HIV Reservoirs in the Brain: Where, When, How, and What Do They Mean for Our Patients? Serena S. Spudich, MD, MA Professor of Neurology Yale University New Haven, Connecticut FORMATTED: // HIV reservoirs in the brain: Where, when, how, and what do they mean for our patients? Slide of IAS USA New York, NY November, Serena S. Spudich, MD Department of Neurology Yale University Berlin patient revealed possibility of HIV cure, creating new critical question is the brain an HIV reservoir? Slide of Doing well off ART > 8 years No replication competent HIV Waning HIV antibodies No HIV specific T cells Slide courtesy of Steve Deeks
Key questions relevant to brain reservoirs for HIV Slide of Do HIV reservoirs exist in the brain during cart? How should we consider the brain in our management of patients? How/when are HIV reservoirs established in the brain? How will HIV cure strategies impact the brain? Thuso: year old man with difficulty walking Slide of yo man presented / with leg weakness and balance difficulty, vague cognitive symptoms, + urinary incontinence. Diagnosed with HIV in 8, cart naïve. Labs: Plasma HIV RNA. million cps/ml and CD cells/ul. CSF microbiology all negative, except CSF HIV RNA > million cps/ml. MRI Brain (FLAIR sequence) shown below with atrophy and diffuse subcortical white matter changes. Slide 8 of Thuso: year old man with difficulty walking HIV RNA(lo Diagnosis: HIV associated dementia. QNZP- - - - Since the beginning of the epidemic, CNS involvement has been a hallmark of HIV. In some individuals, HIV particularly manifests as CNS dysfunction with profound CNS HIV replication. Days post ART initiation Digit Symbol (DSY) -8 - QNPZ summarized neurologic DSY performance How does this CNS impact change with potent ART? Do reservoirs for HIV exist within the brain in most patients? Days
Mechanisms of CNS HIV infection prior to ART Brain Neurotoxic products (free radicals, cytokines) Slide 9 of HIV proteins (gp, tat) Neopterin Chemokines (IP, MCP ) Blood brain barrier breakdown Blood HIV tat Key questions relevant to brain reservoirs for HIV Slide of Do HIV reservoirs exist in the brain during cart? How should we consider the brain in our management of patients? How/when are HIV reservoirs established in the brain? How will HIV cure strategies impact the brain? Persistent macrophage/microglial activation on cart with plasma viral suppression / HIV Slide of Positron emission tomography (PET): Abnormal brain uptake of ligand specific for activated microglial cells (> years of ART vs HIV ). Brain autopsy: Increased activated microglia (CD8+ cells) in (>. years ART vs HIV ). CSF: Elevated CSF neopterin, marker of macrophage activation, associates with detectable CSF HIV RNA by single copy assay (> years of ART). Garvey et al, AIDS. ; Anthony et al, J Neuropath Exp Neur, ; Dahl et al, AIDS.
HIV DNA detected in brain on ART with plasma viral suppression (sudden death) Slide of HIV RNA seldom measurable in brain Slide and data courtesy of Joe Wong Wong, Yukl, et al, Keystone HIV Persistence Conference, April HIV DNA detected in brain on ART with plasma viral suppression Sample type Sequence # Unique Patient ID # +ve PCR reactions /cell # determined sequences GPDH V T8 / / N - / / N - / / N - / / N - > / / Y Slabs / / Y T8 PBMC - - Slide of CTRPNNNTRK S I H I - - GPGR AFYTTGE I I G D I RQAHC............ N. - -..... L......................... R. R. QR...... V. I. K. -. NM................... - -.......... D.............. S......... - -...................... R. -.......... - -. R...... R............. R.... -....... - -.......... D........... R. -.......... - -. R...... R........ E......... -....... - -.......... D........... I.......... P. - -.. R...... E............... D.. S...... - -.... S. FA.. DV............. D......... - -.... S.. A.. DV.......... I.......... R. - -... Q T.. A.. D. V...... Y............... - -.... SC. A.. VV...... P. R Slide and data courtesy of Melissa Churchill Churchill, et al, Keystone HIV Persistence Conference, April Persistent CNS HIV replication on ART with plasma viral suppression: CNS escape Slide of Lamivudine Abacavir Lopinavir/r hand tremor, ataxia, slurred speech, aphasia Latest CD 8 cells/ul; nadir CD cells/ul Peluso et al., AIDS,.
