Combinatorial anti-HIV gene therapy: using a multipronged approach to reach beyond HAART

Abstract

The “Berlin Patient,” who maintains suppressed levels of HIV viremia in the absence of antiretroviral therapy, continues to be a standard bearer in HIV eradication research. However, the unique circumstances surrounding his functional cure are not applicable to most HIV+ patients. To achieve a functional or sterilizing cure in a greater number of infected individuals worldwide, combinatorial treatments, targeting multiple stages of the viral life cycle, will be essential. Several anti-HIV gene therapy approaches have recently been explored, including disruption of the CCR5 and CXCR4 coreceptor loci in CD4+ T-cells and CD34+ hematopoietic stem cells. However, less is known about the efficacy of these strategies in patients and more relevant HIV model systems such as nonhuman primates. Combinatorial approaches, including genetic disruption of integrated provirus, functional enhancement of endogenous restriction factors, and/or the use of pharmacological adjuvants, could amplify the anti-HIV effects of CCR5/CXCR4 gene disruption. Importantly, delivering gene disruption molecules to genetic sites of interest will likely require optimization on a cell type-by-cell type basis. In this review, we highlight the most promising gene therapy approaches to combat HIV infection, methods to deliver these therapies to hematopoietic cells, and emphasize the need to target viral replication pre- and post-entry in order to mount a suitably robust defense against spreading infection.

Editing CCR5: A Novel Approach to HIV Gene Therapy

“…Many HIV gene therapy trials based on the ex vivo modifi cation of CD4+ T cells or HSPCs have used ribozymes, aptamers, and siRNAs [ 75 ]. Although none of these studies have reported clinical benefi t in terms of decreased viral load or protection from HIV replication so far, they showed promising outcomes in terms of safety, long-term engraftment and survival of modifi ed peripheral cells [ 76 , 77 ], including maintenance of the genetic modifi cation in mature myeloid and T cells [ 77 , 78 ].…”

Novel Prospective Treatment Options

“…To overcome this challenge, non viral vectors based on nanoparticles like dendrimers are being developed. Cell electroporation is yet another technique that has been developed for the in vitro delivery of nucleic acids into target cells [147]. The second common feature is that, both the techniques can be developed for either in vitro or in vivo use.…”

“…Newer studies advocate the combination of both surface and intracellular modifications of the target cells to obtain improved resilience against HIV [147]. Apart from their role in enhancing resilience to HIV infection, techniques of genetic manipulation are also useful in conferring resistance to viral integration and thereby restricting the reservoir formation [155].…”

Hematopoietic cell transplantation and HIV cure: where we are and what next?

“…14 It is possible that to be effective any gene therapy approach may need to be combinatorial in nature, simultaneously targeting multiple stages of the viral life cycle. 24,25 Allogeneic hematopoietic stem/progenitor cell transplant without gene transfer but with cART may represent another approach toward HIV cure Henrich et al 26 reported long-term reduction in peripheral blood HIV-1 reservoirs following reduced-intensity conditioning allogeneic stem cell transplantation in 2 HIV-positive individuals, both of whom were heterozygous for the CCR5D32 mutation. In-depth analyses of the HIV-1 reservoir size in peripheral blood, coreceptor use, and specific antibody responses on samples obtained before and up to 3.5 years after hematopoietic stem cell transplantation (HSCT) revealed that although HIV-1 DNA was detected in peripheral blood mononuclear cells before and 2 to 3 months after HSCT, HIV-1 DNA and RNA were undetectable in peripheral blood mononuclear cells, CD4 Early cART may prevent HIV from establishing a reservoir A 2-year-old child born with HIV infection and treated with antiretroviral drugs beginning in the first days of life lost evidence of detectable levels of virus by conventional testing despite cessation of HIV medication for 10 months.…”