Variability of Bio-Clinical Parameters in Chinese-Origin Rhesus Macaques Infected with Simian Immunodeficiency Virus: A Nonhuman Primate AIDS Model

BACKGROUND: Although Chinese-origin Rhesus macaques (Ch RhMs) infected with simian immunodeficiency virus (SIV) have been used for many years to evaluate the efficacy of AIDS vaccines and therapeutics, the bio-clinical variability of such a nonhuman primate AIDS model was so far not established. METHODOLOGY/PRINCIPAL FINDINGS: By randomizing 150 (78 male and 72 female) Ch RhMs with diverse MHC class I alleles into 3 groups (50 animals per group) challenged with intrarectal (i.r.) SIVmac239, intravenous (i.v.) SIVmac239, or i.v. SIVmac251, we evaluated variability in bio-clinical endpoints for 118 weeks. All SIV-challenged Ch RhMs became seropositive for SIV during 1-2 weeks. Plasma viral load (VL) peaked at weeks 1-2 and then declined to set-point levels as from week 5. The set-point VL was 30 fold higher in SIVmac239 (i.r. or i.v.)-infected than in SIVmac251 (i.v.)-infected animals. This difference in plasma VL increased overtime (>100 fold as from week 68). The rates of progression to AIDS or death were more rapid in SIVmac239 (i.r. or i.v.)-infected than in SIVmac251 (i.v.)-infected animals. No significant difference in bio-clinical endpoints was observed in animals challenged with i.r. or i.v. SIVmac239. The variability (standard deviation) in peak/set-point VL was nearly one-half lower in animals infected with SIVmac239 (i.r. or i.v.) than in those infected with SIVmac251 (i.v.), allowing that the same treatment-related difference can be detected with one-half fewer animals using SIVmac239 than using SIVmac251. CONCLUSION/SIGNIFICANCE: These results provide solid estimates of variability in bio-clinical endpoints needed when designing studies using the Ch RhM SIV model and contribute to the improving quality and standardization of preclinical studies

Research Progression of Anti-HIV Chinese Medicines and Their Natural Active Ingredients

Objective: To review the research progression of Chinese medicines for anti-human immunodeficiency virus (HIV) and their natural active ingredients at home and abroad so as to provide references for pharmaceutical research and clinical medication. Methods: Abundant representative literatures at home and abroad were classified to introduce the anti-HIV monomers, compounds and natural active ingredients of Chinese medicines. Results: The researches on anti-HIV natural medicines have obtained great achievements, in which medicines with anti-virus and immunity-improving functions have had rapid progression and new-types for anti-virus also have had dramatic development. Conclusion: The progression of anti-HIV Chinese medicines and their active ingredients has favorable prospect

Low level expression of the Mitochondrial Antiviral Signaling protein (MAVS) associated with long-term nonprogression in SIV-infected rhesus macaques

Abstract Background Abnormally increased immune activation is one of the main pathological features of acquired immunodeficiency syndrome (AIDS). This study aimed to determine whether long-term nonprogression (LTNP) suppresses the upregulation of immune activation and to elucidate the mechanisms whereby the LTNP state is maintained. Methods For this study we selected 4 rhesus macaques(RMs) infected with simian immunodeficiency virus (SIV) that were long-term nonprogressors (LTNP); for comparison we chose 4 healthy RMs that were seronegative for SIV (hereafter referred to as the Control group), and 4 progressing infection (Progressive group) SIV RMs. We observed these animals for 6 months without intervention and explored the immunological and pathological differences among the 3 groups. A series of immune activation and inflammation markers—such as C- C chemokine receptor type 5 (CCR5), beta 2- microglobulin (β2-MG), Human Leukocyte Antigen - antigen D Related (HLA-DR), CD38, the levels of microbial translocation (LPS -binding protein), and MAVS—and histological features were monitored during this period. Results Both SIV RNA and SIV DNA in the plasma and lymph nodes (LNs) of the LTNP group were at significantly lower levels than those of the Progressive group (P < 0.05). The CD4/CD8 ratio and CD4 cell count and proportion in the LTNP group were between those of the Progressive and Control groups (P < 0.05): that is, they were higher than in the Progressive group and lower than in the Control group. The LTNP macaques manifested slow progression and decreased immune activation and inflammation; they also had lower levels of CCR5, LPS-binding protein, and β2-MG than the Progressive RMs (P < 0.05). Activation of LTNP in both CD4+ and CD8+ T cells was significantly lower than in the Progressive group and closer to that in the Control group. The histological features of the LTNP macaques were also closer to those of the Control group, even though they had been infected with SIV 4 years earlier. These data point to low viral replication in the LTNP macaques but it is not static. The expression of MAVS in peripheral blood and LNs was lower in the LTNP group than that in the Progressive group (P < 0.01), and MAVS was positively correlated with SIV DNA in LNs (P < 0.05). This may reflect the low activation of T lymphocytes. It was speculated that MAVS may be the link between innate and acquired antiviral immunity in SIV infection. Conclusions The LTNP RMs in our study were in a relatively stable state of low activation and inflammation, some biological progression with no disease events. This may have been associated with their low levels of the mitochondrial antiviral signaling protein (MAVS)

