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Although antiretroviral therapy has made human immunodeficiency virus (HIV) infection a controllable disease, it is still unclear how viral replication persists in untreated patients and causes CD4(+) T-cell depletion leading to acquired immunodeficiency syndrome (AIDS) in several years. Theorists tried to explain it with the diversity threshold theory in which accumulated mutations in the HIV genome make the virus so diverse that the immune system will no longer be able to recognize all the variants and fail to control the viraemia. Although the theory could apply to a number of cases, macaque AIDS models using simian immunodeficiency virus (SIV) have shown that failed viral control at the set point is not always associated with T-cell escape mutations. Moreover, even monkeys without a protective major histocompatibility complex (MHC) allele can contain replication of a super infected SIV following immunization with a live-attenuated SIV vaccine, while those animals are not capable of fighting primary SIV infection. Here we propose a recursion-based virus-specific naive CD4(+) T-cell depletion hypothesis through thinking on what may happen in individuals experiencing primary immunodeficiency virus infection. This could explain the mechanism for impairment of virus-specific immune response in the course of HIV infection. [ABSTRACT FROM AUTHOR]

Development of an effective AIDS vaccine is crucial for the control of global human immunodeficiency virus type 1 (HIV-1) prevalence. We have developed a novel AIDS vaccine using a Sendai virus (SeV) vector and investigated its efficacy in a macaque AIDS model of simian immunodeficiency virus (SIV) infection. Its immunogenicity and protective efficacy have been shown, indicating that the SeV vector is a promising delivery tool for AIDS vaccines. Here, we describe the potential of SeV vector as a vaccine antigen delivery tool to induce effective immune responses against HIV-1 infection. [ABSTRACT FROM AUTHOR]

Abstract: Fv-4 is a mouse gene that confers resistance against ecotropic murine leukemia virus (MLV) infection on mice. While receptor interference by the Fv-4 env gene product, Fv-4 Env, that can bind to the ecotropic MLV receptor has been shown to play an important role in the resistance, other mechanisms have also been suggested because it confers extremely efficient, complete resistance in vivo. Here, we have examined the effect of Fv-4 Env on infectious MLV production. Infectious MLV titers in supernatants obtained after transfection with a Friend MLV (FMLV) Env-expressing plasmid from MLV gag–pol producer cells harboring a retroviral vector were largely reduced by coexpression of Fv-4 Env. Syncytia formation mediated by R-peptide-deleted FMLV Env in NIH 3T3 cells was impaired by Fv-4 Env coexpression. Similarly, Fv-4 Env inhibited infectious amphotropic MLV production and syncytia formation mediated by R-peptide-deleted amphotropic MLV Env. Immunoprecipitation analysis revealed interaction of Fv-4 Env with amphotropic MLV Env as well as FMLV Env. These results indicate that Fv-4 Env inhibits infectious ecotropic and amphotropic MLV production by exerting dominant negative effect on MLV Env, suggesting contribution of this inhibitory effect to the resistance against ecotropic MLV infection in Fv-4-expressing mice. [Copyright &y& Elsevier]

• The protective effect of HLA-B*57:01/58:01 on HIV-1 CRF01_AE infection was examined. • The protective impact is impaired against CRF01_AE infection. • TW10-specific CD8+ T cells select for T242N even in CRF01_AE with viral fitness cost. • Less non-TW10 epitope presentation may contribute to the impaired protective impact. Human Leukocyte Antigen HLA-B*57:01 and B*58:01 are considered anti-HIV-1 protective alleles. HLA-B*57:01/58:01-restricted HIV-1 Gag TW10 (TSTLQEQIGW, Gag residues 240-249) epitope-specific CD8+ T cell responses that frequently select for a Gag escape mutation, T242N, with viral fitness cost are crucial for HIV-1 control. Although this finding has been observed in cohorts where HIV-1 subtype B or C predominates, the protective impact of HLA-B*57:01/58:01 has not been reported in Southeast Asian countries where HIV-1 CRF01_AE is the major circulating strain. Here, the effect of HLA-B*57:01/58:01 on CRF01_AE infection was investigated. The correlation of HLA-B*57:01/58:01 with viral load and CD4 counts were analyzed in the CRF01_AE-infected Vietnamese cohort (N = 280). The impact of the T242N mutation on CRF01_AE replication capacity was assessed. HLA-B*57:01/58:01 -positive individuals mostly had HIV-1 with T242N (62/63) but showed neither a significant reduction in viral load nor increased CD4 counts relative to B*57:01/58:01 -negative participants. In vitro and in vivo analyses revealed a significant reduction in viral fitness of CRF01_AE with T242N. In silico analysis indicated reduced presentation of epitopes in the context of CRF01_AE compared to subtype B or C in 10/16 HLA-B*57:01/58:01-restricted HIV-1 epitopes. The protective impact of HLA-B*57:01/58:01 on CRF01_AE infection is impaired despite strong suppressive pressure by TW10-specific CD8+ T cells. [ABSTRACT FROM AUTHOR]

