G. Marzio et al., In vitro evolution of a highly replicating, doxycycline-dependent HIV for applications in vaccine studies, P NAS US, 98(11), 2001, pp. 6342-6347
Citations number
44
Categorie Soggetti
Multidisciplinary
Journal title
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
A major concern associated with the use of vaccines based on live-attenuate
d viruses is the possible and well documented reversion to pathogenic pheno
types. In the case of HIV, genomic deletions or mutations introduced to att
enuate viral pathogenicity can be repaired by selection of compensating mut
ations. These events lead to increased virus replication rates and, eventua
lly, disease,progression. Because replication competence and degree of,prot
ection appear to be directly correlated, further attenuation of a vaccine v
irus may compromise the ability to elicit a protective immune response. Her
e, we describe an approach toward a safe attenuated HIV vaccine. The system
is not based on permanent reduction of infectivity by alteration of import
ant viral genomic sequences, but on strict control of replication through t
he insertion of the tetracycline (Tet) system in the HIV genome. Furthermor
e, extensive in vitro evolution was applied to the prototype Tet-controlled
HIV to select for variants with optimized rather than diminished replicati
on capacity. The final product of evolution has properties uniquely suited
for use as a vaccine strain. The evolved virus is highly infectious, as opp
osed to a canonically attenuated virus. It replicates efficiently in T cell
lines and in activated and unstimulated peripheral blood mononuclear cells
. Most importantly, replication is strictly dependent on the nontoxic Tet-a
nalogue doxycycline and can be turned on and off. These results suggest tha
t this in vitro evolved, doxycycline-dependent HIV might represent a useful
tool toward the development of a safer, live-attenuated HIV vaccine.