Genetically engineering a functional cure to HIV/AIDS?

CD4+-T-cells and CD8+-T-cells form part of the adaptive immune system’s first-responder team against infections. A normal CD4-T-cell-count (500 to 1,500 cells per cubic millimeter of blood) – the hallmark of a robust immune response – remains the clinical gold standard for monitoring the effective treatment of HIV/AIDS. Alternatively, low CD4+/CD8+ T-cell ratios can be used to monitor responses to anti-retroviral treatment and to identify patient subsets potentially amenable to novel interventions (1).

What happens when the rapidly mutating HIV strain hijacks the immune system? HIV can infect many cells such as CD4+ T-cells and macrophages that express the CD4 molecule on their surfaces. The CCR5 chemokine co-receptor serves as the main entry point into the CD4+-T-cell for almost all primary HIV-1 isolates. Researchers have discovered that people with a homozygous CCR5-Δ32 mutation i.e., a deletion in both alleles of the CCR5 gene, are naturally resistant to HIV. Timothy Brown – a patient with acute myeloid leukemia and HIV – provided an inspiring moment for researchers and other patients. He received a bone marrow transplant from a naturally resistant donor and was deemed to be functionally cured after his viral load dropped to undetectable levels.

Can these results be replicated in other individuals with different genetic makeups and immune systems? Investigators are now looking at ways to snip out regions of 2 co-receptors that serve as HIV entry-points into CD4-T-cells i.e., CCR5 and CXCR4. Some of their results being presented at the American Society of Gene & Cell Therapy (ASGTC) in Washington D.C. (21 – 24 May 2014) point to positive strides made in the long march towards a cure.

Sources

1.            Serrano-Villar S, Sainz T, Lee SA, et al. HIV-Infected Individuals with Low CD4/CD8 Ratio despite Effective Antiretroviral Therapy Exhibit Altered T Cell Subsets, Heightened CD8+ T Cell Activation, and Increased Risk of Non-AIDS Morbidity and Mortality. PLoS Pathog. 2014;10(5):e1004078.

2.             ASGTC Meeting Abstract: Protected Autologous Zinc Finger Nuclease Driven CCR5 Modified CD4 T-Cells CCR5 (SB-728-T) Reduce HIV Viral Load in CCR5 Δ32 Heterozygote Subjects During Treatment Interruption (TI): Correlates of Effect, and Effect of Cytoxan Pre-Conditioning Regimen; [Abstract #283]; Session: "Results of Preclinical and Clinical Development for Hematological and Immunological Diseases," Thursday, May 22, 2014.

3.             ASGTC Meeting Abstract: Cross-Clade Inhibition of HIV on Primary Cells by CXCR4 or CCR5 Fused to the C34 Peptide from gp41 HR2 [Abstract #783]; Session:  "Immune Response to Gene Transfer and Cell Therapy," Saturday, May 24, 2014.