Increased cellular immune responses and CD4+ T-cell proliferation correlate with reduced plasma viral load in SIV challenged recombinant simian varicella virus - simian immunodeficiency virus (rSVV-SIV) vaccinated rhesus macaques.

BACKGROUND: An effective AIDS vaccine remains one of the highest priorities in HIV-research. Our recent study showed that vaccination of rhesus macaques with recombinant simian varicella virus (rSVV) vector - simian immunodeficiency virus (SIV) envelope and gag genes, induced neutralizing antibodies and cellular immune responses to SIV and also significantly reduced plasma viral loads following intravenous pathogenic challenge with SIVMAC251/CX1. FINDINGS: The purpose of this study was to define cellular immunological correlates of protection in rSVV-SIV vaccinated and SIV challenged animals. Immunofluorescent staining and multifunctional assessment of SIV-specific T-cell responses were evaluated in both Experimental and Control vaccinated animal groups. Significant increases in the proliferating CD4+ T-cell population and polyfunctional T-cell responses were observed in all Experimental-vaccinated animals compared with the Control-vaccinated animals. CONCLUSIONS: Increased CD4+ T-cell proliferation was significantly and inversely correlated with plasma viral load. Increased SIV-specific polyfunctional cytokine responses and increased proliferation of CD4+ T-cell may be crucial to control plasma viral loads in vaccinated and SIVMAC251/CX1 challenged macaques.

Sendai virus-based RSV vaccine protects African green monkeys from RSV infection.

Respiratory syncytial virus (RSV) is a serious disease of children, responsible for an estimated 160,000 deaths per year worldwide. Despite the ongoing need for global prevention of RSV and decades of research, there remains no licensed vaccine. Sendai virus (SeV) is a mouse parainfluenza virus-type 1 which has been previously shown to confer protection against its human cousin, human parainfluenza virus-type 1 in African green monkeys (AGM). Here is described the study of a RSV vaccine (SeVRSV), produced by reverse genetics technology using SeV as a backbone to carry the full-length gene for RSV F. To test for immunogenicity, efficacy and safety, the vaccine was administered to AGM by intratracheal (i.t.) and intranasal (i.n.) routes. Control animals received the empty SeV vector or PBS. There were no booster immunizations. SeV and SeVRSV were cleared from the URT and LRT of vaccinated animals by day 10. Antibodies with specificities toward SeV and RSV were detected in SeVRSV primed animals as early as day ten after immunizations in both sera and nasal wash samples. One month after immunization all test and control AGM received an i.n. challenge with RSV-A2. SeVRSV-vaccinated animals exhibited reduced RSV in the URT compared to controls, and complete protection against RSV in the LRT. There were no clinically relevant adverse events associated with vaccination either before or after challenge. These data encourage advanced testing of the SeVRSV vaccine candidate in clinical trials for protection against RSV.

Relationship between human T lymphotropic virus (HTLV) type 1/2 viral burden and clinical and treatment parameters among patients with HIV type 1 and HTLV-1/2 coinfection.

BACKGROUND: Human T lymphotropic virus types 1 (HTLV-1) and 2 (HTLV-2) are frequent copathogens among individuals infected with human immunodeficiency virus type 1 (HIV-1). The long-term effects of coinfection are unknown, and little information exists regarding how levels of HTLV-1/2 viral burden are affected by antiretroviral medications. METHODS: Factors associated with HTLV-1/2 viral burden were examined in patients with HIV-HTLV-1/2 coinfection. A total of 72 subjects were evaluated. The variables analyzed included HTLV-1/2 proviral load, HTLV-1/2 tax/rex mRNA expression, HIV load, HTLV-1/2 viral antigen detection in peripheral blood mononuclear cell (PBMC) cultures, T cell subsets, demographic variables (age, race, sex, and reported use of injection drugs), and administration of highly active antiretroviral therapy. RESULTS: An HTLV-1/2 proviral DNA copy number >20,000 copies/10(6) PBMCs was significantly associated with the following variables: (1) a positive HTLV-1 Western blot test result, (2) a positive HTLV-1/2 PBMC culture result, (3) a positive tax/rex mRNA result, (4) an HIV load <10,000 copies/mL, and (5) higher CD4 cell counts among subjects with HIV-HTLV-1 coinfection. There was no correlation between HTLV-1/2 proviral copy number or HTLV-1/2 tax/rex mRNA detection and administration of antiretroviral therapy. CONCLUSIONS: HTLV-1/2 proviral burden was significantly higher among patients with HIV-HTLV-1 coinfection than among patients with HIV-HTLV-2 coinfection. Highly active antiretroviral therapy may be of limited value in controlling virus expression of HTLV-1/2 in patients with HIV-HTLV-1/2 coinfection.

