Inhibition of Adaptive Immune Responses Leads to a Fatal Clinical Outcome in SIV-Infected Pigtailed Macaques but Not Vervet African Green Monkeys

African green monkeys (AGM) and other natural hosts for simian immunodeficiency virus (SIV) do not develop an AIDS-like disease following SIV infection. To evaluate differences in the role of SIV-specific adaptive immune responses between natural and nonnatural hosts, we used SIVagmVer90 to infect vervet AGM and pigtailed macaques (PTM). This infection results in robust viral replication in both vervet AGM and pigtailed macaques (PTM) but only induces AIDS in the latter species. We delayed the development of adaptive immune responses through combined administration of anti-CD8 and anti-CD20 lymphocyte-depleting antibodies during primary infection of PTM (n = 4) and AGM (n = 4), and compared these animals to historical controls infected with the same virus. Lymphocyte depletion resulted in a 1-log increase in primary viremia and a 4-log increase in post-acute viremia in PTM. Three of the four PTM had to be euthanized within 6 weeks of inoculation due to massive CMV reactivation and disease. In contrast, all four lymphocyte-depleted AGM remained healthy. The lymphocyte-depleted AGM showed only a trend toward a prolongation in peak viremia but the groups were indistinguishable during chronic infection. These data show that adaptive immune responses are critical for controlling disease progression in pathogenic SIV infection in PTM. However, the maintenance of a disease-free course of SIV infection in AGM likely depends on a number of mechanisms including non-adaptive immune mechanisms

Transcriptional Profiling in Pathogenic and Non-Pathogenic SIV Infections Reveals Significant Distinctions in Kinetics and Tissue Compartmentalization

Simian immunodeficiency virus (SIV) infection leads to AIDS in experimentally infected macaques, whereas natural reservoir hosts exhibit limited disease and pathology. It is, however, unclear how natural hosts can sustain high viral loads, comparable to those observed in the pathogenic model, without developing severe disease. We performed transcriptional profiling on lymph node, blood, and colon samples from African green monkeys (natural host model) and Asian pigtailed macaques (pathogenic model) to directly compare gene expression patterns during acute pathogenic versus non-pathogenic SIV infection. The majority of gene expression changes that were unique to either model were detected in the lymph nodes at the time of peak viral load. Results suggest a shift toward cellular stress pathways and Th1 profiles during pathogenic infection, with strong and sustained type I and II interferon responses. In contrast, a strong type I interferon response was initially induced during non-pathogenic infection but resolved after peak viral load. The natural host also exhibited controlled Th1 profiles and better preservation of overall cell homeostasis. This study identified gene expression patterns that are specific to disease susceptibility, tissue compartmentalization, and infection duration. These patterns provide a unique view of how host responses differ depending upon lentiviral infection outcome

CCL19 as an adjuvant for intradermal gene gun immunization in a Her2/neu mouse tumor model: improved vaccine efficacy and a role for B cells as APC

The aim of this study was to evaluate the efficacy of the chemokine CCL19 (ELC) as an adjuvant for intradermal gene gun delivery of Her2/neu DNA and to investigate the role of B cells in CCL19-mediated enhancement of immune responses. Balb/c mice were immunized intramuscularly (i.m.) on days 1 and 15 with plasmid DNA (pDNA) (100 {Mu}g DNA) or intradermally (i.d.) by gene gun delivery (1-2 {Mu}g DNA). Administration of pDNA encoding Her2/neu (pDNA(Her2/neu) was compared with pDNA(Her2/neu) plus pDNA(CCL19), pDNA(CCL19), mock vector or uncoated gold particles/phosphate-buffered saline (PBS). Tumor challenge was performed subcutaneously on day 25 with syngeneic Her2/neu(+) tumor cells (D2F2/E2). Intradermal immunization by gene gun led to an enhancement of tumor protection by the DNA vaccine as compared with i.m. immunization. The protective effect of the vaccine was further enhanced by coadministration of pDNA(CCL19) both after i.m. and i.d. immunization. Tumor protection was associated with Her2/neu-specific T cell and humoral immune responses. Experiments in B-cell-deficient {Mu}MT mice showed that B cells are crucial for CCL19-mediated enhancement of tumor rejection, most likely as antigen-presenting B cells. DNA vaccines against Her2/neu may play a future role in the treatment of Her2/neu-positive breast cancer patients in a clinical situation of minimal residual disease