Identification of novel virus-specific antigens by CD4 + and CD8 + T cells from asymptomatic HSV-2 seropositive and seronegative donors

Abstract

Reactivation of latent herpes simplex virus 2 (HSV-2) infections can be characterized by episodic recurrent genital lesions and/or viral shedding. We hypothesize that infected (HSV-2(pos)) asymptomatic individuals have acquired T cell responses to specific HSV-2 antigen(s) that may be an important factor in controlling their recurrent disease symptoms. Our proteomic screening technology, ATLAS, was used to characterize the antigenic repertoire of T cell responses in infected (HSV-2(pos)) and virus-exposed seronegative (HSV-2(neg)) subjects. T cell responses, determined by IFN-γ secretion, were generated to gL, UL2, UL11, UL21, ICP4, ICP0, ICP47 and UL40 with greater magnitude and/or frequency among cohorts of exposed HSV-2(neg) or asymptomatic HSV-2(pos) individuals, compared to symptomatic recurrent HSV-2(pos) subjects. T cell antigens recognized preferentially among individuals who are resistant to infection or who are infected and have mild or no clinical disease may provide new targets for the design of vaccines aimed at treating and/or preventing HSV-2 infection.

Discordant humoral and cellular immune responses toCytomegalovirus(CMV) in glioblastoma patients whose tumors are positive for CMV

“…confirmed the presence of CD8 C T cell reactivity to nine peptides of HSV proteins in more than 15% of seronegative individuals. 26 The same phenomena is well known in HIV-exposed individuals; T cells reactive to HIV present in some individuals exist in the absence of HIV-specific antibodies. [27][28][29][30][31][32][33][34] Similar observations are also made in Hepatitis Cand B-exposed individuals.…”

Human Asymptomatic Epitopes Identified from the Herpes Simplex Virus Tegument Protein VP13/14 (UL47) Preferentially Recall Polyfunctional Effector Memory CD44highCD62LlowCD8+TEMCells and Protect Humanized HLA-A*02:01 Transgenic Mice against Ocular Herpesvirus Infection

“…Tegument proteins are delivered to the cytoplasm of host cells during viral entry, resulting in immediate processing by APCs shortly after infection (9-12). Tegument proteins hence constitute an immediate target Ag for T cells (9,10). Considering the failures during the last 2 decades of clinical herpes simplex vaccine trials using envelope glycoproteins gB and gD (21,22), it is surprising how only a few reports of studies assessing the vaccine potential of tegument proteins exist.…”

“…Relative mRNA expression levels were calculated using the following formula: ratio ϭ (E target Δ CP target (control Ϫ Tetramer-VP13/14 peptide staining. Fresh PBMCs were analyzed for the frequency of CD8 ϩ T cells recognizing the VP13/14 peptide-tetramer complexes, as we previously described (9)(10)(11)(12). The cells were incubated with the VP13/14 peptide-tetramer complex for 30 to 45 min at 37°C.…”

“…Among the 84-plus open reading frames (ORFs) of the HSV-1 genome, those encoding tegument protein Ags are the least immunologically characterized (9)(10)(11)(12). In animal models of herpesvirus infection and disease, HSV-specific CD8 ϩ T cells play a critical role in aborting attempts of virus reactivation from latency and in clearing herpetic disease (2,4,14,(23)(24)(25).…”

Prophylactic Herpes Simplex Virus 2 (HSV-2) Vaccines Adjuvanted with Stable Emulsion and Toll-Like Receptor 9 Agonist Induce a Robust HSV-2-Specific Cell-Mediated Immune Response, Protect against Symptomatic Disease, and Reduce the Latent Viral Reservoir

“…The choice of antigen targets to which CD4/CD8 T cell responses should be directed during HSV-2 infection has been less clear, in part due to a panoply of viral proteins that have been identified in preclinical and clinical studies as having potential for T cell induction (36)(37)(38). We identified the HSV-2 ribonucleotide reductase small subunit (UL40) (15,16) as an effective target antigen for robust CD4 and CD8 T cell responses in immunized mice. This subunit, also known as RR2, forms a holoenzyme with the subunit RR1 that is responsible for providing precursors necessary for viral DNA synthesis (39).…”