**6.1. Replacement therapy**

The discovery of HIV cure by replacement therapy happened by chance from the observations made on Timothy Brown, widely referred as the 'Berlin patient'. The patient was seropositive for HIV and had undergone an allogenic bone marrow transplant on developing acute myelogenous leukemia. Incidentally, the transplanted donor stem cells carried a homozygous CCR5Δ32 deletion and produced T-cells with a truncated chemokine receptor CCR5 conferring resistance to infection with CCR5 utilizing virus. The patient had discontinued HAART after the transplant yet has had no detectable viremia for over five years [141]. The experiences with the Berlin patient, introduced the concept of 'sterilizing cure' which essentially comprises of eradicating all replication competent viruses from the body including the ones inside the latent reservoirs.

Replacement with resilient target cells alone does not suffice to achieve a sterilizing cure. As seen with the Berlin patient, the replacement therapy must be preceded by eradication of latent reservoirs. This has been effectively achieved in the Berlin patient by the myelo-ablative procedures prior to bone marrow transplant and continued by the graft versus host disease which occurred following the transplant [142].

Attempts to replicate the cure of the Berlin patient have not been successful so far. A similar treatment provided for two adults in Boston resulted in a brief period of aviremic state, subsequently followed by rebound viremia in both the patients. A few reasons have been postulated for the failure of sterilizing cure in the Boston patients. The first reason being, the initial myelo-ablative procedure was milder than that which was given to the Berlin patient and hence would have not effectively destroyed the viral reservoirs. Also, the donor cells transplanted to the Boston patients carried a heterozygous CCRΔ32 deletion which might allow HIV infection, when compared to the more resilient homozygous mutant cells trans‐ planted to the Berlin patient [143].

Although well substantiated, the concept of sterilizing cure still has many lacunae. The exact correlates of protection involved in pre-transplant reservoir ablation, establishment of a graft versus host disease and homozygous versus heterozygous CCR5Δ32 deletion are yet to be identified. It has been observed that CCR5Δ32 deletion is associated with increased suscepti‐ bility to infections with West Nile virus. There may be other serious adverse effects which are to be identified before using defective CCR5 as replacement therapy for HIV infection. Another thought provoking issue is the ability of defective CCR5 in protecting infections caused by CXCR4 tropic viruses [144].

Apart from the above mentioned hurdles, the major setback which could limit the reality of this strategy is the availability of matched donors with the required mutation. Autologous bone marrow transplant has been considered to overcome these stringent requirements of allogenic transplants. Transplants of uninfected haematopoietic stem cells harvested earlier from the same person and made resilient to HIV infection by *in vitro* genetic modification (discussed below) do not confer as much protection as their allogenic counterparts. The poor performance of autologous transplants is attributed to the lack of the 'allo-effect' in clearing the infected reservoirs by establishing a graft versus host disease [145]. Hence it has to be borne in mind that replacement with resilient target cells is not a stand-alone strategy and must be compulsorily preceded by reservoir eradication procedures, in order to achieve an effective sterilizing cure.