Abstract: Human immunodeficiency virus type 1 (HIV-1) and pathogenic simian immunodeficiency virus (SIV)-infected naïve hosts experience a characteristic absence of early and potent virus-specific neutralizing antibody (NAb) responses preceding establishment of persistent infection. Yet conversely, we have recently shown that NAbs passively immunized in rhesus macaques at early post-SIV challenge are capable of playing a critical role in non-sterile viremia control with implications of antibody-enhanced antigen presentation. In a current follow-up study we have further reported that NAbs mediate rapid elicitation of polyfunctional virus-specific CD4+ T-cells in vivo. The NAb-immunized macaques mounting these responses exhibited sustained viremia control for over 1 year, accompanied with robust anti-SIV cellular immunity. Perspectives obtained from the results are discussed. [Copyright &y& Elsevier]

Induction of antibodies targeting viral glycoproteins is a key for the development of a vaccine against enveloped virus infection. Glycoproteins on the virion exhibiting native multimer structure may be a good immunogen to present antibody epitopes, but it is often difficult to prepare immunogenic inactivated virions. Preparation of soluble glycoprotein multimers has been attempted, while virus-like particles carrying target glycoproteins can be a more immunogenic antigen. In the present study, a target glycoprotein-embedded Sendai virus (SeV) particle was developed for induction of anti-virus antibodies. We constructed a chimeric antigen, HIV-1 EnvF, consisting of HIV-1 Env ectodomain and SeV F transmembrane-cytoplasmic domain, which was shown to be efficiently incorporated into the SeV virion. EnvF was recognized by anti-HIV-1 broadly-neutralizing monoclonal antibodies (bnAbs) including 35O22 that targets an Env trimer-dependent epitope. Analysis revealed that HIV-1 AD8 EnvF can mediate viral entry into the cells, which is inhibited by anti-HIV-1 bnAbs and HIV-1 entry inhibitors, suggesting that the EnvF exhibits an HIV-1 Env native-like functional structure to present bnAb epitopes. Immunization of mice with replication-defective SeVs expressing HIV EnvF and non-infectious SeV particles (NVP) carrying HIV EnvF efficiently induced anti-HIV Env antibodies. HTLV-1 EnvF also showed the potential to efficiently induce anti-HTLV-1 Env antibodies. These results indicate that SeV particles carrying EnvF can be a promising vaccine platform for induction of antibodies targeting enveloped virus glycoproteins. [ABSTRACT FROM AUTHOR]

Abstract: IL-21 signaling is important for T cell and B cell-mediated clearance of chronic viral infections. While non-cognate follicular helper CD4+ T cells (TFH) are indicated to be pivotal in providing IL-21-mediated help to activated B cells within germinal centers, how this signaling may be disrupted in early AIDS virus infection is not clear. In this study, we assessed the lineage and kinetics of peripheral blood IL-21-producing CD4+ T cells in primary simian immunodeficiency virus (SIV) infection of rhesus macaques. After SIV challenge, antigen-nonspecific IL-21 production was observed in Th1, Th2 and Th17 cells with Th1 dominance. While IL-21+ Th2 and IL-21+ Th17 showed variable kinetics, an increase in total IL-21+ CD4+ T cells and IL-21+ Th1 from week 3 to week 8 was observed, preceding plasma SIV-specific IgG development from week 5 to week 12. SIV Gag-specific IL-21+ CD4+ T cells detectable at week 2 were decreased in frequencies at week 5. Results imply that kinetics of IL-21+ CD4+ T cells comprised of multiple lineages, potentially targeted by SIV with a bias of existing frequencies during their precursor stage, associate with availability of cooperative B-cell help provided through a proportionate precursor pool developing into TFH and subsequent anti-SIV antibody responses. [Copyright &y& Elsevier]

