Recent studies, including the above shPromA study, indicate that ideal anti-HIV gene therapy targets should be hematopoietic stem cells rather than more differentiated cells, such as peripheral CD4
+ T cells, because the transduced cells could engraft the host bone marrow and act as a lifelong source of HIV-resistant CD4
+ cells [
26,
32,
33]. Potential gene therapies using CD34
+ cells have been investigated in vitro using cell culture experiments [
26,
34,
35,
36] or in vivo using humanized mice [
26,
35,
37,
38,
39,
40]. Furthermore, the transplantation of macaques with gene-modified autologous CD34
+ cells followed by an infection with SIV has also been tested [
41,
42] although strategies may differ between gene therapies [
33]. Based on such basic study results, the clinical trials using the transplantation of retrovirally or lentivirally gene-modified CD34
+ cells in HIV-positive patients have been carried out [
43,
44,
45]. Gene therapies of CD34
+ cells have been considered as a cure for monogenic immune diseases. For example, the patients with adenosine deaminase deficiency [
46], Wiskott–Aldrich syndrome (WAS) [
47] and X-linked severe combined immunodeficiency [
48,
49] were successfully treated in clinical trials by transplantation of autologous CD34
+ cells retrovirally or lentivirally transduced with the wild-type gene. Lentiviral vectors may be more efficient in gene transfer into resting stem cells at the G0/G1 phase compared with murine retroviral vectors [
50]. If applied to the gene therapy of HSPCs, both retroviral and lentiviral vectors could have adverse effects, including the deregulation of gene expression [
51] and the triggering of the p53 protein [
52]. However, lentiviral vectors may be safer than retroviral vectors because the latter may occasionally cause insertional mutagenesis near the active start regions of genes, which could possibly lead to oncogenesis and cancers, such as leukemias [
48]. Self-inactivating retroviral or lentiviral vectors lacking the U3 region of 3′ LTRs have further safety advantages [
53]. Moreover, recent evidence has shown that the transplantation of WAS patients with autologous CD34
+ cells transduced with lentiviral vectors encoding WAS protein results in the long-term survival of genetically engineered hematopoietic stem cells and lymphoid-committed progenitors [
54]. Thus, this provides hope for lifelong protection from HIV.
Induced pluripotent stem cells (iPSCs) may also be candidates for anti-HIV gene transfer. iPSCs can be generated from the somatic cells of patients, which can differentiate to any cells in vitro and are expected to be utilized for the treatment of a broad range of genetic diseases [
55,
56,
57,
58]. Although CD34
+ cells can engraft in the bone marrow following transplantation and differentiate to hematopoietic cells in vivo, iPSCs may be more convenient for in vitro hematopoiesis compared to CD34
+ cells because of their ease of culture [
59]. Interestingly, the impact of shPromA-transduced iPSCs on the suppression of viral replication in vitro has recently been demonstrated, suggesting that the large-scale production of gene-modified monocytes or lymphocytes in vitro for adoptive therapy could be a future option [
60]. Additionally, the generation of iPSCs from HIV epitope-specific CD8
+ cytotoxic T cells followed by their redifferentiation into the identical epitope-specific CD8
+ T cells for adoptive transfer could be an effective immunotherapy [
61].