A cell model of HIV latency for finding novel small-molecule therapeutics

Contributed by Guest Blogger: Jack Bulat, ’11

Highly active antiretroviral therapy (HAART) has extended the quality and expectancy of life for people infected with HIV-1, but has been unsuccessful in leading to a cure for AIDS. This is because it proves ineffective at targeting the latent HIV-1 reservoir – a pool of memory CD4+ T cells in the quiescent phase of the cell cycle that harbor inactive integrated virus. Should an HIV-infected patient ever come off HAART, activation of this latent pool would cause the virus to re-emerge. Because HAART has become both expensive and toxic in the long-run, significant efforts have been directed at targeting HIV-1 latency for more effective treatment.

A considerable obstacle to studying HIV-1 latency in memory CD4+ T cells has been the lack of a latency cell model. Because only a small portion of CD4+ T cells infected with HIV-1 survive to become latently-infected memory cells, a resilient cell line mimicking latency has practical value for therapeutic screening. In a study, Yang and colleagues transduced primary CD4+ T cells with a lentiviral vector for constitutive expression of Bcl-2, an antiapoptotic signaling factor implicated in the generation and maintenance of memory CD4+ T cells. Upon confirming that the physical and biochemical properties of these Bcl-2-expressing cells are highly similar to those of freshly-isolated primary resting CD4+ T cells, they activated and infected the cells with an HIV-1 strain mutated to mitigate cytopathic effects. After establishing latency in the infected cells, the researchers screened more than 4400 drugs and natural products for the ability to activate the latent HIV-1 mutant. 5-hydroxynaphthalene-1,4-dione (5HN), a compound found in the leaves, roots, and bark of the black walnut tree, was a promising hit because it did not cause global T cell activation, which would be too dangerous for clinical use.

Despite this, it looks like 5HN will not be hitting the pharmacy shelves any time soon, since it is chemically reactive, affects several cellular proteins, and leads to the stimulation of inflammatory genes. Nevertheless, the study is significant for presenting a methodology for generating potentially useful cell lines modeling HIV-1 latency. A noteworthy criticism has been that a mutated strain, rather than wild-type virus, was used to infect the model cells. The scientists contended that the strain is suitable to study latency specifically because the genes implicated in HIV-1 activation were not modified.


3 thoughts on “A cell model of HIV latency for finding novel small-molecule therapeutics”

  1. Cd3 and CD28 don’t bind cytokines. CD3 is a component of the T cell receptor and CD28 ligates a protein on the cell surface of other cells, such as B cells. The antibodies act to ligate and stimulate the proteins as if the T cell were actually making contact with another cell.

  2. Well, in the study the researchers infected the Bcl-2 transduced cells after activating them with anti-CD3 and anti-CD28 antibodies. They then got the infected cells to enter the latency stage. I figure they could’ve used chemokines rather than antibodies to activate the cells. As long as receptor binding sites get occupied, it should do the trick, right? But that’s my molecular bio/biochem reasoning. My background in immunology is limited. One thing they did say is that the Bcl-2-transduced cells appeared to retain their full capability of being activated.

  3. Really interesting! Do you know if the Bcl-2-transduced cells could model latency by direct infection after chemokine stimulation in addition to modeling activation of the resting T cells?

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