Evolution of ocular defects in infant macaques following in utero Zika virus infection.

Congenital Zika syndrome (CZS) is associated with microcephaly and various neurological, musculoskeletal, and ocular abnormalities, but the long-term pathogenesis and postnatal progression of ocular defects in infants are not well characterized. Rhesus macaques are superior to rodents as models of CZS because they are natural hosts of the virus and share similar immune and ocular characteristics, including blood-retinal barrier characteristics and the unique presence of a macula. Using a previously described model of CZS, we infected pregnant rhesus macaques with Zika virus (ZIKV) during the late first trimester and characterized postnatal ocular development and evolution of ocular defects in 2 infant macaques over 2 years.

Miscarriage and stillbirth following maternal Zika virus infection in nonhuman primates.

Zika virus (ZIKV) infection is associated with congenital defects and pregnancy loss. Here, we found that 26% of nonhuman primates infected with Asian/American ZIKV in early gestation experienced fetal demise later in pregnancy despite showing few clinical signs of infection. Pregnancy loss due to asymptomatic ZIKV infection may therefore be a common but under-recognized adverse outcome related to maternal ZIKV infection.

Emerging diagnostic challenges and characteristics of simian betaretrovirus infections in captive macaque colonies.

To better understand Simian betaretrovirus (SRV) seropositivity in virus-negative macaques, we transfused blood from SRV-infected or suspect donors into immunosuppressed naive recipients. Our results do not support typical SRV1-5 infection as the cause, but provide evidence for several possibilities including serological artifact, new/different SRV, or an endogenous virus.

Hippocampal Neuronal Loss in Infant Macaques Orally Infected with Virulent Simian Immunodeficiency Virus (SIV).

The neurological impact of Human Immunodeficiency Virus (HIV) on children includes loss of brain growth, motor abnormalities and cognitive dysfunction. Despite early antiretroviral treatment (ART) intervention to suppress viral load, neurological consequences of perinatal HIV-1 infection persist. Utilizing the pediatric simian immunodeficiency virus (SIV) infection model, we tested the hypothesis that early-life SIV infection depletes neuronal population in the hippocampus.

Evidence of simian retrovirus type D by polymerase chain reaction.

Background: Over the past few years, there have been reports of finding Simian retrovirus type D (SRV) in macaque colonies where some animals were characterized as antibody positive but virus negative raising questions about how SRV was transmitted or whether there is a variant strain detected by antibody but not polymerase chain reaction (PCR) in current use.

Methods: We developed a three-round nested PCR assay using degenerate primers targeting the pol gene to detect for SRV serotypes 1-5 and applied this newly validated PCR assay to test macaque DNA samples collected in China from 2010 to 2015.

Results: Using the nested PCR assay validated in this study, we found 0.

Zika Virus Tissue and Blood Compartmentalization in Acute Infection of Rhesus Macaques.

Animal models of Zika virus (ZIKV) are needed to better understand tropism and pathogenesis and to test candidate vaccines and therapies to curtail the pandemic. Humans and rhesus macaques possess similar fetal development and placental biology that is not shared between humans and rodents. We inoculated 2 non-pregnant rhesus macaques with a 2015 Brazilian ZIKV strain.

Balancing Trained Immunity with Persistent Immune Activation and the Risk of Simian Immunodeficiency Virus Infection in Infant Macaques Vaccinated with Attenuated Mycobacterium tuberculosis or Mycobacterium bovis BCG Vaccine.

Our goal is to develop a pediatric combination vaccine to protect the vulnerable infant population against human immunodeficiency virus type 1 (HIV-1) and tuberculosis (TB) infections. The vaccine consists of an auxotroph Mycobacterium tuberculosis strain that coexpresses HIV antigens. Utilizing an infant rhesus macaque model, we have previously shown that this attenuated M.

Engineering Paper-Based Sensors for Zika Virus.

