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Posted: 2 Dec 2011
Journal Club: Where will the cure for HIV come from?

Welcome to HIVe's Journal Club! In its first issue, Yegor Voronin reviews recent developments in the search for an HIV cure - a way to completely clear the virus from an infected person.   

A debate was held in August at the IAS conference in Rome on whether the cure for HIV is more likely to come from gene therapy or drugs.  As Dr. Keith Jerome from the University of Washington explained, gene therapy aims to either introduce an antiviral gene into the human genome or disrupt a gene, whose product is required for viral replication.  Dr. Sharon Lewin, Monash University, argued for “anti-latency” drugs, which would awaken the latent virus in patients on HAART, without inducing viral replication, and allow the immune system to recognize and clear infected cells. Both sides presented their best arguments, but a quick vote after the debate showed that the audience by far favored the drugs.

 

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Fig.1. The list of drugs, which are currently approved or are in development, and which show promise for eliminating cells latently infected with HIV (the slide is from Sharon Lewin's presentation).

In September, at the Interscience Conference on Antimicrobial Agents and Chemotherapy in Chicago, the fans of the gene therapy approach received some good news from the biopharmaceutical company Sangamo BioSciences.  It presented the preliminary results of their clinical trial in which zink-finger-targeted nucleases were used to disrupt the gene for viral receptor CCR5 in patients' lymphocytes.  The lymphocytes’ precursors were isolated from patients' blood, treated with the nucleases, and then injected back.  The outcome was encouraging – patients had no serious side effects and CCR5-deficient lymphocytes were found in their blood.  One patient, in whom the therapy was the most successful, went off the antiviral therapy and no viral rebound was observed.  However, that patient had an advantage - one of his CCR5 gene copies was deffective even before the beginning of therapy.  (Conference website requires a subscription, but you can read the story on The New Scientist.)

Proponents of the “anti-latency” drugs got mixed messages from a study by Bosque et al., published in PLoS Pathogens on October 6.  One of the potential drugs to awaken the HIV from latency, IL-7, was shown to be somewhat effective in vitro, activating some of the latent proviruses, but it also stimulated homeostatic proliferation of CD4 cells. Since both infected and uninfected memory CD4 cells responded equally well to the cytokine, proliferation of infected cells cancelled the beneficial effect from eradication of cells with activated proviruses.

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Fig.2. Data from the paper by Bosque et al., showing that after stimulation with IL-2+IL-7, TCM cells enter cell cycle (Ki67 marker) and begin expressing HIV (p24Gag). Authors note that activation of the cell cycle was equal for mock-infected and HIV-infected cells and that IL-2+IL-77-induced HIV expression was similar in dividing (Ki67+) and non-dividing (Ki67-) cells.

But gene therapy and drugs are not the only game in town.  Many groups are working on boosting immune responses in infected people with therapeutic vaccines.  These vaccines typically aim to provide what is called “functional cure”, that is suppression (not elimination) of the virus by the immune system without the need for drugs, but they may help clear the latent reservoir as well.  For example, in the study by Persaud et al., published in the AIDS journal in September, the size of the latent reservoir slightly decreased after prime-boost vaccination with MVA- and Fowlpox-based vectors.  It is not clear why there was an effect on the latent reservoir.  The authors suggest two possibilities, first, the reduction may be due to more robust vaccine-induced elimination of latently infected cells, which still express low levels of HIV.  Second, the presence of HIV antigens in the vaccine may have activated memory cells, which awakened the latent provirus in HIV-specific cells and allowed their elimination.

All of these approaches are attempting to tackle the remarkably stable reservoir of latent HIV proviruses, which seems to persist in patients on antiretroviral therapy for decades.  However, David Baltimore and others recently argued that the stability of the reservoir may be overestimated.  In the study published in Nature on September 1, they show that local cell-to-cell spread of HIV is possible in vitro in the presence of therapeutic concentrations of antiviral drugs.  This would suggest that HIV may replicate at very low levels in patients on HAART and, thus, replenish the reservoir of infected cells.  Of course, this finding is hard to reconcile with results of treatment intensification studies, which showed that increasing the potency of drug therapy has no effect on the size of latent reservoir of the virus, or with the lack of observable long-term viral evolution in patients on HAART, which would have been inevitable if the virus was replicating.

It’s clear that the search for a cure to HIV has more questions than answers for now, but given the multiple directions of active research, we can hope that the answers will start appearing soon.

About the author: Yegor Voronin is a Science Officer at the Global HIV Vaccine Enterprise.


Journal Club discusses scientific literature to raise awareness of the recent advances in HIV vaccine research and inspire discourse important to advance HIV vaccine research and development.  Visit the Submission Guidelines if you are interested in submitting a journal club post.