Characterization of peripheral blood T lymphocyte subsets in Chinese rhesus macaques with repeated or long-term infection with Plasmodium cynomolgi.

T lymphocytes play a vital role in antimalaria immunity, but there is little information about the role of T cells in malaria infection. In order to explore the profile of T cells in malaria immunity, we infected Chinese rhesus macaques with the malaria parasite (Plasmodium cynomolgi) and examined the dynamics of T cell subsets. Both repeated and long-term infections were involved. Our results showed that the monkeys in the repeated infection group acquired protective immunity through primary infection, which was evidenced by a much lower parasitemia, milder anemia, and milder fever during reinfection; the monkeys in the long-term infection group also developed protective immunity, but this was not sufficient to eliminate the parasite. The total counts of leukocytes, neutrophils, CD3+ T cells, CD4+ or CD8+ T cells, and naïve and memory CD4+ and CD8+ T cells declined during the acute phase of malaria but increased after the parasite was controlled. The total number of activated CD4+ T cells significantly increased during malaria in animals with a long-term infection, which remained at least 3 months after the termination of malaria. However, the activated CD4+ T cells decreased during the acute phase of infection in the repeated infection group and converted to preinfection levels after malaria was cured. Regulatory CD4+ T cells continued to increase during the malaria infections and quickly reverted to preinfection levels after the parasite was controlled. Our study provides a systematic analysis of the kinetic profiles of T lymphocyte subsets during malaria infections and provides some experimental insight into malaria immunology.

Antimalarial effects of human immunodeficiency virus protease inhibitors in rhesus macaques.

The antimalarial activity of the human immunodeficiency virus protease inhibitors indinavir and saquinavir was evaluated in rhesus macaques for the first time. Indinavir effectively suppressed the growth of Plasmodium cynomolgi and Plasmodium knowlesi in vivo after a 7- or 3-day treatment, respectively, with clinically relevant doses, whereas saquinavir showed only weak activity against P. cynomolgi.

Synergy of human immunodeficiency virus protease inhibitors with chloroquine against Plasmodium falciparum in vitro and Plasmodium chabaudi in vivo.

The synergy of the activities between chloroquine and various human immunodeficiency virus protease inhibitors was investigated in chloroquine-resistant and -sensitive malaria parasites. In both in vitro and in vivo assay systems, ritonavir was found to be the most potent in potentiating the antimalarial action of chloroquine.

Dynamic balance of pSTAT1 and pSTAT3 in C57BL/6 mice infected with lethal or nonlethal Plasmodium yoelii.

Signal transducer and activator of transcription (STAT) proteins play an important role in cytokine signaling pathways and regulation of immune responses. The balance of the phosphorylated (activated) STAT1 (pSTAT1) and STAT3 (pSTAT3) has been documented in cancer immunology. In this study, we investigated the dynamic balance of pSTAT1 and pSTAT3 in C57BL/6 mice infected with either a nonlethal (Py17XNL) or lethal (Py17XL) strain of Plasmodium yoelii. Both Py17XNL and Py17XL infections induced a maximum activation of STAT1 and STAT3 on the first day after parasite inoculation. Additionally, the Py17XNL infection induced a pSTAT1-dominant response in mice during the early stage of infection, with the resolution of parasitemia. In contrast, Py17XL infection induced a pSTAT3-dominant response during the early phase of infection, with the death of the animals. Our results indicated that maximum activation of STAT1 and STAT3 occurred much earlier than the peak levels of cytokines induced by Plasmodium yoelii infection based on previous reports and that infection with Py17XNL and Py17XL induced different dynamic patterns of pSTAT1 and pSTAT3 balance.

Transgenic Plasmodium that expresses HIV-1 Gag elicits immunity and protects mice against vaccinia virus-gag and malarial parasites.

Malaria and human immunodeficiency virus type 1 (HIV-1) infection overlap in many regions of the world. Our goal was to determine the feasibility of developing transgenic Plasmodium berghei that expresses HIV-1 Gag, PbGAG, as a conceptual bivalent vaccine against both HIV-1 infection and malaria. Immunization of mice with PbGAG induced specific responses to the HIV-1 Gag. Importantly, mice vaccinated with PbGAG were significantly protected from challenge with vaccinia virus-gag (VV-gag) with an average 30-fold reduction in titer (P<0.05). In addition, mice immunized with PbGAG developed Plasmodium-specific immune responses and the immunized animals were protected from challenges with blood-stage P. berghei NK65 and Plasmodium yoelii 17XL. We demonstrated a novel vaccination strategy that uses a live transgenic protozoan parasite-based bivalent vaccine to immunize mice and confer significant levels of protection against VV-gag and malarial parasite challenges. These observations have important implications for the development of a new form of bivalent vaccine against both HIV-1 and malaria.