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Cure Research Review at OAR NIH Meeting, The Brain, Treatment Interruptions
  Jules Levin, NATAP
Cure Panel Discussions, Review of Care the DARE Collabortories work
OAR Webcast: https://videocast.nih.gov/summary.asp?Live=20129&bhcp=1
Steve Deeks:"Its hard to imagine these therapies [cure] will be safer than HAART.....where the science is there used to be a lot of funding for"shock & kill"but there is not now a lot of funding forshockand kill was and more funding for immunotherapies for DARE....most of the DARE Collaboratives are focused on remission, vaccines, immunotherapies, gene therapy [presumably because LRA [latency reversing agents]shock& kill is not looking so promising anymore]". David Margolis said"there was a recognition that LRAs alone will not clear infection"so we are now looking at combinations of various therapies, the next step will be to find a way to measure how much virus there is left if ant=y, that could take 2-10 years; maybe too generous. RonMitsuyasu said remission in cancer can look like a cure, its a meter of perspective so "I do not think there's that much of a difference" between sustained remission & cure.In the end will it safer or more effective to be on HAART long term compared to cure or functional cure therapy, the rate of recurrence or relapse is what matters [if a patient relapses fromremissionmight they have not been better off on HAART, perhaps?; a research question or a personal decision. At this point we do not have definition for what a"cure"in HIV means. Dan Barouch said its sustained remission without a relapse. So how long would it be to establish this, no relapse - perhaps many many years, 10-20 years? or more; when are you satisfied that there are no relapses and is HAART better]. Deeks went on to say how unusual it is to maintain viral suppression over a decade but Trip Gulick countered & I agree its not rare and that 85% in NYC are virally suppressed [but NYC is not the South - Lynda Dee said & I agree - or likemany otherareas who unlike NYC where they may have better capacity in accomplishing this], in fact many people remain virally suppressed forever. Dan Kuritzkes added in Massachusetts viral suppression rates are good. [Still I agree with Lynda - the viral suppression rates even if they are 85% in NYC they are significantly lower I believe in most other areas like in LA 60%]. Of particular note, even if s cure were found, eradication, the life long affect of having HIV on organ systems like kidney disease or CVD, or the brain may leave irreparable damage that a cure would not help much if at all. David Margolis weighed in, inNC we have many who remain virally suppressed but many who are not and have episodes of viral suppression & loss of viral suppression, and he emphasized the importance despitelimitationsof finding a cure - and I agree with that. In the end however if a cure or functional cure therapy is discovered it will have to be compared in a long term study vs HAART regarding long term safety & efficacy, that is a long & bumpy road.Trip went on to say that new long acting therapies like long acting agents and implants play a key role in the broad context of ART therapy & cure therapy. And yes of course I agree, within the context of what will be effective and safe. And deeks added that within the context of his comments that patients who are lost to care if they get a long acting therapy & don't return to care they have to deal with the long tail, meaning drug resistance asa potential risk.
AGING: More resources are needed for HIV & Aging. in the context of cure research Aging with HIV is at least as important if not more important. Maureen Goodenow the OAR Director has dedicated her opening sessions discussion to aging & HIV emphasizing how much she appreciates aging's importance. In fact, 80% with HIV are over 45, 50% over 50, and 20% over 60, in NY, SF, Boston & Florida as reported by their DOHs. The devastating affects of many older patients is not well appreciated or understood, it is leading to patients often taking 9-12 non ART medications and 4-6 multiple comorbidities, including accelerated frailty & incapacity to perform normal independent daily activities.
http://www.natap.org/2017/HIV/012717_03.htm The new 2015 CDC Surveillance Death report says survival decreased in HIV+ >60 while it has increased in younger patients.
I think there was agreement by many at this meeting that communication to potential patient participants is not being well done, patients too often don't understand what they are getting into. Participation in these studies will not provide healthcare benefit to the individual patient. Capacity to include African-Americans, Latinos and women is even more challenging; the need to continue and expand cure research for kids,pediatricscure researchwads discussed and emphasized by Debbie Persuad and of course there is a bunch of pediatric cure research ongoing now. Monica Gandhi mentioned her study in women was very hard to enroll and they found reservoir differences for women. The The risks of interruption were discussed and worth listening too on webcast. There was discussion about expanding community engagement incrd research & CABs. 80% are older than 45 & 50%older than 50 & 20% older than 60 & this will grow rapidly. Aging with HIV is more important to patients once they understand & appreciate its affect on their health & survival, I propose.
interruption risks - reseeding reservoirs, stimulalting inflammatuion and affects on comorbidities including the brain, what is affect of turning virus on and off? no.
