Gene therapy for HIV is “progress towards functional cure” say researchers

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Investigators of a new gene therapy approach to HIV treatment claim that their findings represent “significant progress towards a `functional cure`”, after results from Sangamo Biosciences phase 1 study of SB-728-T showed no evidence of viral rebound after treatment interruption in one of six patients treated with the drug.

The findings were presented on September 17 at the 51st ICAAC in Chicago.

SB-728-T is a one-off procedure rather than an ongoing medication. It uses a zinc finger nuclease to `edit` the genetic material of CD4+ T-cells harvested from each individual in the study. The zinc finger nuclease is designed to bind to a specific position in the DNA sequence of the target gene, causing a break that is repaired by normal DNA repair mechanisms.



A protein on the surface of certain immune system cells, including CD4 cells. CCR5 can act as a co-receptor (a second receptor binding site) for HIV when the virus enters a host cell. A CCR5 inhibitor is an antiretroviral medication that blocks the CCR5 co-receptor and prevents HIV from entering the cell.

CD4 cells

The primary white blood cells of the immune system, which signal to other immune system cells how and when to fight infections. HIV preferentially infects and destroys CD4 cells, which are also known as CD4+ T cells or T helper cells.


A unit of heredity, that determines a specific feature of the shape of a living organism. This genetic element is a sequence of DNA (or RNA, for viruses), located in a very specific place (locus) of a chromosome.

treatment interruption

Taking a planned break from HIV treatment, sometimes known as a ‘drugs holiday’. As this has been shown to lead to worse outcomes, treatment interruptions are not recommended. 

deoxyribonucleic acid (DNA)

The material in the nucleus of a cell where genetic information is stored.

However, this cleavage edits out a small portion of the DNA sequence, and this is enough to cripple the functioning of the gene.

This particular genetic modification process is designed to reduce the expression of the CCR5 receptor on the surface of these cells, which would otherwise be used by HIV to gain entry to these cells. This approach follows the observation that individuals with a natural mutation that limits expression of CCR5 are resistant to HIV infection.

After the genetic modification takes place the modified cells are stimulated to copy themselves in vast numbers in the laboratory, and then reintroduced into the patient’s body.

The aim of the treatment approach is that the CCR5-deficient CD4 cells will begin to replace the existing population of CD4 cells. When this is accomplished, the target cells for HIV infection will be removed, and so viral replication will be impossible even when antiretroviral therapy is halted.

The findings presented in Chicago come from two cohorts of patients who took part in the phase 1 dose-ranging and safety study of SB-728-T. This study was not designed to assess efficacy, so any results are suggestive, and the soundest conclusions that can be drawn from the study are that the process of introducing genetically engineered CD4 cells worked to some extent in all patients, and did not cause any major adverse events.

The first cohort of nine patients, who had CD4 cell counts between 200 and 500 cells/mm3 after several years of fully suppressive antiretroviral treatment, and were therefore judged to be immunological non-responders, were divided into three successive dosing groups, who received infusions of 10, 20 and 30 billion genetically modified cells. The only adverse events were mild, related to the infusion, and cleared up quickly.

The researchers observed that the CCR5-modified CD4 cells were successfully transferred, and then multiplied and persisted for a median of 337 days. The median CD4 cell increase in those who had completed more than six months of observation was 163 cells/mm3.

After 28 days genetically modified cells comprised between 0.2 and 2.8% of cells in peripheral blood samples, but the proportion of CD4 cells that had been modified reached 6% in the gut mucosa after 90 days. The gut mucosa is an important reservoir of HIV-infected cells in people on antiretroviral treatment.

The proportion of gene-modified cells was 5.5 times higher than predicted and at least 1 log higher than observed in any previous studies of CD4+ T-cell transfer. This suggests that expansion of the modified CD4 cells is occurring after infusion, say the investigators.

All patients treated experienced an increase in CD4 cell count, and a normalisation in CD4+: CD8+ ratio occurred in the majority of patients, indicating a return towards normal immunologic health.

In the second cohort of six patients, each had fully suppressed viral load on antiretroviral treatment and a CD4 count above 450 cells/mm3 (median 974). They underwent a 12-week treatment interruption four weeks after receiving an infusion of 10 billion SB-728-T-modified CD4+ cells.

After 12 weeks investigators noted a statistically significant relationship between the proportion of circulating CD4 cells with genetically modified CCR5 genes and both viral load at the end of the treatment interruption (p=0.001) and the total amount of measurable viral replication during the treatment interruption (expressed as area under the curve) (p=0.037).

In three of six patients viral load decreased by at least 0.8 log after an initial rebound during the treatment interruption. In one case viral load became undetectable, and remained so for the rest of the 12-week treatment interruption. This patient had the highest levels of genetically modified CD4 cells.

However, this patient underscores the challenge involved in attempting to use genetically modified cells. He entered the study with an advantage: he had inherited one copy of the delta 32 CCR5 mutation that provides protection against HIV infection. Each of us inherits two copies of the gene that codes for the CCR5 receptor, one from each parent.

Individuals with two copies are described as homozygous, and are fairly resistant to infection. Individuals with one copy of the gene are described as heterozygous, and have partial protection, and also tend to have slower disease progression if they do become infected. Around 10% of people of northern European descent are heterozygous for this mutation, but the mutant gene is far less common in other ethnic groups.

Sangamo said that one of the avenues it will explore in the development of SB-728-T is a larger study that will recruit people who are naturally heterozygous for the CCR5 delta-32 mutation. Other research will look at how to improve the introduction and persistence of genetically modified cells.

"The next step is to increase the frequency of the modified cells in HIV-infected patients with the ultimate hope that if we do, we will achieve a `functional cure` and eliminate the need for continued HAART," said Dr Carl June, Director of Translational Research at the Abramson Family Cancer Research Institute at the University of Pennsylvania School of Medicine.

A functional cure for HIV would consist of a treatment intervention that could stop or control HIV replication without the need for lifelong treatment, even though HIV was not eliminated from the body.


Mitsuyasu R et al. Adoptive transfer of zinc finger nuclease (ZFN) modified autologous CD4+ T cells to aviremic HIV-infected subjects with suboptimal CD4+ counts. 51st ICAAC, Chicago, abstract H1-375, 2011.

Andro D et al. HAART treatment interruption following adoptive transfer of zinc finger nuclease (ZFN) modified autologous CD4+ T-cells (SB-728-T) to HIV-infected subjects demonstrates durable engraftment and suppression of viral load. 51st ICAAC, Chicago, abstract H2-794a, 2011.