421 CD4-independent Co-receptor Use of Sequential SIVsm Isolates Varies with the Neutralizing Antibody Response D. Vödrös*1,2, R. Thorstensson3, R.W. Doms4, E.M. Fenyö2, J.D. Reeves4 1Karolinska Inst, Stockholm, Sweden; 2Lund Univ, Lund, Sweden; 3Swedish Inst for Infectious Disease Control, Stockholm, Sweden; and 4Univ of Pennsylvania, Philadelphia,
Background: Co-receptor use of sequential SIVsm re-isolates from experimentally infected cynomolgus macaques with fast or slow disease progression and known neutralizing antibody pattern was previously tested in GHOST(3) indicator cells. We found that CCR5 use was highly efficient and stable over time. BOB/gpr15 and CXCR6 (formerly Bonzo/strl33) use by early isolates was also efficient but varied greatly among late isolates, which often could not establish productive infection via these receptors.
Methods: Full-length envelopes were cloned from sequential SIVsm isolates and tested for their ability to mediate fusion with cells expressing CCR5, CXCR4, CXCR6, BOB, CCR2b, CCR8, Apj and gpr1, in the presence or absence of CD4.
Results: The receptor use of the envelopes correlated with that of the corresponding viral isolates. In addition, we found that all clones were able to fuse efficiently with cells expressing Apj or gpr1 in the presence of CD4. Interestingly, clones obtained from animals 12 days post-infection varied greatly in their capacity to mediate fusion with CCR5 in the absence of CD4. In fact, some clones were able to fuse with CCR5 with the same efficiency whether CD4 was present or absent. At later times after infection CD4 independent fusion with CCR5 was less pronounced in animals that produced neutralizing antibodies against their own virus; however, it remained variable in animals that lacked detectable neutralizing antibodies.
Conclusions: Our results demonstrate broad and complex coreceptor use of sequential SIVsm isolates. Initial, high level virus replication in the infected macaques resulted in the appearance of a virus population that was less dependent on CD4 for infection via CCR5 compared to the inoculum virus. CD4-independent CCR5 use became controlled over time perhaps by the pressure exerted by the humoral immune response to the corresponding isolates.