This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. We recently described coreceptor switch in rapid progressor (RP) R5 SHIVSF162P3N-infected rhesus macaques that had high virus replication, and undetectable or weak and transient antiviral antibody response. The lack of antibody selective pressure, together with the observation that the emerging X4 variants were neutralization sensitive, suggested that the absence or weakening of virus-specific humoral immune response could be an environmental factor fostering coreceptor switching in vivo. To test this possibility, we treated four macaques with 50 mg/kg of the anti-CD20 antibody rituximab every 2-3 weeks starting from the week prior to intravenous infection with SHIVSF162P3N for a total of six infusions. Rituximab treatment successfully depleted peripheral and lymphoid CD20+ cells for up to 25 weeks when analyzed by flow cytometry and immunohistochemical staining, with partial to full recovery in two of the four treated monkeys thereafter. Three of the four treated macaques failed to mount a detectable anti-SHIV antibody response while response was delayed in the remaining animal. The three seronegative macaques progressed to disease, but in none of them could be demonstrated the presence of X4 variants by V3 sequence and tropism analyses. Furthermore, viruses did not evolve early in these diseased macaques to be more sCD4-sensitive. These results demonstrate that the absence or diminution of humoral immune responses by itself is insufficient to drive R5-to-X4 switch and neutralization susceptibility of the evolving viruses.
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