• CRF01_AE began to spread among MSM, with frequent cluster formations, in the 2000s. • CRF01_AE transmission risk has shifted from heterosexuals/IDUs to MSM since 2014. • Nevertheless, CRF01_AE transmissions among heterosexuals and IDUs have persisted. • Prevention measures need to target CRF01_AE in various populations in Japan. HIV-1 circulating recombinant form (CRF) 01_AE is the second major subtype in Japan. Our previous study indicated that CRF01_AE was predominantly circulating in heterosexuals/injecting drug users (IDUs). With implications of increased CRF01_AE infections among men who have sex with men (MSM), this study sought to investigate whether the transmission dynamics of CRF01_AE infections in Japan have changed. Sequences from 8032 newly diagnosed HIV-1-infected individuals were analysed. For 614 (7.6%) of CRF01_AE cases, clusters were identified and categorised by transmission risks. Median times to the most recent common ancestors (tMRCA) were estimated. The individuals were predominantly Japanese (64%) and male (72%). MSM became the predominant transmission risk from 2014. Thirty transmission clusters (TCs) and 48 pairs, including 40% of individuals, were identified. MSM were approximately five times more likely to be in a TC compared to heterosexuals, and were the major contributors to TCs. tMRCA data suggest that MSM TCs emerged from 1996 and became predominant around 2000. CRF01_AE has spread among MSM, with frequent and continuous cluster formations, and MSM has become the predominant transmission risk. Our study suggested that CRF01_AE transmission has shifted from heterosexuals/IDUs to MSM. Prevention measures targeting key populations should be considered for controlling CRF01_AE spread. [ABSTRACT FROM AUTHOR]

Abstract Numbers of HLA-associated polymorphisms have been reported on HIV-1 subtypes B and C, but few on other subtypes. Here, we analyzed HLA-associated gag and nef polymorphisms in HIV-1 subtype A/E prevalent in Vietnam. We determined HLA-A, B and C genotypes in 179 HIV-1-infected Vietnamese by next generation sequencing and analyzed proviral genome sequences in 144 of them, showing that 142 of the 144 were subtype A/E. Analysis revealed HLA-associated subtype A/E gag and nef polymorphisms at nineteen residues including those newly determined. Accumulation of these data would contribute to our understanding of HIV-1 subtype A/E and host immune interaction. [ABSTRACT FROM AUTHOR]

Abstract: HIV-1 is strictly adapted to humans, and cause disease-inducing persistent infection only in humans. We have generated a series of macaque-tropic HIV-1 (HIV-1mt) to establish non-human primate models for basic and clinical studies. HIV-1mt clones available to date grow poorly in macaque cells relative to SIVmac239. In this study, viral adaptive mutation in macaque cells, G114E in capsid (CA) helix 6 of HIV-1mt, that enhances viral replication was identified. Computer-assisted structural analysis predicted that another Q110D mutation in CA helix 6 would also increase viral growth potential. A new proviral construct MN4Rh-3 carrying CA-Q110D exhibited exquisitely enhanced growth property specifically in macaque cells. Susceptibility of MN4Rh-3 to macaque TRIM5α/TRIMCyp proteins was examined by their expression systems. HIV-1mt clones so far constructed already completely evaded TRIMCyp restriction, and further enhancement of TRIMCyp resistance by Q110D was not observed. In addition, Q110D did not contribute to evasion from TRIM5α restriction. However, the single-cycle infectivity of MN4Rh-3 in macaque cells was enhanced relative to the other HIV-1mt clones. Our results here indicate that CA-Q110D accelerates viral growth in macaque cells irrelevant to TRIM5 proteins restriction. [Copyright &y& Elsevier]

Abstract: Induction of durable cellular immune responses by vaccination is an important strategy for the control of persistent pathogen infection. Viral vectors are promising vaccine tools for eliciting antigen-specific T-cell responses. Repeated vaccination may contribute to durable memory T-cell induction, but anti-vector antibodies could be an obstacle to its efficacy. We previously developed a Sendai virus (SeV) vector vaccine and showed the potential of this vector for efficient T-cell induction in macaques. Here, we examined whether repeated SeV vector vaccination with short intervals can enhance antigen-specific CD8+ T-cell responses. Four rhesus macaques possessing the MHC-I haplotype 90-120-Ia were immunized three times with intervals of three weeks. For the vaccination, we used replication-defective F-deleted SeV vectors inducing CD8+ T-cell responses specific for simian immunodeficiency virus Gag206–216 and Gag241–249, which are dominant epitopes restricted by 90-120-Ia-derived MHC-I molecules. All four animals showed higher Gag206–216-specific and Gag241–249-specific CD8+ T-cell responses after the third vaccination than those after the first vaccination, indicating enhancement of antigen-specific CD8+ T-cell responses by the second/third SeV vector vaccination even with short intervals. These results suggest that repeated SeV vector vaccination can contribute to induction of efficient and durable T-cell responses. [Copyright &y& Elsevier]