Human T cell leukemia virus type 1 up-regulation after simian immunodeficiency virus-1 coinfection in the nonhuman primate.

The effects that human T cell leukemia virus (HTLV) type 1 and simian immunodeficiency virus (SIV) coinfection have on HTLV-1 dynamics and disease progression were tested in a nonhuman primate model. Seven rhesus macaques were experimentally inoculated with HTLV-1, and a persistent infection was established. Coinfection with SIV/smB670 resulted in increased HTLV-1 p19 antigens in peripheral blood mononuclear cells and HTLV-1 proviral loads. Circulating CD2(+) and CD8(+) T lymphocytes increased over preinoculation levels, along with a progressive decrease in CD4(+) T cells, typical for terminal SIV disease. Finally documented was the striking emergence of up to 19% of HTLV-associated "flower cell" lymphocytes in the circulation, as seen in patients with adult T cell leukemia/lymphoma. CD8(+)CD25(+) T cell subpopulation increases were positively correlated with flower cell appearance and suggested their possible role in this process. We conclude that SIV may have the potential to up-regulate HTLV-1 and disease expression.

Molecular epidemiology of simian T-cell lymphotropic virus type 1 in wild and captive sooty mangabeys.

A study was conducted to evaluate the prevalence and diversity of simian T-cell lymphotropic virus (STLV) isolates within the long-established Tulane National Primate Research Center (TNPRC) colony of sooty mangabeys (SMs; Cercocebus atys). Serological analysis determined that 22 of 39 animals (56%) were positive for STLV type 1 (STLV-1). A second group of thirteen SM bush meat samples from Sierra Leone in Africa was also included and tested only by PCR. Twenty-two of 39 captive animals (56%) and 3 of 13 bush meat samples (23%) were positive for STLV-1, as shown by testing with PCR. Nucleotide sequencing and phylogenetic analysis of viral strains obtained demonstrated that STLV-1 strains from SMs (STLV-1sm strains) from the TNPRC colony and Sierra Leone formed a single cluster together with the previously reported STLV-1sm strain from the Yerkes National Primate Research Center. These data confirm that Africa is the origin for TNPRC STLV-1sm and suggest that Sierra Leone is the origin for the SM colonies in the United States. The TNPRC STLV-1sm strains further divided into two subclusters, suggesting STLV-1sm infection of two original founder SMs at the time of their importation into the United States. STLV-1sm diversity in the TNPRC colony matches the high diversity of SIVsm in the already reported colony. The lack of correlation between the lineage of the simian immunodeficiency virus from SMs (SIVsm) and the STLV-1sm subcluster distribution of the TNPRC strains suggests that intracolony transmissions of both viruses were independent events.

Evaluation of recombinant respiratory syncytial virus gene deletion mutants in African green monkeys for their potential as live attenuated vaccine candidates.

Towards the goal of developing live attenuated respiratory syncytial virus (RSV) vaccines to prevent severe respiratory tract infections caused by respiratory syncytial virus, recombinant RSV containing a deletion of single or multiple NS1, NS2, SH and M2-2 genes have been generated. In this study, recombinants, rA2DeltaM2-2, rA2DeltaNS2, rA2DeltaNS1NS2, rA2DeltaSHNS2, rA2DeltaM2-2NS2 were evaluated in African green monkeys (AGMs) for their infectivity, immunogenicity and protection against wild type (wt) RSV challenge. Replication of rA2DeltaNS2 and rA2DeltaSHNS2 was not attenuated in either the upper or the lower respiratory tracts of AGMs. On the other hands, rA2DeltaNS1NS2 was over-attenuated; it did not replicate in the respiratory tracts of the infected monkeys and did not provide sufficient protection against wild type RSV challenge. rA2DeltaM2-2NS2 was slightly more attenuated than rA2DeltaM2-2 and provided partial protection against wt RSV challenge. rA2DeltaM2-2, and possibly rA2DeltaM2-2NS2, exhibited the attenuated but protective phenotypes in the monkeys that could be further evaluated as potential live attenuated RSV vaccine candidates in the clinical studies.