The Programmed Death-1 (PD-1) pathway limits the function of virus-specific T cells during chronic infection. We have previously shown that blockade of the PD-1 pathway increases HIV-1 associated T cell function in vitro. However the effect of PD-1 blockade on HIV-1 disease progression in vivo has not been examined. As in humans, HIV-1 infected humanized Balb/c-Rag2−/−gc−/− (Rag-hu) mice express elevated levels of PD-1 on T cells during chronic infection. To examine the effect of PD-1 blockade on disease progression, Rag-hu mice with chronic HIV-1 infection were treated with a blocking monoclonal antibody (mab) directed against PD-L1, the ligand for PD-1. PD-L1 treated Rag-hu mice exhibited a progressive decrease in the HIV-1 plasma viral load with a 7 fold decrease by day 7, 20 fold by day 14, 178 fold by day 21 and 269 fold by day 28 post initiation of treatment. By day 7 the percentage of CD4+ T cells was statistically higher in the treated compared with the untreated group and this trend was sustained throughout the 28 day treatment period. Moreover, there was a strong inverse correlation between plasma viral load and the percentage of both CD4+ (r= −0.66; P<0.0001) and CD8+ (r=−0.64; P<0.0001) T cells in the treated mice but not the untreated mice. This study provides “proof of concept” that humanized mice can be used to examine the effects of immunotherapeutic interventions on HIV-1 infection. Furthermore, these data demonstrate for the first time that blockade of the PD-1 pathway reduces HIV-1 viral loads.
Lactic acid bacteria (LAB) have been utilized since the 1990s for therapeutic heterologous gene expression. The ability of LAB to elicit an immune response against expressed foreign antigens has led to their exploration as potential mucosal vaccine candidates.
Pre-exposure prophylaxis (PrEP) strategies utilizing anti-retroviral drugs show considerable promise for HIV prevention. However there is insufficient pharmacokinetic (PK) data on drug concentrations required for protection at the relevant mucosal tissues where the infection is initiated. Here we evaluated the utility of a humanized mouse model to derive PK data on two leading drugs, the RT inhibitor tenofovir (TFV) and CCR5 inhibitor maraviroc (MVC). Following oral dosing, both the drugs and the intracellular active TFV-diphosphate could be detected in vaginal, rectal and intestinal tissues. The drug exposures (AUC24hr) were found to be higher in vaginal tissue compared to plasma with even higher levels detected in rectal and intestinal tissues. The overall trends of drug concentrations seen in humanized mice reflect those seen in the human thus establishing the utility of this model complementing the present non-human primate (NHP) models for future pre-clinical evaluations of promising HIV PrEP drug candidates.
Feline infectious peritonitis is a devastating, fatal disease of domestic cats caused by a pathogenic mutant virus derived from the ubiquitous feline enteric coronavirus (FECV). Infection by FECV is generally subclinical, and little is known about the mucosal immune response that controls and eliminates the virus. We investigated the mucosal immune response against FECV in an endemically infected breeding colony over a seven-month period. Thirty-three cats were grouped according to FECV seropositivity and fecal virus shedding into naïve/immunologically quiescent, convalescent and actively infected groups. Blood, fecal samples and colon biopsies were collected to assess the mucosal and systemic immunologic and virologic profile. Results showed that cats with active FECV infections have strong systemic IgG and mucosal IgA responses that wane after virus clearance. Significant FECV-specific mucosal T cell IFNγ responses were not detected in any of the three groups. A shift toward an inflammatory state in the mucosa was suggested by increased IL17:FoxP3 expression. However, no histologic abnormalities were observed, and no shifts in lymphocyte subpopulation phenotype or proliferation were noted. Together, the results suggest that control of FECV is mediated by humoral mucosal and systemic responses and that perturbations in the primary reservoir organ (colon) are minimal.
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