Persistent CNS HIV replication on ART with plasma viral suppression: CNS escape Slide of CSF HIV RNA CSF WBC = cells/ul Peluso et al., AIDS,. Persistent CNS HIV replication on ART with plasma viral suppression: CNS escape PI: IV, KR, MI, IV, LP, V8A RT: ML, ED, DN, V8I, M8V, LW, TY Abacavir Lamivudine Darunavir/r Nevirapine Zidovudine Resolution of signs and symptoms Zidovudine Didanosine Lamivudine Stavudine Abacavir Tenofovir Nevirapine Delavirdine Efavirenz Saquinavir Indinavir Ritonavir Nelfinavir Amprenavir Lopinavir/r Atazanavir Possible Possible Slide of No Evidence of No Evidence of No Evidence of Possible Possible Peluso et al., AIDS,. Log Log HIV HIV viral viral load load (RNA (RNA copies/ cp/ml) THINC Subject : CSF escape at two time intervals Pre- HAART T T Blood plasma St ar t ed DRV/ r/ TDF/ FTC years after diagnosis CSF Months on HAART Slide of Persistent CNS HIV replication on ART with plasma viral suppression: CNS escape Perc ent Infectivity at Low CD Elevated macrophage tropism of CSF escape population Ba L JRCSF D E9 F A UNC Joseph et al., THINC study
Jake: Young man with recent infection, hesitant to start ART 9 yo man diagnosed in May,, probable acute HIV syndrome in Oct. On no meds, works as an electrical engineer; lives alone and has good support network. He wants to avoid treatment as long as possible. / / 9/ CD count 8 CD % HIV RNA 9 Slide 8 of Key questions relevant to brain reservoirs for HIV Slide 9 of Do HIV reservoirs exist in the brain during cart? How should we consider the brain in our management of patients? How/when are HIV reservoirs established in the brain? Early HIV infection studies How will HIV cure strategies impact the brain? HIV traffics into the CNS in early infection Slide of 8 HIV RNA Levels Plasma log copies/ml 9 8 Days Post HIV Transmission
HIV traffics into the CNS in early infection Slide of 8 HIV RNA Levels Plasma CSF log copies/ml 9 8 Days Post HIV Transmission HIV traffics into the CNS in early infection Slide of 8 HIV RNA Levels CSF log copies/ml 9 8 Days Post HIV Transmission CSF Neopterin Slide of Macrophage activation in the CNS is triggered in early infection 8 nmol/l 9 8 Days Post HIV Transmission Neopterin, biomarker of macrophage activation, is elevated in the CNS compared to HIV negative (dotted line) throughout early infection.
Neuronal injury begins during early infection Slide of CSF NFL ng/l HIV- AHI PHI CHI Neurofilament Light Chain (NFL) specific CSF biomarker of axonal injury Peluso et al., JID Slide of 8 HIV RNA Levels CSF log copies/ml 9 8 Days Post HIV Transmission Variable compartmentalization of env sequences between plasma and CSF in primary infection Slide of A % % % % % % 8% % % - months (n=) - months (n=) Blood CSF Not Analyzed Equilibrated (-) Equilibrated (+) Intermediate Compartmentalized Sturdevant C., PloS Pathogens 8
Slide of Key questions relevant to brain reservoirs for HIV Slide 8 of Do HIV reservoirs exist in the brain during cart? How should we consider the brain in our management of patients? How/when are HIV reservoirs established in the brain? How will HIV cure strategies impact the brain? CSF HIV and CNS inflammation after ART interruption HIV RNA (log cps/ml) Plasma HIV RNA Slide 9 of 8 HIV RNA (log cps/ml) CSF HIV RNA 8 CSF WBCs cells/ L Price, Deeks, J Neurovirology. 8 Days 9
