Mosaic HIV-1 Gag Antigens Can Be Processed and Presented to Human HIV-Specific CD8+ T Cells

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Analyses of the breadth and specificity of virus-specific CD8؉ T cell responses associated with control of HIV have largely relied on measurement of cytokine secretion by effector T cells. These have resulted in the identification of HIV elite controllers with low or absent responses in which non-T-cell mechanisms of control have been suggested. However, successful control of HIV infection may be associated with central memory T cells, which have not been consistently examined in these individuals. Gagspecific T cells were characterized using a peptide-based cultured enzyme-linked immunosorbent spot assay (ELISpot). Peripheral blood mononuclear cells from HIV elite controllers (n ‫؍‬ 10), progressors (n ‫؍‬ 12), and antiretroviral-treated individuals (n ‫؍‬ 9) were cultured with overlapping peptides for 12 days. Specificity was assessed by tetramer staining, functional features of expanded cells were assessed by cytokine secretion, and virus inhibition and phenotypic characteristics were assessed by cell sorting and coculture assays. After peptide stimulation, elite controllers showed a greater number of previously undetectable (new) responses compared to progressors (P ‫؍‬ 0.0008). These responses were highly polyfunctional, with 64.5% of responses having 3 to 5 functions. Expandable epitope-specific CD8 ؉ T cells from elite controllers had strong virus inhibitory capacity and predominantly displayed a central memory phenotype. These data indicate that elite controllers with minimal T cell responses harbor a highly functional, broadly directed central memory T cell population that is capable of suppressing HIV in vitro. Comprehensive examination of this cell population could provide insight into the immune responses associated with successful containment of viremia.

Section: Methodsmentioning

confidence: 99%

Elite Controllers with Low to Absent Effector CD8 ⁺ T Cell Responses Maintain Highly Functional, Broadly Directed Central Memory Responses

Ndhlovu

Proudfoot

Cesa

et al. 2012

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“…A pair of mosaic antigens used in combination elicited more potent and cross-reactive responses than a nonmosaic pair of immunogens that represented a B and C clade combination (26). Furthermore, Ndhlovu et al demonstrated that mosaic HIV antigens expressed by rAd26 are processed into natural epitopes that are recognized by human HIV-specific CD8 ϩ T lymphocytes (28). In a rhesus monkey vaccine study, we demonstrated that an increase from 2-valent to 3-valent mosaic Envs enhanced the breadth and potency of T cell and antibody responses against natural variants (29).…”

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confidence: 99%

Comparison of Immunogenicity in Rhesus Macaques of Transmitted-Founder, HIV-1 Group M Consensus, and Trivalent Mosaic Envelope Vaccines Formulated as a DNA Prime, NYVAC, and Envelope Protein Boost

Hulot

Korber

Giorgi

et al. 2015

An effective human immunodeficiency virus type 1 (HIV-1) vaccine must induce protective antibody responses, as well as CD4 ؉ and CD8؉ T cell responses, that can be effective despite extraordinary diversity of HIV-1. The consensus and mosaic immunogens are complete but artificial proteins, computationally designed to elicit immune responses with improved cross-reactive breadth, to attempt to overcome the challenge of global HIV diversity. In this study, we have compared the immunogenicity of a transmitted-founder (T/F) B clade Env (B.1059), a global group M consensus Env (Con-S), and a global trivalent mosaic Env protein in rhesus macaques. These antigens were delivered using a DNA prime-recombinant NYVAC (rNYVAC) vector and Env protein boost vaccination strategy. While Con-S Env was a single sequence, mosaic immunogens were a set of three Envs optimized to include the most common forms of potential T cell epitopes. Both Con-S and mosaic sequences retained common amino acids encompassed by both antibody and T cell epitopes and were central to globally circulating strains. Mosaics and Con-S Envs expressed as full-length proteins bound well to a number of neutralizing antibodies with discontinuous epitopes. Also, both consensus and mosaic immunogens induced significantly higher gamma interferon (IFN-␥) enzyme-linked immunosorbent spot assay (ELISpot) responses than B.1059 immunogen. Immunization with these proteins, particularly Con-S, also induced significantly higher neutralizing antibodies to viruses than B.1059 Env, primarily to tier 1 viruses. Both Con-S and mosaics stimulated more potent CD8-T cell responses against heterologous Envs than did B.1059. Both antibody and cellular data from this study strengthen the concept of using in silico-designed centralized immunogens for global HIV-1 vaccine development strategies. IMPORTANCEThere is an increasing appreciation for the importance of vaccine-induced anti-Env antibody responses for preventing HIV-1 acquisition. This nonhuman primate study demonstrates that in silico-designed global HIV-1 immunogens, designed for a human clinical trial, are capable of eliciting not only T lymphocyte responses but also potent anti-Env antibody responses.

“…An alternative strategy to contend with global HIV-1 diversity is to use polyvalent full-length mosaic immunogens (4,10) that are designed to maximize immunologic coverage of HIV-1 sequence diversity while maintaining conserved sequences in their natural context (4,18). These full-length mosaic immunogens have been shown to induce an increased breadth and depth of HIV-1-specific cellular immune responses compared to those of natural and consensus HIV-1 antigens in rhesus monkeys (3,24).…”

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confidence: 99%

Full-Length HIV-1 Immunogens Induce Greater Magnitude and Comparable Breadth of T Lymphocyte Responses to Conserved HIV-1 Regions Compared with Conserved-Region-Only HIV-1 Immunogens in Rhesus Monkeys

Stephenson

SanMiguel

Simmons

et al. 2012

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A global HIV-1 vaccine will likely need to induce immune responses against conserved HIV-1 regions to contend with the profound genetic diversity of HIV-1. Here we evaluated the capacity of immunogens consisting of only highly conserved HIV-1 sequences that are aimed at focusing cellular immune responses on these potentially critical regions. We assessed in rhesus monkeys the breadth and magnitude of T lymphocyte responses elicited by adenovirus vectors expressing either full-length HIV-1 Gag/Pol/Env immunogens or concatenated immunogens consisting of only highly conserved HIV-1 sequences. Surprisingly, we found that the full-length immunogens induced comparable breadth (P ‫؍‬ 1.0) and greater magnitude (P ‫؍‬ 0.01) of CD8؉ T lymphocyte responses against conserved HIV-1 regions compared with the conserved-region-only immunogens. Moreover, the fulllength immunogens induced a 5-fold increased total breadth of HIV-1-specific T lymphocyte responses compared with the conserved-region-only immunogens (P ‫؍‬ 0.007). These results suggest that full-length HIV-1 immunogens elicit a substantially increased magnitude and breadth of cellular immune responses compared with conserved-region-only HIV-1 immunogens, including greater magnitude and comparable breadth of responses against conserved sequences.