The emergence of Zika virus (ZIKV) infections in Latin America and Southeast Asia has created an urgent need for new, simple, yet sensitive, diagnostic tests. We highlight recent work using paper-based sensors coupled with CRISPR/Cas9 to detect ZIKV RNA as a new approach to achieve rapid development and deployment of field-ready diagnostics for emerging infectious diseases.

Persistent effects of early infant diet and associated microbiota on the juvenile immune system.

Early infant diet has significant impacts on the gut microbiota and developing immune system. We previously showed that breast-fed and formula-fed rhesus macaques develop significantly different gut microbial communities, which in turn are associated with different immune systems in infancy. Breast-fed animals manifested greater T cell activation and proliferation and harbored robust pools of T helper 17 (TH17) cells.

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.

The interplay between immune maturation, age, chronic viral infection and environment.

Background: The worldwide increase in life expectancy has been associated with an increase in age-related morbidities. The underlying mechanisms resulting in immunosenescence are only incompletely understood. Chronic viral infections, in particular infection with human cytomegalovirus (HCMV), have been suggested as a main driver in immunosenescence.

Efficacy of HIV Postexposure Prophylaxis: Systematic Review and Meta-analysis of Nonhuman Primate Studies.

Background: The efficacy of antiretrovirals as postexposure prophylaxis (PEP) to prevent viral acquisition was demonstrated in nonhuman primate models of human immunodeficiency virus (HIV) in the early 1990s. To complement the evidence base for efficacy of HIV PEP in humans, we systematically reviewed the published data on PEP efficacy across animal studies.

Methods: PubMed, Web of Science, and Embase were searched from inception to 31 May 2014 for randomized and nonrandomized studies reporting seroconversions among uninfected animals exposed to HIV or simian immunodeficiency virus, irrespective of route of exposure.

Binding of Complement Factor H (FH) Decreases Protective Anti-FH Binding Protein Antibody Responses of Infant Rhesus Macaques Immunized With a Meningococcal Serogroup B Vaccine.

Background: The meningococcal vaccine antigen, factor H (FH)-binding protein (FHbp), binds human complement FH. In human FH transgenic mice, binding decreased protective antibody responses.

Methods: To investigate the effect of primate FH binding, we immunized rhesus macaques with a 4-component serogroup B vaccine (4CMenB).

Breast-fed and bottle-fed infant rhesus macaques develop distinct gut microbiotas and immune systems.

Diet has a strong influence on the intestinal microbiota in both humans and animal models. It is well established that microbial colonization is required for normal development of the immune system and that specific microbial constituents prompt the differentiation or expansion of certain immune cell subsets. Nonetheless, it has been unclear how profoundly diet might shape the primate immune system or how durable the influence might be.

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 compared with adults, which is exacerbated by coinfections.

Variation of human immunodeficiency virus type-1 reverse transcriptase within the simian immunodeficiency virus genome of RT-SHIV.

RT-SHIV is a chimera of simian immunodeficiency virus (SIV) containing the reverse transcriptase (RT)-encoding region of human immunodeficiency virus type 1 (HIV-1) within the backbone of SIVmac239. It has been used in a non-human primate model for studies of non-nucleoside RT inhibitors (NNRTI) and highly active antiretroviral therapy (HAART). We and others have identified several mutations that arise in the "foreign" HIV-1 RT of RT-SHIV during in vivo replication.

A neonatal oral -SIV prime / intramuscular MVA-SIV boost combination vaccine induces both SIV and -specific immune responses in infant macaques.

Mother-to-child-transmission of HIV by breast-feeding remains a major obstacle in the eradication of HIV infection. Compared to adults, HIV-infected infants have more rapid disease and show higher susceptibility to co-infections like tuberculosis (TB). Although the Bacille Calmette-Guérin vaccine can be administered at birth to protect against TB, BCG can disseminate in HIV-infected infants and increase mortality.