How will HIV cure strategies affect the CNS? ART cure intervention ART Interruption ART Slide of Pre ART On ART During intervention/ before ATI At plasma rebound (or before) On ART in follow up protocol CSF: inflammatory markers, virology, injury markers Neuroimaging: MRS, volumetrics, DTI & rs fmri at Tesla magnet strength Clinical: Neurological exams & neuropsychological assessments Collaborators: V. Valcour, J. Ananworanich Slide of SEARCH : HIV cure intervention with HDAC inhibitor, followed by treatment interruption Wk LP/MRI/NP Start VHM Wk Detectable plasma HIV LP/NP RNA Stop VHM, LP/NP Begin ART interrup9on Resume ART F/u on ART MRI/NP Kroon, et al., IAS Cure Symposium & IAS, SEARCH : HIV cure intervention with HDAC inhibitor, followed by treatment interruption A. Plasma HIV RNA B. CSF HIV RNA Standard Assay Slide of HIV RNA (cps/ml) HIV RNA (cps/ml) Baseline Wk VHM ATI On ART Baseline Wk VHM ATI C. CSF HIV RNA Single Copy Assay VHM: Vorinostat (HDAC inhibitor) + Hydroxychloroquine + Maraviroc HIV RNA (cps/ml) Baseline Wk VHM ATI Kroon, et al., IAS Cure Symposium & IAS,
SEARCH : HIV cure intervention with HDAC inhibitor, followed by treatment interruption Protein (mg/dl) A. CSF Protein IP-/CXCL (pg/ml) B. CSF IP-/CXCL p =. Slide of Baseline Wk VHM ATI Baseline Wk VHM ATI C. CSF MCP-/CCL- D. CSF Neopterin MCP-/CCL- (pg/ml) Baseline Wk VHM ATI VHM: Vorinostat (HDAC inibitor) + Hydroxychloroquine + Maraviroc CSF Neopterin (nmol/l) Baseline Wk VHM ATI Kroon, et al., IAS Cure Symposium & IAS, Key questions relevant to brain reservoirs for HIV Slide of Do HIV reservoirs exist in the brain during cart? How should we consider the brain in our management of patients? How/when are HIV reservoirs established in the brain? How will HIV cure strategies impact the brain? ACTG A: Effects of ART intensification on the brain Slide of Randomized, placebo controlled, double blinded phase IV clinical trial, 9 weeks Study Population (n=8; arms=) Mild neurocognitive impairment (includes neuroasymptomatic) On stable ART treatment > year Plasma HIV RNA less than copies/ml Study Regimens A: No intensification B: Intensification with DTG C: Intensification with DTG and MVC Weill Cornell Uptown Site E 8 th St at York Avenue Valery Hughes, FNP 9 Weill Cornell Chelsea Site W rd St between th and th Todd Stroberg, RN 98
Slide of Clinical management of HIV and the brain in USA HIV treatment guidelines (http://aidsinfo.nih.gov/guidelines) Treat all individuals at the time of HIV diagnosis. HIV guidelines now incorporate CNS considerations: Due to CNS toxicities, efavirenz no longer in first line recommended regimens. Treatment recommendations for HIV Associated Dementia (no efavirenz, favor regimens with higher presumed CNS penetration). Evaluation/treatment of symptomatic CNS escape including lumbar puncture for CSF viral load, CSF drug resistance testing and consideration of CNS penetration. Acknowledgements Yale: Michael Kozal Brinda Emu Leah Le Jen Chiarella Barbara Turcotte Laurie Andrews Sebastian Urday Michael Peluso Andrew Young Joome Suh Idil Kore Elham Rahimy Andrew Silverman Tess O Meara UCSF/San Francisco: Victor Valcour Joanna Hellmuth Collin Adams Lauren Wendelken Richard W. Price Evelyn Lee Julia Peterson Rick Hecht Chris Pilcher UCSF Options Study Magnet Staff Teri Liegler Study Participants UNC: Ron Swanstrom Sarah Joseph Christa Sturdevant Gretja Schnell Kevin Robertson Joe Eron THINC team Sydney: Bruce Brew Sarah Palmer Innsbruck: Dietmar Fuchs WRAIR/MHRP Jintanat Ananworanich Sodsai Tovanabutra Gustavo Kijak Suteeraporn Pinyakorn Nelson Michael Jerome Kim Merlin Robb U. Gothenburg: Lars Hagberg Magnus Gisslen Funding Support Henrik Zetterberg Milan: Paola Cinque NIH RMH RMH9999 RMH8 RMH9 R NS89 KMH W8XWH ; IAA number NIAID Y AI US Military HIV Research Program Slide of Study Participants Thai Red Cross AIDS Res Center/SEARCH Nittaya Phanuphak Praphan Phanuphak Mark de Souza Frits van Griensven James Fletcher Eugene Kroon Donn Colby Carlo Nitiya Chomchey Duanghathai Suttichom Somprartthana Rattanamanee Peeraya Mungu Putthachard Saengtawan Tippawan Pankam