Effective Suppression of HIV-1 Replication by Cytotoxic T Lymphocytes Specific for Pol Epitopes in Conserved Mosaic Vaccine Immunogens

Abstract

Cytotoxic T lymphocytes (CTLs) with strong abilities to suppress HIV-1 replication and recognize circulating HIV-1 could be key for both HIV-1 cure and prophylaxis. We recently designed conserved mosaic T-cell vaccine immunogens (tHIVconsvX) composed of 6 Gag and Pol regions. Since the tHIVconsvX vaccine targets conserved regions common to most global HIV-1 variants and employs a bivalent mosaic design, it is expected that it could be universal if the vaccine works. Although we recently demonstrated that CTLs specific for 5 Gag epitopes in the vaccine immunogens had strong ability to suppress HIV-1 replication in vitro and in vivo, it remains unknown whether the Pol region-specific CTLs are equally efficient. In this study, we investigated CTLs specific for Pol epitopes in the immunogens in treatment-naive Japanese patients infected with HIV-1 clade B. Overall, we mapped 20 reported and 5 novel Pol conserved epitopes in tHIVconsvX. Responses to 6 Pol epitopes were significantly associated with good clinical outcome, suggesting that CTLs specific for these 6 Pol epitopes had a strong ability to suppress HIV-1 replication in HIV-1-infected individuals. In vitro T-cell analyses further confirmed that the Pol-specific CTLs could effectively suppress HIV-1 replication. The present study thus demonstrated that the Pol regions of the vaccine contained protective epitopes. T-cell responses to the previous 5 Gag and present 6 Pol protective epitopes together also showed a strong correlation with better clinical outcome. These findings support the testing of the conserved mosaic vaccine in HIV-1 cure and prevention in humans. IMPORTANCE It is likely necessary for an effective AIDS vaccine to elicit CD8+ T cells with the ability to recognize circulating HIV-1 and suppress its replication. We recently developed novel bivalent mosaic T-cell vaccine immunogens composed of conserved regions of the Gag and Pol proteins matched to at least 80% globally circulating HIV-1 isolates. Nevertheless, it remains to be proven if vaccination with these immunogens can elicit T cells with the ability to suppress HIV-1 replication. It is well known that Gag-specific T cells can suppress HIV-1 replication more effectively than T cells specific for epitopes in other proteins. We recently identified 5 protective Gag epitopes in the vaccine immunogens. In this study, we identified T cells specific for 6 Pol epitopes present in the immunogens with strong abilities to suppress HIV-1 in vivo and in vitro. This study further encourages clinical testing of the conserved mosaic T-cell vaccine in HIV-1 prevention and cure.

Therapeutic Vaccine in Chronically HIV-1-Infected Patients: A Randomized, Double-Blind, Placebo-Controlled Phase IIa Trial with HTI-TriMix

“…Still, the combination of subdominant, protective CTL regions, such HTI or other strategies, such as mosaic CTL vaccines aiming at more HIV-1 clades, is supported by several studies [34][35][36].…”

T cell-based strategies for HIV-1 vaccines

“…19 Red numbers mark 5 epitopes in Gag and 6 in Pol that are included in this conserved vaccine that was subsequently found to be strongly associated with viral control in vitro and in vivo (the key to these epitopes is at bottom right). 40,41 Hanke HIVconsv 2007: 14 concatenated peptide fragments derived from different subtype consensus sequences (median length 40, range 27-130 amino acids (aa)); 17 Mothe HTI 2015: 16 fragments (median length 22.5, range 11-78 aa), concatenated with three joining alanine residues, based on regions that were preferentially targeted by individuals with low viral loads, published as European Patent EP2620446A1; 25 Korber Ultra CE: 40 highly conserved peptides (median length 18, range 14-22 aa), selected based on contiguous HIV-1 M group 9-mer coverage >80%, designed using the Epigraph tools, 42 currently under study, and first published here; Mullins p24 CE: Two variants each, of 7 regions of Gag (median 18, range 12-24 aa), concatenated with 2-4 aa alanine-rich linkers. 43. responses, 44,45 many of the observed CD8+ T-cell responses would have been immunologically silent against circulating viruses in the study population.…”

“…tHIVconsvX was highly immunogenic in mice, and in a Japanese treatment-naïve HIV+ population, natural responses to epitopes within the vaccine were associated with lower viral loads and higher CD4+ T-cell counts. 19 Five specific epitopes were identified in Gag, 40 and six in Pol, 41 that suppress HIV-1 both in vivo and in vitro (Figure 1, red annotations); of note, regions containing these potentially advantageous conserved epitopes are usually missing from more tightly focused conserved-region designs (Figure 1). Components of the tHIVconsvX vaccine are currently being tested in a Phase I clinical trial (NCT03844386).…”

Novel Nested Peptide Epitopes Recognized by CD4+ T Cells Induced by HIV-1 Conserved-Region Vaccines

“…The convention is to regard CD8 + T cells as the effector cells killing HIV-1-infected cells and CD4 + T cells as the helper cells to both CD8 + cytolytic cells and B cells producing antibodies, however, it is well documented that CD4 + T cells can also exert cytolytic activity [3][4][5][6][7]. Both CD8 + [8][9][10][11] and CD4 + [5,6,[12][13][14][15][16] T-cell responses have been associated with HIV-1 immune control and their broadly specific coordinated actions are likely to be important for protection.…”