CD8+ T-cell Cytotoxic Capacity Associated with Human Immunodeficiency Virus-1 Control Can Be Mediated through Various Epitopes and Human Leukocyte Antigen Types

Abstract

Understanding natural immunologic control over Human Immunodeficiency Virus (HIV)-1 replication, as occurs in rare long-term nonprogressors/elite controllers (LTNP/EC), should inform the design of efficacious HIV vaccines and immunotherapies. Durable control in LTNP/EC is likely mediated by highly functional virus-specific CD8+ T-cells. Protective Human Leukocyte Antigen (HLA) class I alleles, like B*27 and B*57, are present in most, but not all LTNP/EC, providing an opportunity to investigate features shared by their HIV-specific immune responses. To better understand the contribution of epitope targeting and conservation to immune control, we compared the CD8+ T-cell specificity and function of B*27/57neg LTNP/EC (n = 23), B*27/57pos LTNP/EC (n = 23) and B*27/57neg progressors (n = 13). Fine mapping revealed 11 previously unreported immunodominant responses. Although B*27/57neg LTNP/EC did not target more highly conserved epitopes, their CD8+ T-cell cytotoxic capacity was significantly higher than progressors. Similar to B*27/57pos LTNP/EC, this superior cytotoxicity was mediated by preferential expansion of immunodominant responses and lysis through the predicted HLA. These findings suggest that increased CD8+ T-cell cytotoxic capacity is a common mechanism of control in most LTNP/EC regardless of HLA type. They also suggest that potent cytotoxicity can be mediated through various epitopes and HLA molecules and could, in theory, be induced in most people.

Antigen recognition-triggered drug delivery mediated by nanocapsule-functionalized cytotoxic T-cells

“…We note that substantially greater levels of both degranulation and of cargo release were observed with the FK10-specific as compared to the SL9-specific NC-CTLs. HIV-specific CTLs are well known to be functionally heterogeneous and to have differential abilities to kill HIV-infected and peptide pulsed cells [23]. Thus, we speculate that the degree of cargo release that occurs following an encounter with an antigen-presenting target cells may also be tunable by virtue of the cytotoxic capacity of the selected CTL.…”

Adoptive lymphocyte transfer to an HIV-infected progressor from an elite controller

“…This antibody was selected among 4 commercially available candidates for brightest fluorescence intensity on PBMCs of HLA-A*2 + donors and lowest nonspecific staining on PBMCs from HLA-A*2donors. Flow cytometric analysis was performed by standard protocols on a BD FACSAria Cell Sorter (BD) as previously described (11). Color compensations were performed using single-stained samples for each of the fluorochromes used.…”

“…Certain human leukocyte antigen (HLA) genotypes, including B*27 and B*57, are overrepresented in the EC population. This suggests an important role for CD8 + cytotoxic T lymphocytes (CTLs) in the control of HIV replication in ECs (11,12). The demonstration of enhanced HIV-specific CD8 + T cell responses in ECs compared with chronic progressors has lent further support to the hypothesis that CTLs play a dominant role in mediating control (13,14).…”

Evaluation of antiviral T cell responses and TSCM cells in volunteers enrolled in a phase I HIV-1 subtype C prophylactic vaccine trial in India

“…It is a recombinant Modified Vaccinia Ankara (MVA) virus containing the coding sequences of gag, env, reverse transcriptase (RT), tat, rev and nef of an Indian HIV-1 clade C strain [34]. The vaccine was suspended in phosphate-buffered saline and 10% glycerol to contain 5x10 6 PFU in a total volume of 0.5 mL. The amino acid sequence homology between the two vector inserts was found to be greater than 85% (ENV: 87.1%; GAG: 95%; POL/RT: 96.4%).…”

“…There is strong evidence to suggest that T cell-mediated responses play an important role in suppression of virus replication and clearance of infected cells from the host [4][5][6]. Several cohort studies have reported that generation and proliferation of HIV-specific CD8 + T cells correlate inversely with viral load [7][8][9][10].…”