Abstract: Viral vectors are promising vaccine tools for eliciting potent cellular immune responses. Pre-existing anti-vector antibodies, however, can be an obstacle to their clinical use in humans. We previously developed a Sendai virus (SeV) vector vaccine and showed the potential of this vector for efficient CD8+ T-cell induction in macaques. Here, we investigated the immunogenicity of SeV vector vaccination in the presence of anti-SeV antibodies. We compared antigen-specific CD8+ T-cell responses after intranasal or intramuscular immunization with a lower dose (one-tenth of that in our previous studies) of SeV vector expressing simian immunodeficiency virus Gag antigen (SeV-Gag) between naive and pre-SeV-infected cynomolgus macaques. Intranasal SeV-Gag immunization efficiently elicited Gag-specific CD8+ T-cell responses not only in naive but also in pre-SeV-infected animals. In contrast, intramuscular SeV-Gag immunization induced Gag-specific CD8+ T-cell responses efficiently in naive but not in pre-SeV-infected animals. These results indicate that both intranasal and intramuscular SeV administrations are equivalently immunogenic in the absence of anti-SeV antibodies, whereas intranasal SeV vaccination is more immunogenic than intramuscular in the presence of anti-SeV antibodies. It is inferred from a recent report investigating the prevalence of anti-SeV antibodies in humans that SeV-specific neutralizing titers in more than 70% of people are no more than those at the SeV-Gag vaccination in pre-SeV-infected macaques in the present study. Taken together, this study implies the potential of intranasal SeV vector vaccination to induce CD8+ T-cell responses even in humans, suggesting a rationale for proceeding to a vaccine clinical trial using this vector. [Copyright &y& Elsevier]

Abstract: Human immunodeficiency virus type 1 (HIV-1) hardly replicates in Old World monkeys. Recently, a mutant HIV-1 clone, NL-DT5R, in which a small part of gag and the entire vif gene are replaced with SIVmac239-derived ones, was shown to be able to replicate in pigtail monkeys but not in rhesus monkeys (RM). In the present study, we found that a modified monkey-tropic HIV-1 (HIV-1mt), MN4-5S, acquired the ability to replicate efficiently in cynomolgus monkeys as compared with the NL-DT5R, while neither NL-DT5R nor MN4-5S replicated in RM cells. These results suggest that multiple determinants may be involved in the restriction of HIV-1 replication in macaques, depending on the species of macaques. The new HIV-1mt clone will be useful for studying molecular mechanisms by which anti-viral host factors regulate HIV-1 replication in macaques. [ABSTRACT FROM AUTHOR]

The cytoplasmic RNA vector would be promising for use in gene vaccines to large population of patients or infected persons in urgent or in hospitals of various conditions because of its important genotoxicity-free nature. The candidate intranasal gene vaccines have been developed using Sendai virus (SeV) vector for both infectious and neurodegenerative diseases such as AIDS and Alzheimer's disease (AD), respectively. SeV belonging to the Genus Respirovirus, infects and multiplies its genome copy in most mammalian cells. Its replication is strictly in cytoplasm and independent of nuclear functions of host cells. Moreover, SeV does not have a DNA phase during its life cycle, so SeV-based vectors that express high-level of transgene do not need to be concerned about the transformation of cells by integration of vector materials into the host chromosomes. These properties of the vector enable us to propose the new concepts, CYTOPLASMIC GENE THERAPY and CYTOPLASMIC VACCINATION with RNP-based treatment.For the treatment of AD, the F gene-deleted non-transmissible SeV (SeV/ΔF) vector carrying amyloid-β (Aβ) gene was used. According to the “Amyloid Cascade Theory”, the formation of senile plaques through aggregation and deposition of Aβ peptides in the brain is considered as a major cause of the disease. Thus, immune-mediated strategy known as Aβ vaccination has been thought to be a promising therapeutic approach for the treatment of Alzheimer's disease. Single intranasal administration of SeV vector carrying Aβ gene (Aβ 1–43) to the 24 to 25-month-old APP transgenic mice induced the expression of the Aβ peptide in the epithelial cells of the nasal mucosa. Serum antibody level was elevated and the amyloid burdens in the brain were decreased to 10–20% of the control mice after eight weeks treatment. Importantly, no lymphocytes infiltration that into the central nervous system was detected.For the AIDS vaccine, the Gag-expressing SeV/ΔF vector was used. Macaques vaccinated with DNA-prime/Gag-expressing SeV/ΔF-boost were challenged intravenously with the pathogenic simian immunodeficiency virus (SIVmac239) that induces chronic disease progression. The SeV boost induced Gag-specific CD4+ T cells, and its level in peripheral T lymphocytes was maintained for more than 40 weeks. The vaccine-induced cytotoxic T lymphocytes (CTLs) controlled SIVmac239 replication well. Thus, the mucosal immunotherapy with SeV vector has the great potential of prevention and treatment for both infectious and neurodegenerative diseases and might be a novel, attractive approach in gene vaccines of coming age.Molecular Therapy (2006) 13, S294–S295; doi: 10.1016/j.ymthe.2006.08.845 [ABSTRACT FROM AUTHOR]

