Dr Alex Sigal Interview: HIV Persistence Despite ART
Doctor Sigal is the author of 2 recent papers: "Cell-to-cell spread of HIV permits ongoing replication despite antiretroviral therapy" (1) and "As Good As It Gets? The Problem of HIV Persistence despite Antiretroviral Drugs" (2) giving new insights into the mechanisms of HIV persistence during antiretroviral therapy (ART).
Doctor Sigal kindly agreed to answer a few questions on this topic.
Alain Lafeuillade: Could you please introduce yourself?
Alex Sigal: I am interested in the mechanisms of persistence of chronic infectious diseases such as HIV and TB. In HIV, I believe these mechanisms can be broken down into latency, incomplete drug penetration, and directed spread of the virus in the immediate vicinity of the infected cell. I work on understanding the role of the last of these mechanisms, referred to as cell-to-cell spread, in the persistence of infection despite the immune response, and in the formation of reservoirs in the face of therapy.
I have recently joined the HHMI supported Kwazulu-Natal Research Institute for Tuberculosis and HIV (K-RITH) to gain more insight into clinical aspects of reservoirs.
A.L.: What cells are involved in cell-to-cell spread of HIV?
A.S.: So far we found that cell-to-cell spread of HIV plays a role in reducing drug sensitivity in PBMC-to-PBMC virus transmission, and DC-to-PBMC transmission in trans, where the DCs themselves are not infected. I suspect that the number of cell types involved is much larger, since the virus need not infect the donor cell for it to transmit by cell-to-cell spread in trans to new target cells.
A.L.: Is this mechanism of HIV propagation equally effective at each stage of the disease?
A.S.: Without drugs, cell-to-cell spread probably contributes both at the early stages of HIV infection, where reservoir seeding takes place, and in the persistence of mature infection. This is supported by the key role of lymph nodes -environments that are particularly conducive to cell-to-cell spread- in maintaining the infection. It is still an open question whether and at what stage cell-to-cell spread occurs in vivo in the presence of ART. However, given that post-exposure prophylaxis stops working after about three days and that latent cells are rare and probably need the acute phase of infection to be seeded in sufficient numbers, its seems reasonable that early reservoirs of infection involve ongoing replication even in the presence of ART.
A.L.: Is there ‘true’ ongoing viral replication during effective ART?
A.S.: There is evidence for this, including the presence of labile viral DNA long after ART has been initiated. Further work is needed to establish if there is continuous ongoing replication that is compartmentalized in areas of the gut or other sites.
A.L.: What is the role of other cells than latently-infected CD4+ T lymphocytes in HIV persistence?
A.S.: The potential contribution in the face of ART of other cells can be separated into long lived cells that may persist without ongoing replication (infected neurons or stem cells, though the contribution of stem cells is debatable), and cells that persist due to ongoing cycles of infection. For the latter, it is more useful to think of environments rather than cell types, since it is the microenvironment that will determine the drug concentration and whether cell-to-cell spread can occur in an efficient way. So far, we know very little about the contribution of such in vivo environments to the reservoir in the presence of drugs. Certainly in the absence of drugs, latently-infected CD4+ T lymphocytes do not play a role in the persistence of infection despite the immune response, and their role in the presence of drugs is not due to evolutionary selection, but is rather an accident.
A.L.: What kind of intervention could be effective against persistent HIV reservoirs?
A.S.: For latency, reactivation of infected CD4+ T memory cells in the presence of drugs will be effective provided this reservoir plays an important role – reactivation trials should give an answer to that. If the reservoir has an ongoing replication component, then one possible intervention is to design inhibitors to the virological synapse formed between the virus donor and the uninfected target cell. Another intervention would be to better target infected cells with CD8+ CTLs.
1-Sigal A, Kim JT, Balazs AB, Dekel E, Mayo A, Milo R, Baltimore D. Cell-to-cell spread of HIV permits ongoing replication despite antiretroviral therapy. Nature. 2011 Aug 17;477(7362):95-8.
2-Sigal A, Baltimore D. As Good As It Gets? The Problem of HIV Persistence despite Antiretroviral Drugs. Cell Host Microbe. 2012 Aug 16;12(2):132-8.
Key words: HIV cure, HIV persistence, HIV reservoirs