Reduction of pyramidal and immature hippocampal neurons in pediatric simian immunodeficiency virus infection

Pediatric HIV infection remains a global health crisis with a worldwide infection rate of 2.5 million (WHO, Geneva Switzerland, 2009). Children are much more susceptible to HIV-1 neurological impairments than adults, which is exacerbated by co-infections. A major obstacle in pediatric HIV research is sample access. The proposed studies take advantage of ongoing pediatric SIV pathogenesis and vaccine studies to test the hypothesis that pediatric SIV infection diminishes neuronal populations and neurogenesis in the hippocampus. Newborn rhesus macaques (Macaca mulatta) that received intravenous inoculation of highly virulent SIVmac251 (n=3) or vehicle (control n=4) were used in this study. After a 6–18 week survival time, the animals were sacrificed and the brains prepared for quantitative histopathological analysis. Systematic sections through the hippocampus were either Nissl stained or immunostained for doublecortin (DCX+), a putative marker of neurogenesis. Using design-based stereology, we report a 42% reduction in the pyramidal neuron population of the CA1, CA2, and CA3 fields of the hippocampus (p < 0.05) in SIV-infected infants. The DCX+ neuronal population was also significantly reduced within the dentate gyrus of the hippocampus. The loss of hippocampal neurons and neurogenic capacity may contribute to the rapid neurocognitive decline associated with pediatric HIV infection. These data suggest that pediatric SIV infection, which leads to significant neuronal loss in the hippocampus within 3 months, closely models a subset of pediatric HIV infections with rapid progression

Of Mice and Monkeys: Can Animal Models Be Utilized to Study Neurological Consequences of Pediatric HIV-1 Infection?

Pediatric human immunodeficiency virus (HIV-1) infection remains a global health crisis. Children are much more susceptible to HIV-1 neurological impairments than adults, which can be exacerbated by coinfections. Neurological characteristics of pediatric HIV-1 infection suggest dysfunction in the frontal cortex as well as the hippocampus; limited MRI data indicate global cerebral atrophy, and pathological data suggest accelerated neuronal apoptosis in the cortex. An obstacle to pediatric HIV-1 research is a human representative model system. Host-species specificity of HIV-1 limits the ability to model neurological consequences of pediatric HIV-1 infection in animals. Several models have been proposed including neonatal intracranial injections of HIV-1 viral proteins in rats and perinatal simian immunodeficiency virus (SIV) infection of infant macaques. Nonhuman primate models recapitulate the complexity of pediatric HIV-1, neuropathogenesis while rodent models are able to elucidate the role specific viral proteins exert on neurodevelopment. Nonhuman primate models show similar behavioral and neuropathological characteristics to pediatric HIV-1 infection and offer a stage to investigate early viral mechanisms, latency reservoirs, and therapeutic interventions. Here we review the relative strengths and limitations of pediatric HIV-1 model systems

Partial efficacy of a VSV-SIV/MVA-SIV vaccine regimen against oral SIV challenge in infant macaques

Despite antiretroviral medications, the rate of pediatric HIV-1 infections through breast-milk transmission has been staggering in developing countries. Therefore, the development of a vaccine to protect vulnerable infant populations should be actively pursued. We previously demonstrated that oral immunization of newborn macaques with vesicular stomatitis virus expressing simian immunodeficiency virus genes (VSV-SIV) followed 2 weeks later by an intramuscular boost with modified vaccinia ankara virus expressing SIV (MVA-SIV) successfully induced SIV-specific T and B cell responses in multiple lymphoid tissues, including the tonsil and intestine [13]. In the current study, we tested the oral VSV-SIV prime/systemic MVA-SIV boost vaccine for efficacy against multiple oral SIVmac251 challenges starting two weeks after the booster vaccination. The vaccine did not prevent SIV infection. However, in vaccinated infants, the level of SIV-specific plasma IgA (but not IgG) at the time of challenge was inversely correlated with peak viremia. In addition, the levels of SIV-specific IgA in saliva and plasma were inversely correlated with viral load at euthanasia. Animals with tonsils that contained higher frequencies of SIV-specific TNF-α- or IFN-γ-producing CD8+ T cells and central memory T cells at euthanasia also had lower viremia. Interestingly, a marked depletion of CD25+ FoxP3+ CD4+ T cells was observed in the tonsils as well as the intestine of these animals, implying that T regulatory cells may be a major target of SIV infection in infant macaques. Overall, the data suggest that, in infant macaques orally infected with SIV, the co-induction of local antiviral cytotoxic T cells and T regulatory cells that promote the development of IgA responses may result in better control of viral replication. Thus, future vaccination efforts should be directed towards induction of IgA and mucosal T cell responses to prevent or reduce virus replication in infants