Induction of CD8+ Regulatory T Cells Protects Macaques against SIV Challenge

Efforts to develop a vaccine against HIV have so far met with limited success. Given that CD4+ T cell activation drives the initial burst of viral replication, we explored in macaques whether an oral vaccine comprised of Lactobacillus plantarum, a commensal bacterium that favors immune tolerance, and inactivated simian immunodeficiency virus mac239 (SIVmac239) would induce CD4+ T cell unresponsiveness/tolerance toward SIV antigens and thereby prevent the establishment of SIV infection. The tolerogenic vaccine induced MHC-Ib/E-restricted CD8+ regulatory T cells (Tregs) that suppressed SIV-harboring CD4+ T cell activation and ex vivo SIV replication in 15 of 16 animals without inducing SIV-specific antibodies or cytotoxic T lymphocytes. Of 16 macaques that were intrarectally challenged with SIVmac239 or heterologous strain SIVB670, 15 were sterilely protected. In four macaques that were rechallenged intravenously, plasma SIV levels peaked slightly and then dropped to undetectable levels, although the animals subsequently harbored intracellular SIV DNA. Infusion of CD8 antibodies confirmed the role of CD8+ Tregs in preventing/suppressing SIV in vivo. These findings suggest a new avenue of research toward developing an HIV-1 vaccine

Evolving molecular epidemiological profile of human immunodeficiency virus 1 in the southwest border of China.

We have previously reported in Xishuangbanna (Banna) Dai Autonomous Prefecture, a well-developed tourist destination in the southwest border of China, that HIV-1 transmitted dominantly through heterosexual contact with less divergent genotypes and few drug resistant mutations. Due to the rapid increase of newly diagnosed HIV-1 cases per year in Banna in recent years, it's important to evaluate the evolution of HIV-1 molecular epidemiology for the better understanding of ongoing HIV-1 outbreak in this region.By sequencing of HIV-1 pol genes and phylogenetic analysis, we conducted a molecular epidemiologic study in 352 HIV-1-seropositive highly active antiretroviral treatment (HAART)-naïve individuals newly diagnosed at the Banna Center for Disease Control and Prevention between 2009 and 2011. Of 283 samples (84.1% taken from heterosexually acquired adults, 10.6% from needle-sharing drug users, 2.8% from men who have sex with men, 0.4% from children born from HIV-1-infected mothers, and 2.1% remained unknown) with successful sequencing for pol gene, we identified 108 (38.2%) HIV-1 subtype CRF08_BC, 101 (35.7%) CRF01_AE, 49 (17.3%) CRF07_BC, 5 (1.8%) C/CRF57_BC, 3 (1.1%) B', 1 (0.4%) B/CRF51_01B, and 16 (5.7%) unique recombinants forms. Among these infected individuals, 104 (36.7%) cases showed drug resistant or resistance-relevant mutations, and 4 of them conferring high-level resistance to 3TC/FTC, EFV/NVP or NFV. Phylogenetic analysis revealed 21 clusters (2-7 sequences) with only 21.2% (60/283) sequences involved.In contrast to our previous findings, CRF08_BC, replaced CRF01_AE, became the dominant genotype of HIV-1 in Banna prefecture. The viral strains with drug resistance mutations were detected frequently in newly diagnosed HIV-1-infected individuals in this region