Cure Research Ethics, Risks for Participants- (01/20/17)
PetScan used in macaques are able to identify reservoirs which would help in cure research so you could see where reservoir is & after cure therapy what is outcome. -The detection of viral dynamics and localization in the context of controlled HIV infection remains a challenge and is limited to blood and biopsies. We developed a method to capture total-body simian immunodeficiency virus (SIV) replication using immunoPET (antibody-targeted positron emission tomography). The administration of a poly(ethylene glycol)-modified, 64Cu-labeled SIV Gp120-specific antibody led to readily detectable signals in the gastrointestinal and respiratory tract, lymphoid tissues and reproductive organs of viremic monkeys. Viral signals were reduced in aviremic antiretroviral-treated monkeys but detectable in colon, select lymph nodes, small bowel, nasal turbinates, the genital tract and lung. In elite controllers, virus was detected primarily in foci in the small bowel, select lymphoid areas and the male reproductive tract, as confirmed by quantitative reverse-transcription PCR (qRT-PCR) and immunohistochemistry. This real-time, in vivo viral imaging method has broad applications to the study of immunodeficiency virus pathogenesis, drug and vaccine development, and the potential for clinical translation. http://www.nature.com/nmeth/journal/v12/n5/full/nmeth.3320.html
Eradication of HIV from the brain: Reasons for pause [AIDS 2011. Janice Clements]- Importantly, animal studies suggest that the virus enters the brain [within 10 days following infection] and infects resident macrophages soon after systemic infection [11-14]. Further, the level of viral DNA in the brain did not diminish on combined antiretroviral therapy (cART) [15].Reactivation of the virus in the brain could potentially have devastating consequences by causing neuronal injury. Even in the presence of cART, early viral proteins are expected to be formed by the proviral DNA, and within the brain these proteins can cause neuronal injury not only at the site of infection but also at distant regions [24, 25].The virus may also evolve in the brain and adapt to this environment resulting in specific mutations in both the regulatory [16] and structural regions of the virus[17] [18, 19]. Signature mutations specific to the CSF in the V3 loop of env region of HIV have also been identified [20]illai S, Brain 2006). Hence eradication strategies focused on T cell reservoirs alone may not be sufficient, and consideration needs to be given to the reservoirs within the brain that involve other cells types.This article discusses the fundamental questions that need to be addressed with regards to the biology of the virus in the brain before successful attempts to eradicate the virus can be made.Careful consideration needs to be given to the viral reservoirs in the brain, where it may infect cell types such as macrophages, microglia and astrocytes.....Recent advances in HIV research have made it possible to scientists to consider approaches to eradicate HIV infection from T cell reservoirs. These include either engineering cells that would be resistant to HIV infection of suppression of HIV replication with intensified antiretroviral therapy followed by activation of HIV reservoirs and elimination of these cells by cytotoxic immune responses. Several variations of this theme are being considered. Careful consideration needs to be given to the viral reservoirs in the brain, where it may infect cell types such as macrophages, microglia and astrocytes. The life cycle of the virus in these cells is distinct compared to that in T cells and thus the antiviral approaches may not be effective in fully suppressing viral replication. Even small amounts of viral proteins produced by these cells can be neurotoxic. And if T cells in the periphery are restored before impacting the brain reservoirs these cells may enter the brain causing a T cell mediated encephalitis. This article discusses the fundamental questions that need to be addressed with regards to the biology of the virus in the brain before successful attempts to eradicate the virus can be made.
Conclusion: The central nervous system harbors latent SIV genomes after long-term viral suppression by ART, indicating that the brain represents a potential viral reservoir and should be seriously considered during AIDS cure strategies.....The study by Gama et al.[8] adds additional information in the rhesus macaque model to the increasing accumulated data supporting the CNS, as well as the macrophage/microglia as an occult reservoir of HIV. For those HIV cure strategists, we warn that you ignore the CNS as an HIV reservoir at your patients' peril....Thus, our data suggest that the presence of virus-producing genomes in the CNS should be a cause of concern during AIDS cure strategies aimed at reactivating latent viral genomes. Increased immune activation in the brain, as we observed, may lead to reactivation of latent reservoirs followed by an exacerbated and harmful inflammatory response even in the presence of ART. As the CNS harbors macrophages with persistent replication-competent virus, monitoring CSF for viral activation or residual viremia should be seriously considered during eradication strategies.