Vaccine-Elicited Mucosal and Systemic Antibody Responses Are Associated with Reduced Simian Immunodeficiency Viremia in Infant Rhesus Macaques

ABSTRACT Despite significant progress in reducing peripartum mother-to-child transmission (MTCT) of human immunodeficiency virus (HIV) with antiretroviral therapy (ART), continued access to ART throughout the breastfeeding period is still a limiting factor, and breast milk exposure to HIV accounts for up to 44% of MTCT. As abstinence from breastfeeding is not recommended, alternative means are needed to prevent MTCT of HIV. We have previously shown that oral vaccination at birth with live attenuated Mycobacterium tuberculosis strains expressing simian immunodeficiency virus (SIV) genes safely induces persistent SIV-specific cellular and humoral immune responses both systemically and at the oral and intestinal mucosa. Here, we tested the ability of oral M. tuberculosis vaccine strains expressing SIV Env and Gag proteins, followed by systemic heterologous (MVA-SIV Env/Gag/Pol) boosting, to protect neonatal macaques against oral SIV challenge. While vaccination did not protect infant macaques against oral SIV acquisition, a subset of immunized animals had significantly lower peak viremia which inversely correlated with prechallenge SIV Env-specific salivary and intestinal IgA responses and higher-avidity SIV Env-specific IgG in plasma. These controller animals also maintained CD4 + T cell populations better and showed reduced tissue pathology compared to noncontroller animals. We show that infants vaccinated at birth can develop vaccine-induced SIV-specific IgA and IgG antibodies and cellular immune responses within weeks of life. Our data further suggest that affinity maturation of vaccine-induced plasma antibodies and induction of mucosal IgA responses at potential SIV entry sites are associated with better control of viral replication, thereby likely reducing SIV morbidity. IMPORTANCE Despite significant progress in reducing peripartum MTCT of HIV with ART, continued access to ART throughout the breastfeeding period is still a limiting factor. Breast milk exposure to HIV accounts for up to 44% of MTCT. Alternative measures, in addition to ART, are needed to achieve the goal of an AIDS-free generation. Pediatric HIV vaccines constitute a core component of such efforts. The results of our pediatric vaccine study highlight the potential importance of vaccine-elicited mucosal Env-specific IgA responses in combination with high-avidity systemic Env-specific IgG in protection against oral SIV transmission and control of viral replication in infant macaques. The induction of potent mucosal IgA antibodies by our vaccine is remarkable considering the age-dependent development of mucosal IgA responses postbirth. A deeper understanding of postnatal immune development may inform the design of improved vaccine strategies to enhance systemic and mucosal SIV/HIV antibody responses

A Recombinant Attenuated Mycobacterium tuberculosis Vaccine Strain Is Safe in Immunosuppressed Simian Immunodeficiency Virus-Infected Infant Macaques

