremia, 54–57 demonstrating a CD8-dependent immunological mechanisms of viral control. 58–67 Failure to contain viral replication in macaques correlated with the emergence of viral mutants that escaped from CTL immune surveillance.…”

“…Our strategy to design interventions capable of inducing protective cellular responses has been the generation of DNA vaccines encoding immunogens that focus the immune response to conserved elements (CE) of HIV p24 Gag 1 , 2 , 8 , 9 , 19 resulting in the development of p24CE DNA vaccine. 20 , 21 , 73 Seven CE, spanning 12 to 24 AA in length, were selected based on their stringent conservation across all known HIV sequences, broad HLA-coverage, and association with HIV control.…”

“…20 , 21 , 73 Seven CE, spanning 12 to 24 AA in length, were selected based on their stringent conservation across all known HIV sequences, broad HLA-coverage, and association with HIV control. 19 , 53 , 74 , 75 By positional analogy and sequence homology to the HIV p24CE, an SIV p27 Gag (p27CE) derived molecule was generated. 76 Using a similar approach based on sequence conservation, association with virologic control, and CTL escape resulting in a loss in viral fitness, we generated HIV Env CE molecules 77 comprising 12 highly conserved regions of Env, spanning 11 to 43 AA in length.…”

DNA Prime-Boost Vaccine Regimen To Increase Breadth, Magnitude, and Cytotoxicity of the Cellular Immune Responses to Subdominant Gag Epitopes of Simian Immunodeficiency Virus and HIV

“…To address the problem of viral variability, many approaches have been tested including strategies that use consensus, center-of-tree or ancestral sequences, multiple strains or mosaic immunogens, immunogens consisting of known epitopes, and chimeric molecules expressing a selection of the most conserved epitopes from different clades of HIV . In our approach (20)(21)(22), we designed a plasmid DNA (pDNA) vaccine to focus the immune response to conserved elements (CE) of the HIV-1 proteome based on stringent conservation, broad HLA-coverage, and association with HIV control (19,(23)(24)(25). The p24…”