A vaccine against CCR5 protects a subset of macaques upon intravaginal challenge with simian immunodeficiency virus SIVmac251.

As an alternative to targeting human immunodeficiency virus (HIV), we have developed vaccines targeting CCR5, a self-protein critically involved in HIV replication and pathogenesis. By displaying peptides derived from CCR5 at high density on the surface of virus-like particles, we can efficiently induce high-titer IgG antibodies against this self-molecule. Here, we investigated whether prophylactic immunization of rhesus macaques with a particle-based vaccine targeting two regions of macaque CCR5 could prevent or suppress vaginal infection with highly virulent SIVmac251.

Prolonged tenofovir treatment of macaques infected with K65R reverse transcriptase mutants of SIV results in the development of antiviral immune responses that control virus replication after drug withdrawal.

Background: We reported previously that while prolonged tenofovir monotherapy of macaques infected with virulent simian immunodeficiency virus (SIV) resulted invariably in the emergence of viral mutants with reduced in vitro drug susceptibility and a K65R mutation in reverse transcriptase, some animals controlled virus replication for years. Transient CD8+ cell depletion or short-term tenofovir interruption within 1 to 5 years of treatment demonstrated that a combination of CD8+ cell-mediated immune responses and continued tenofovir therapy was required for sustained suppression of viremia. We report here follow-up data on 5 such animals that received tenofovir for 8 to 14 years.

Compared to subcutaneous tenofovir, oral tenofovir disoproxyl fumarate administration preferentially concentrates the drug into gut-associated lymphoid cells in simian immunodeficiency virus-infected macaques.

To compare tissue-based pharmacokinetics and efficacy of oral tenofovir disoproxyl fumarate (TDF) versus subcutaneous tenofovir (TFV), macaques were treated for 2 weeks starting 1 week after simian immunodeficiency virus inoculation. Despite lower plasma TFV levels in the oral TDF arm, similar TFV diphosphate levels and antiviral activities were measured in lymphoid cells of most tissues. In intestinal tissues, however, oral TDF resulted in higher active drug levels, associated with lower virus levels and better immune preservation.

A recombinant attenuated Mycobacterium tuberculosis vaccine strain is safe in immunosuppressed simian immunodeficiency virus-infected infant macaques.

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.

SIV replication in the infected rhesus macaque is limited by the size of the preexisting TH17 cell compartment.

The mechanisms by which some HIV-infected subjects resist disease progression, whereas others progress rapidly, are incompletely understood. Viral and host genetic factors, such as nef deletions and major histocompatibility complex alleles, explain a portion of the observed variability. However, it has been difficult to identify host immune functions that may be present before infection and that allow resistance to lentiviral disease progression.

The use of nonhuman primate models of HIV infection for the evaluation of antiviral strategies.

Several nonhuman primate models are used in HIV/AIDS research. In contrast to natural host models, infection of macaques with virulent simian immunodeficiency virus (SIV) isolates results in a disease (simian AIDS) that closely resembles HIV infection and AIDS. Although there is no perfect animal model, and each of the available models has its limitations, a carefully designed study allows experimental approaches that are not feasible in humans, but that can provide better insights in disease pathogenesis and proof-of-concept of novel intervention strategies.

Pharmacokinetics and safety of single-dose tenofovir disoproxil fumarate and emtricitabine in HIV-1-infected pregnant women and their infants.

Tenofovir (TFV) is effective in preventing simian immunodeficiency virus (SIV) transmission in a macaque model, is available as the oral agent tenofovir disoproxil fumarate (TDF), and may be useful in the prevention of mother-to-child transmission of human immunodeficiency virus (HIV). We conducted a trial of TDF and TDF-emtricitabine (FTC) in HIV-infected pregnant women and their infants. Women received a single dose of either 600 mg TDF, 900 mg TDF, or 900 mg TDF-600 mg FTC at labor onset or prior to a cesarean section.