ABSTRACT Many resource-poor countries are faced with concurrent epidemics of AIDS and tuberculosis (TB) caused by human immunodeficiency virus (HIV) and Mycobacterium tuberculosis , respectively. Dual infections with HIV and M. tuberculosis are especially severe in infants. There is, however, no effective HIV vaccine, and the only licensed TB vaccine, the Mycobacterium bovis bacillus Calmette-Guérin (BCG) vaccine, can cause disseminated mycobacterial disease in HIV-infected children. Thus, a pediatric vaccine to prevent HIV and M. tuberculosis infections is urgently needed. We hypothesized that a highly attenuated M. tuberculosis strain containing HIV antigens could be safely administered at birth and induce mucosal and systemic immune responses to protect against HIV and TB infections, and we rationalized that vaccine safety could be most rigorously assessed in immunocompromised hosts. Of three vaccine candidates tested, the recombinant attenuated M. tuberculosis strain mc 2 6435 carrying a simian immunodeficiency virus (SIV) Gag expression plasmid and harboring attenuations of genes critical for replication ( panCD and leuCD ) and immune evasion ( secA2 ), was found to be safe for oral or intradermal administration to non-SIV-infected and SIV-infected infant macaques. Safety was defined as the absence of clinical symptoms, a lack of histopathological changes indicative of M. tuberculosis infection, and a lack of mycobacterial dissemination. These data represent an important step in the development of novel TB vaccines and suggest that a combination recombinant attenuated M. tuberculosis -HIV vaccine could be a safe alternative to BCG for the pediatric population as a whole and, more importantly, for the extreme at-risk group of HIV-infected infants

Confirmation of Skywalker Hoolock Gibbon (Hoolock tianxing) in Myanmar extends known geographic range of an endangered primate

Characterizing genetically distinct populations of primates is important for protecting biodiversity and effectively allocating conservation resources. Skywalker gibbons (Hoolock tianxing) were first described in 2017, with the only confirmed population consisting of 150 individuals in Mt. Gaoligong, Yunnan Province, China. Based on river geography, the distribution of the skywalker gibbon has been hypothesized to extend into Myanmar between the N’Mai Kha and Ayeyarwaddy Rivers to the west, and the Salween River (named the Thanlwin River in Myanmar and Nujiang River in China) to the east. We conducted acoustic point-count sampling surveys, collected noninvasive samples for molecular mitochondrial cytochrome b gene identification, and took photographs for morphological identification at six sites in Kachin State and three sites in Shan State to determine the presence of skywalker gibbons in predicted suitable forest areas in Myanmar. We also conducted 50 semistructured interviews with members of communities surrounding gibbon range forests to understand potential threats. In Kachin State, we audio-recorded 23 gibbon groups with group densities ranging between 0.57 and 3.6 group/km2. In Shan State, we audio-recorded 21 gibbon groups with group densities ranging between 0.134 and 1.0 group/km2. Based on genetic data obtained from skin and saliva samples, the gibbons were identified as skywalker gibbons (99.54–100% identity). Although these findings increase the species’ known population size and confirmed distribution, skywalker gibbons in Myanmar are threatened by local habitat loss, degradation, and fragmentation. Most of the skywalker gibbon population in Myanmar exists outside protected areas. Therefore, the IUCN Red List status of the skywalker gibbon should remain as Endangered

A Combination of Two Human Monoclonal Antibodies Prevents Zika Virus Escape Mutations in Non-human Primates

Summary: Zika virus (ZIKV) causes severe neurologic complications and fetal aberrations. Vaccine development is hindered by potential safety concerns due to antibody cross-reactivity with dengue virus and the possibility of disease enhancement. In contrast, passive administration of anti-ZIKV antibodies engineered to prevent enhancement may be safe and effective. Here, we report on human monoclonal antibody Z021, a potent neutralizer that recognizes an epitope on the lateral ridge of the envelope domain III (EDIII) of ZIKV and is protective against ZIKV in mice. When administered to macaques undergoing a high-dose ZIKV challenge, a single anti-EDIII antibody selected for resistant variants. Co-administration of two antibodies, Z004 and Z021, which target distinct sites on EDIII, was associated with a delay and a 3- to 4-log decrease in peak viremia. Moreover, the combination of these antibodies engineered to avoid enhancement prevented viral escape due to mutation in macaques, a natural host for ZIKV. : Passive administration of anti-Zika human monoclonal antibodies could be an efficacious and safe alternative to vaccines for at-risk populations. Keeffe et al. show that administration of a combination of two monoclonal antibodies to macaques followed by high-dose intravenous Zika challenge reduces viremia and prevents the emergence of viral escape mutations. Keywords: flavivirus, antibodies, crystal structure, escape, macaques, prophylaxis, protection, epitope, antibody dependent enhancemen