In spite of enormous progress in chemotherapy of HIV infected patients, the benefit of HAART is limited by the increasing occurrence of resistant isolates, a host of significant side effects, the lack of restoration of efficient antiviral responses and last but not least significant costs of such therapies. Thus, devising strategies aimed at reconstituting immune responsiveness with the goal of weaning patients off chemotherapy are clearly warranted. Based on data from several labs including ours, the major dysfunction observed early post infection appears to be intrinsic to the CD4+ T cell pool. While strategies for increasing hematopoietic regeneration are being pursued, an issue that remains to be addressed is whether the dysfunction observed in the CD4 + T cell is intrinsic to the cells or secondary to the failure of the micro-environment to allow the development of adequate function. Our lab therefore addressed this issue and has recently provided evidence that the dysfunction is NOT due to the micro-environment as significant reconstitution without additional chemotherapy was achieved in the SIV nonhuman primate model of AIDS. While such successful reconstitution and proof of principle was achieved using transfusion of autologous in vitro activated/expanded CD4 + T cells collected PRIOR to SIV infection, it is important to determine whether such reconstitution can be achieved with similar transfusion of CD4+ T cells collected POST SIV infection and the mechanisms by which such reconstitution occurs. This is the precise goal of the studies proposed herein. The restoration of immune competency in the CD4 compartment will be attempted using an improved protocol of anti- CD3/28 stimulation mediated expansion of purified CD4+T cells in vitro. In the first aim, activated autologous CD4+ T cells collected prevs post SIV infection, during or in the absence of PMPA therapy will be compared for their respective potential at inducing antiviral control following chemotherapy cessation.
Aim 2 will examine the qualitative and quantitative differences in CD4+ T cells collected before and post SIV infection both before and after anti-CD3/28 expansion to define in vitro CD4+ T cell profiles that correlate with the capacity to induce effective antiviral immune responses.
In aim 3, the homing and turnover pattern of adoptively transferred CD4+ T cells will be documented in the absence or the presence of SIV infection in attempts to characterize their role in vivo.
In aim 4, the need for long-term presence of functional (pre SIV collected) activated CD4+ T cells for maintenance of effective immune mediated antiviral control will be addressed. Results of these studies will form the basis for future immune reconstitution strategies in human HIV infected patients.
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