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No Evidence of Ongoing HIV Replication After 7 Years on ART.....but clonal expansion persists/HIV-Cure implications
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Download the PDF here
Download the PDF here
"Our results imply that developing more potent ART will not cure HIV infection....Other types of therapies such as those targeting and eliminating proliferating infected cells are needed if HIV infection is to be cured" from Jules: in Q&A Dr Kearney said she would expect the same finding if a similar analysis were done in adults.
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"We should not give up on eradication ... but I would put my major emphasis on sustained virological remission ... to keep people suppressed as low as they can possible be." Fauci said......http://www.natap.org/2016/IAC/IAC_04.htm
"The primary approach has been a "shock-and-kill" strategy in which expression of latent proviruses is induced ("shock") by a latency reversing agent and then the infected cells are eliminated by viral cytopathic effects or by immune mechanisms ("kill"). In considering whether shock-and-kill is likely to be successful, the stability of the reservoir is germane. It is generally assumed that as long as an HIV-1–infected individual continues ART, the size of the reservoir should not increase, because new infection events are precluded. Hence, sequential rounds of this cure approach should gradually decrease the size of the reservoir and ultimately eliminate it. Unfortunately, it is coming to light that the apparent stability of the reservoir may be masking an underlying proliferative process.......see below Siliciano commentary
Where are we going with HIV cure research, here are some recent directions & efforts: TLR9, TLR7 HIV Cure Research - (01/24/17)
/ TLR9, TLR7 HIV Cure Research - (01/24/17)
/ IL-15 HIV Cure Research - (01/20/17)
/ 2 New HIV Antibodies Studies Reported, combining 3 antibodies - (01/24/17)
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Mary Kearney
NCI
Frederick
HIV Dynamics and Replication Program
CROI: No HIV Evolution in CHER Children With Viral Control Through 7 Years of ART - Mark Mascolini - (02/22/17)
WEBCAST: http://www.croiwebcasts.org/console/player/33577?mediaType=slideVideo&
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Commentary by Siliciano on PNAS paper by Simonetti & Madarella on clonal expansion - Reservoir expansion by T-cell proliferation may be another barrier to curing HIV infection......pdf attached above
Although the Simonetti et al. (3) study focuses on a single patient, the implications of this work are multiple and foreboding. First, it is now clear that at least some cells carrying replication-competent HIV-1 can undergo dramatic clonal expansion. Second, it cannot be assumed that reductions in the latent reservoir will be stable. At least some of the infected cells may be able to proliferate. In this situation, not only must we suppress viral replication and eliminate the current cells in the reservoir, we must also be able to block clonal expansion of any remaining latently infected cells. Whether these important findings are generalizable beyond patient 1 remains to be seen.
The primary approach has been a "shock-and-kill" strategy in which expression of latent proviruses is induced ("shock") by a latency reversing agent and then the infected cells are eliminated by viral cytopathic effects or by immune mechanisms ("kill"). In considering whether shock-and-kill is likely to be successful, the stability of the reservoir is germane. It is generally assumed that as long as an HIV-1–infected individual continues ART, the size of the reservoir should not increase, because new infection events are precluded. Hence, sequential rounds of this cure approach should gradually decrease the size of the reservoir and ultimately eliminate it. Unfortunately, it is coming to light that the apparent stability of the reservoir may be masking an underlying proliferative process. Whereas the overall size of the reservoir is stable in the setting of suppressive ART (1, 2), recent reports have raised the specter that previously underappreciated clonal expansion of HIV-1–infected cells may, in fact, allow some subpopulations of infected cells to increase in frequency (5⇓–7). It was not known, though, whether these clonally expanded HIV-1–infected cells contained replication-competent virus. Simonetti et al. now provide evidence for clonal expansion of HIV-1–infected cells harboring replication-competent virus (3).
Clonally expanded CD4+ T cells can produce infectious HIV-1 in vivo....Simonettia et al & Frank Maldarellia PNAS 2016, pdf attached above
Reservoirs of HIV-infected cells persist during antiretroviral therapy, and understanding persistence is essential to develop HIV curative strategies. During replication, HIV integrates into the host genome; most proviruses are not infectious, but some with replication-competent HIV persist. Cells with integrated HIV can proliferate, potentially expanding the reservoir, but whether cells with replication-competent HIV actually undergo expansion is unknown. HIV reactivation is often lethal to infected cells, and others have reported finding no replication-competent HIV in expanded populations. We describe a highly expanded clone containing infectious HIV that was the source of viremia for years in a patient. Clonally expanded populations can represent a long-lived reservoir of HIV. Curative strategies will require targeting this persistence mechanism.
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