Janice Clements : In the late 1970s, we were studying this strange virus that infected sheep, Visna virus, which caused a disease that was similar to multiple sclerosis. The Visna virus got into the brain and caused a focused, inflammatory infection, and degrades myelin, the conducting material that helps signals pass along neurons, around the infected region. The Visna virus is a type of lentivirus made of RNA. I cloned the virus to study the viral genome and how this virus infected sheep. In the late 70s, I joined the faculty.
Janice Clements [J Infect Dis (2002)] -This study clearly demonstrated that, although viral RNA is down-regulated in the brain after acute infection, viral DNA persists at steady-state levels throughout infection..These data provide direct evidence that the CNS is established as a virus reservoir during acute infection and that viral DNA persists in all parts of the brain throughout infection. Furthermore, the relative levels of viral RNA and DNA in the brains of the macaques during acute infection were remarkably similar, although it would be expected that viral RNA levels would have been 10-1000-fold higher in productively infected cells, particularly lymphocytes.
These data clearly reflect early productive viral replication throughout the brain.Viral DNA in the brains of all animals euthanized at 10, 21, and 56 days after inoculation was detected at surprisingly similar levels (figure 1B). There was no statistically significant difference between DNA levels at the 3 time points. Thus, the down-regulation of viral replication observed at 21 and 56 days after inoculation was not paralleled by a decrease in viral DNA, demonstrating that virus-infected cells were not completely cleared but remained in the CNS.Viral DNA in the brains of all animals euthanized at 10, 21, and 56 days after inoculation was detected at surprisingly similar levels.Plasma viral RNA reached high levels by 7 days after inoculation and generally peaked 10-14 days after inoculation in all infected macaques. This was followed by a decrease in plasma virus load of ∼1-2 logs between 14 and 21 days, and levels of 106-108 copy equivalents/mL were maintained until 56 days after inoculation (figure 2A). Virus loads in the CSF were more variable during acute infection, ranging from 104 to 106 copy equivalents/mL at 10 days after inoculation..Latent virus in the brain must be considered in therapeutic strategies to eliminate HIV from infected persons.Latent reservoirs of human immunodeficiency virus (HIV) present significant challenges for eradicating HIV from infected persons, particularly reservoirs in the brain established during acute infection.A simian immunodeficiency virus (SIV)/macaque model of HIV dementia was used to show that viral DNA levels in the brain remained at constant levels from acute through asymptomatic infection, despite significant down-regulation of viral RNA in the brain after the acute phase of infection.Comparison of viral genotypes in the central nervous system and peripheral blood mononuclear cells suggests that recrudescence of viral replication in brain occurs by reactivation of latent viral DNA.Previous studies have clearly shown that HIV and SIV enter the brain during acute infection, but the fate of virus in the CNS during the asymptomatic period of infection has not been investigated.
With the advent of HAART (highly active antiretroviral therapy) for the treatment of HIV, fewer people develop full-blown AIDS, but the treatment doesn't prevent HAND since the drug can't get in the brain to stop the virus from doing damage. http://www.hopkinsmedicine.org/institute_basic_biomedical_sciences/about_us/scientists/janice_clements.html



Cure Research Review at OAR NIH Meeting
Clinical Trials of HIV Cure: Where have we been? Where are we going? talk by Dan Kuriztkes

At around 50 minutes Dan Kuritzkesbegins his interesting review & summary on Cure Research at the OAR ARAC recent meeting just following the 3 day Cure research NIH meeting in Maryland, and full ARAC panel discussion of Cure research follows Dan's talk https://videocast.nih.gov/summary.asp?Live=20129&bhcp=1
neutralizing antibodies may be more effective in suppressing HIV as therapy perhaps as maintenance as long acting therapy - rather than alone or in combination to reactivate HIV & be effective for cure. It also remains unclear how NAs would be effective in suppressing HIV. What has been the subject of cure research recently has been latency reactivating agents, "at current dosing regimens, LRAs are only modestly effective in reactivating latent HIV-1.... reactivating the entire reservoir will be challenging. It is highly unlikely that reactivation alone will suffice to deplete the latent reservoir of HIV-1. Safety & infrequent toxicities potentials that may not be detected in early phase studies will be focus of research. Safety oflatency reactivating agents is questioned by some, they are used in cancer therapy & can have unknown long term concerns because they up and down regulate gene expression but it is not clear that ongoing LRA cure research studies adequately warn patient study participants of these risks. Safety concerns of new checkpoint inhibitors used for cancer has recently come to light more so the risk/benefit ratio is questionable. There has been quite a bit of recent discussion about the inadequacy of "informed consent" of patient study participants with recent discussions that participants usually do not appear to fully understand the potential risks of these studies nor of treatment interruption which results in repopulating reservoirs with HIV after years of fully suppressive HAART.

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