Abstract: Viral vectors are promising vaccine tools for eliciting antigen-specific T-cell responses. We previously showed the potential of recombinant Sendai virus (SeV) vectors to induce virus-specific T-cell responses in macaque AIDS models. Here, we have evaluated the immunogenicity of replication-competent V-knocked-out and replication-defective F-deleted SeV vectors in macaques. Intranasal replication-competent and replication-defective SeV immunizations both elicited robust systemic antigen-specific T-cell responses, whereas the responses induced by the former were more durable than those by the latter. However, even the latter-induced T-cell responses remained detectable in a local, retropharyngeal lymph node two months after the immunization. These findings are useful for establishment of a vaccine protocol using SeV vectors. [Copyright &y& Elsevier]

Abstract: To study the immune responses elicited by multiple vectors and develop vaccines strategies against prevalent HIV-1 strains in China, we have examined the potency of vaccine regimens of plasmid DNA, adenovirus, and Sendai virus vectors expressing HIV-1 gag consensus sequence of HIV-1 isolates from China for inducing specific immune responses. In BALB/c mice, combination of these vectors induced higher Gag-specific cellular immune response than any regimen using single vector alone. The prime-boost-boost regimen consisting of the triple heterologous vectors induced Gag-specific T-cell responses the most efficiently. In rhesus macaques, the prime-boost-boost regimen induced potent Gag-specific cellular immune responses as well as long lasting humoral immune response, and each booster resulted in rapid and efficient expansion of Gag-specific T cells. These results indicate that this prime-boost-boost regimen using triple heterologous vectors is a promising AIDS vaccine candidate for efficiently inducing HIV-1-specific cellular and humoral immune responses. Its further studies as a promising scheme for therapeutic and/or prophylactic HIV-1 vaccines should be grounded. [Copyright &y& Elsevier]

Abstract: A current promising AIDS vaccine strategy is to elicit CD8+ cytotoxic T lymphocyte (CTL) responses that broadly recognize highly-diversified HIVs. In our previous vaccine trial eliciting simian immunodeficiency virus (SIV) mac239 Gag-specific CTL responses, a group of Burmese rhesus macaques possessing a major histocompatibility complex haplotype 90-120-Ia have shown vaccine-based viral control against a homologous SIVmac239 challenge. Vaccine-induced Gag206–216 epitope-specific CTL responses exerted strong selective pressure on the virus in this control. Here, we have evaluated in vivo efficacy of vaccine-induced Gag206–216-specific CTL responses in two 90-120-Ia-positive macaques against challenge with a heterologous SIVsmE543-3 that has the same Gag206–216 epitope sequence with SIVmac239. Despite efficient Gag206–216-specific CTL induction by vaccination, both vaccinees failed to control SIVsmE543-3 replication and neither of them showed mutations within the Gag206–216 epitope. Further analysis indicated that Gag206–216-specific CTLs failed to show responses against SIVsmE543-3 infection due to a change from aspartate to glutamate at Gag residue 205 immediately preceding the amino terminus of Gag206–216 epitope. Our results suggest that even vaccine-induced CTL efficacy can be abrogated by a single amino acid change in viral epitope flanking region, underlining the influence of viral epitope flanking sequences on CTL-based AIDS vaccine efficacy. [Copyright &y& Elsevier]

Abstract: Recent prophylactic vaccine trials inducing virus-specific CD8+ T-cell responses have shown control of primary infections of a pathogenic simian-human immunodeficiency virus (SHIV) in macaques. In the chronic phase, therapeutic immunization replenishing virus-specific CD8+ T-cells is likely to contribute to sustained control of virus replication. In this study, we have administered a recombinant Sendai virus (SeV) vector into five rhesus macaques that had received prophylactic vaccinations and had controlled SHIV replication for more than 1 year after challenge. Our results indicate that virus-specific CD8+ T-cell responses can be expanded and broadened by therapeutic immunization with SeV vectors in the chronic phase after prophylactic vaccine-based control of primary immunodeficiency virus infections. [Copyright &y& Elsevier]