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Chikungunya virus (CHIKV) has re-emerged as a significant human pathogen in the 21st century, causing periodic, and sometimes widespread, outbreaks over the past 15 years. Although mortality is very rare, a debilitating arthralgia is very common and may persist for months or years. There are no antivirals that are approved for the treatment of CHIKV infection, and current treatment options consist of supportive care only. Herein, we demonstrate the efficacy of a CHIKV-specific antibody in the prophylactic and therapeutic treatment of CHIKV in mouse models of disease. The fully human anti-CHIKV monoclonal Ab SVIR023 demonstrated broad in vitro activity against representative strains from the three major CHIKV clades. Therapeutic treatment with SVIR023 administered 1- or 3-days post-infection resulted in reduced virus in various tissues in a dose- and time-dependent manner. Prophylactic treatment up to 4 weeks prior to virus challenge was also effective in preventing disease in mice. Mice treated with SVIR023 and infected with CHIKV were resistant to secondary challenge and no evidence of antibody enhancement of disease was observed. Treatment with SVIR023 was effective in mouse models of CHIKV infection and disease and further evaluation towards clinical development is warranted.

Zika virus (ZIKV) is a mosquito-borne viral infection that is shed in biological fluids promoting vertical and sexual transmission. Recent outbreaks of ZIKV have been associated with an increase in adult and fetal infection-related diseases. ZIKV infection in rhesus macaques is considered a robust animal model for studying Zika viral infection dynamics and fetal disease. A compelling feature of ZIKV is its ability to persist for long periods of time in immunocompetent hosts and during pregnancy, which may be linked to adverse infection outcomes. One consistent site of viral persistence is lymph node tissues. Utilizing this feature of ZIKV infection could be useful to diagnose viral persistence and to improve efficacy evaluation of antiviral vaccines and therapeutics, as well as for diagnostic and prognostic assessments in humans. We have developed a protocol to isolate lymph node cells using cell type-specific antibody-magnetic bead techniques followed by a one-step qRT-PCR detection of Zika virus RNA. This method fostered the identification of dendritic cells, macrophages, and B cells from the lymph node and spleen as harboring persistent ZIKV RNA.

Chikungunya virus (CHIKV) infection in humans is rarely fatal but is often associated with chronic joint and muscle pain. Chronic CHIKV disease is highly debilitating and is associated with viral persistence. To date, there are no approved vaccines or therapeutics to prevent or treat CHIKV infections once they are established. Current palliative treatments aim to reduce joint inflammation and pain associated with acute and chronic CHIKV disease. Development of novel therapeutics that reduces viral loads should positively impact virus inflammatory disease and improve patient outcomes following CHIKV infection. Therapies that target multiple aspects of CHIKV replication cycle should be developed since the virus is capable of rapidly mutating around any single therapeutic. This review summarizes the current status of small molecule inhibitor development against CHIKV.

Chikungunya virus (CHIKV) infection in humans is rarely fatal but is often associated with chronic joint and muscle pain. Chronic CHIKV disease is highly debilitating and is associated with viral persistence. To date, there are no approved vaccines or therapeutics to prevent or treat CHIKV infections once they are established. Current palliative treatments aim to reduce joint inflammation and pain associated with acute and chronic CHIKV disease. Development of novel therapeutics that reduces viral loads should positively impact virus inflammatory disease and improve patient outcomes following CHIKV infection. Therapies that target multiple aspects of CHIKV replication cycle should be developed since the virus is capable of rapidly mutating around any single therapeutic. This review summarizes the current status of small molecule inhibitor development against CHIKV.

Cytomegalovirus (CMV), a ubiquitous β-herpesvirus, is linked to acceleration of solid organ transplant vascular sclerosis (TVS) and chronic rejection (CR). Latent CMV infection increases cardiac-resident macrophages and T cells that may increase inflammation and promote allograft rejection. To investigate the role of cardiac macrophages in CMV mediated TVS/CR, macrophages were depleted from CMV+ donor allografts prior to transplantation using clodronate liposomes (clod) in our rat heart transplant model. Latently rat CMV infected donor F344 rats were treated with clod or PBS or control liposomes 3 days prior to heterotopic cardiac transplant into CMV-naïve Lewis rats and macrophage depletion was validated. Donor hearts were transplanted and monitored daily for rejection. Clod treatment significantly increased graft survival from 61 days post-transplant to 84 days. The severity of graft vessel disease was decreased compared to controls. Clod treatment significant decreased macrophage and T cell infiltration into allograft tissue versus controls. Clod treatment also altered allograft tissue protein and gene expression cytokine/chemokine profiles toward a phenotype that promotes graft survival by reducing the allograft inflammation. Clod treatment did not prevent CMV reactivation since all recipients seroconverted and CMV DNA was detectable in recipient salivary glands. Depletion of donor macrophages prior to transplant represents a novel method to modulate allograft rejection immunity and prevent the negative impact of CMV on allograft recipient survival.

Chikungunya virus (CHIKV) is a positive-sense RNA, arthropod-borne Alphavirus. In recent years the largest recorded outbreak of CHIKV occurred in the Islands of the Indian Ocean and India. CHIKV has continued to spread causing millions of cases across more than 40 countries. Acute symptoms of infection include the abrupt onset of fever, rash, fatigue, headache, backache, and arthralgia, with arthralgia lasting up to several years in some individuals. Ongoing studies analyzing cohorts of CHIKV infected humans have led to a well-developed understanding of the clinical manifestations of CHIKV disease. What is unknown is the role different components of the immune response play in controlling CHIKV dissemination and disease development. In our current study we utilized a non-human primate (NHP) model of CHIKV infection to characterize the early stage of CHIKV infection. Adult male and female rhesus macaques (RM) were infected subcutaneously with CHIKV-LR. Analysis of vRNA loads in joint tissues of infected RM revealed that the highest viral loads were detectable at 2 dpi with at least a log decrease in vRNA levels by 7 dpi. T cells, B cells, PMNs, macrophages, and mast cells were visible in the joints of CHIKV infected RMs at 2 and 7 dpi. To our knowledge this is the first time mast cells have been identified in the tissue of CHIKV infected NHPs. Levels of key proinflammatory cytokines/chemokines were also increased from 3–7 dpi. The gene expression profile in joint tissues reveled an increase in the expression of genes involved in recruitment, activation, and maintenance of mast cells. These findings suggest that infiltration of immune cells including the newly identified mast cells from 2 to 7 dpi assist in controlling CHIKV infection.

When vaccination is not cost effective or possible, one of the primary alternatives is passive immunotherapies. Passive therapeutic antibodies have been shown to be effective in the treatment, not only of infectious agents, but also for toxins, venoms, and cancer targets. Recent research in our laboratory as well as others, has demonstrated the potential of avian-derived passive therapeutic antibodies. We have demonstrated goose-derived polyclonal antibodies, from either sera or eggs, are therapeutic for several viral diseases. The avian immunoglobulin IgY is the primary avian antibody isotype. IgY is similar to mammalian IgG, but lacks the ability to interact with mammalian Fc receptors, complement, and other factors that promote inflammation. IgY’s potential as a therapeutic agent is boosted by its higher avidity than IgG and recognizes more epitopes than mammalian antibodies. These advantages are due to the evolutionary distance between mammalian and avian species. In this work we present initial studies to develop goose mIgY, utilizing traditional mammalian monoclonal protocol that will be commercialized against viral or other targets responsive to single epitope treatment, with the product displaying the inherent advantages of avian antibodies.