Biology Reference
In-Depth Information
cycles leading to an impressive p24 antigenemia (up to 4 10
3
pg/ml), very
high levels of circulating infectious virus, and up to 5 10
7
/ml copies of viral
RNA in mouse sera. Thus, the high reproducibility, well-de®ned kinetics of
virus production, and long lasting in vivo persistence of virus-infected cells,
together with low cost characteristics, render this model particularly suitable for
some studies of anti-HIV therapy ( Lapenta et al., 1997). In a prototypic study,
we observed a complete inhibition of both p24 and viral load in the sera of
xenochimeric mice treated with AZT (480 mg/kg/day), while at the tumor site a
marked reduction of infected cells and of the level of virus expression could be
evaluated ( Lapenta et al., 1997). This model was also utilized for studying the
e½cacy of IFN-a treatment in SCID mice co-injected with the monocytoid cell
line U937 and HIV-1. IFN-a was highly e¨ective in inducing suppression of
HIV-1 infection in this model. Thus, we evaluated the possible e¨ects of low
levels of endogenous IFN, produced locally as a consequence of viral infection
( Lapenta et al., 1999). We used genetically modi®ed U937 cells expressing the
Tat-transactivable IFN-a2 gene transplanted into SCID mice and infected with
HIV-1. Low levels of locally produced IFN-a not only proved to e¨ectively
inhibit acute HIV infection and replication, but also conferred a strong protec-
tion to bystander parental U937 cells coinjected with genetically modi®ed U937
cells (Lapenta et al., 1999). However, if chimeric models of SCID mice trans-
planted with human cell lines may have some practical advantages for a rapid
evaluation of some antiviral therapies, the hu-PBL-SCID model has the unique
characteristic of allowing evaluation of the impact of antiviral interventions on
human immune cell functions. As an example, we found that the potent anti-
viral activity of IFN-a in hu-PBL-SCID mice infected with HIV-1 is associated
with the development of a primary humoral immune response to HIV, which can
participate in the cytokine-induced suppression of virus replication (Lapenta et
al., 1999).
CONCLUSION
Since its development, the Hu-PBL-SCID mouse model and its wide range of
minor and major modi®cations or adaptations have proved to be very useful as
valuable in vivo approaches for shedding light on several aspects of the patho-
genesis of HIV-1 infection. However, its use in the evaluation of the antiviral
activity of anti-HIV interventions has been partially hampered by the intrinsic
features of xenochimeric mice, which exhibit only a limited number of human
immune functions and lack physiologic mechanisms of immune cell turnover
and replenishment. In fact, once HIV-1 infection has been established, it rapidly
spreads to uninfected cells. Therefore, it becomes quite di½cult to block or re-
verse the infection process in this animal model, thus resulting in a limitation of
its use in drug testing and vaccine development. In spite of this, taking into
account these limitations and ®nely adjusting/adapting the model to address
