2016 CROI Coverage: Wednesday 24
We are following on the same principles since Monday 22 February 2016: Christina Psomas, MD, PhD presents the best selection of the work presented at CROI on Wednesday.
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It's the third day of the conference and the 3912 participants are totally synchronized in the rhythm of sessions.
Paula Cannon opened Wednesday's plenary session with her overview in terms of Gene Therapy for HIV Cure. Gene therapy's principle is to make cells HIV-resistant, either by adding something that inhibits infection (e.g. transdominant RevM10), removing something that is necessary (e.g. CCR5 co-receptor) or sacrifying any newly infected cells (e.g. LTR-inducible suicide genes). Enabling technologies (retroviral and lentiviral gene transfer vectors, adoptive T cell therapy, autologous HSC transplants, and targeted nucleases such as ZFNs, CRISPR/Cas9) we manage a more and more precise and efficient gene therapy. Zinc Finger Nucleases are engineered to create DNA break in the CCR5 gene, with a subsequent repair disrupting this gene. Infusion of ZFN-treated ex vivo expanded T cells is generally safe and well tolerated and induces durable increase in both CD4, total T-cell counts, reservoir decay, as well as partial viral control in some individuals. Ongoing studies use CCR5-modified autologous stem cells after busulfan conditioning and try to harness the immune system using HIV-specific CAR T cells for instance (CD4-zeta chimeric antigen receptor).
Tonia Poteat made a clear presentation on Transgender Populations. They concern 0.1-0.3% of the population in developed countries and HIV incidence estimates in this population is 1.2-3.6 per 100 person-years. Trans women (TW) who have sex with men have the highest HIV burden of any key population (HIV prevalence of 60% in transgender women vs 23% in the general population in Lesotho for instance) but the lower adherence rate during the PrEP studies (iPrex, around 18% of truvada adherence). The shape of the TW HIV Care Continuum is variable by study population and design, which is why gender-affirming approaches, taking into consideration the interplay of biological (hormones, surgery, fillers) and social/structural specificities (sexual networks, employment, mental health/substance use) are necessary to achieve optimal outcomes.
The session O-7 of Oral Abstracts treated how to Push Frontiers of Adaptive Immunity, and filled Room 304.
Cassandra Simonich presented characterization of HIV-1 broadly neutralizing antibodies (bNAb) that are usually isolated from adults about 3-15 years after contamination, and in this case are preferentially isolated from HIV-infected infants during the first 1-2 years of infection. This infant's plasma activity is mediated by polyclonal antibodies, demonstrates cross-clade neutralizing activity, targets N332 supersite, but is distinct from adult NAbs targeting this region. Furthermore, infant NAbs have low somatic hypermutation.
Alexandra Trkola analyzed factors that govern HIV-1 broadly Neutralizing Antibody induction based upon data of the Swiss and the Zurich HIV Cohort Studies. In 239 individuals that had broad Neutralization Activity her team established that parameters that drive bnAb induction are the length of infection, black ethnicity, viral load, CD4 level, as well as diversity. There was no effect of gender, risk group or viral subtype.
Kenneth Mayer of Harvard Medical School presented results of clinical safety and PK evaluation of VRC01, a Broadly Neutralizing mAb. Globally VRC01 administered IV or SC was well tolerated. After a 40 mg/kg IV loading g/ml dose and biweekly 5 mg/kg SC administration, mean VRC01 nadir concentrations was around 14 mc after 6 months. Bimonthly IV VRC01 gave evidence of drug accumulation after each dose.
Magdalena Sips talked about Neutrophil Functions induced by Gp-120 Specific IgA and IgG. Antibodies recruit macrophages and neutrophils at the site of HIV transmission and replication, but neutrophils are the most active antibody-effector population in these sites. Elevated serum IgA titers are associated with spontaneous HIV control. IgA2 and IgG1 gp120-specific titers have the strongest impact on neutrophil activation and recruit distinct neutrophil functions.
Brenda Salantes from Philadelphia showed that upon ATI multiple latently infected cells are activated and result in multiple genetically distinct rebound viral quasispecies, selected by the autologous antibody response.
Geetha Mylvaganam described the phase I study of PD-1 blockade administered during the initiation of ART in 22 SIV-infected Rhesus macaques. This strategy induced proliferation of T4cm and total or SIV specific T8 cells, enhanced the polyfunctionality of these SIV specific T8 cells, resulted in more rapid viral suppression and enhanced rectal Th17 cells. The phase II study of PD-1 blockade administered during suppressive ART according to 3 treatment groups, induced proliferation of CD4 and CD8 T cells, induced transient increases of plasma viremia, and trend towards a lower set-point viral load in anti-PD-1 treated macaques.
Constantinos Petrovas characterized chronic HIV/SIV infection describing accumulation of cytolytic CD8 T cells within the follicle and germinal center, potentially induced by inflammatory mediators.
James Whitney closed the session describing the in vivo effects of an oral TLR7 agonist as a latency reversal agent in SIV+ monkeys. Their first study using repeated administrations of GS-986 (another TLR7 agonist) in macaques did not prove a difference vs placebo concerning the plasma virus rebound kinetics after stopping ART. In this study, they added a clinical candidate (GS-9620), they increased dose number, and lowered the doses of the substance. This strategy induced transient plasma viremia, induction of different cytokines/chemokines and markers of immune activation, with minimal to no plasma IFNalpha. This treatment (up to 19 doses of TLR7 agonist) was well tolerated and 2 of 9 monkeys have remained aviremic for 3 months after ATI. Clinical studies of GS-9620 in HIV-infected individuals are ongoing.
The Themed Discussion session TD-8 about HIV and Microbiomes overwhelmed room 302 of the Hynes Convention Center and gave rise to long and rich discussions.
Muntsa Rocafort described distinct gut microbiota composition in European gay men, as well as reduced bacterial richness, especially in immune discordant subjects, linked with HIV-1 infection.
Jesus Luévano showed phylum-level shifts in the enteric microbiome of a US cohort associated with HIV status, with increase in phylum Bacteroidetes and decrease in phylum Firmicutes, irrespectively of level of viremia control or treatment. Stephanie Dillon used an in vitro model of human intestinal cells, to show that specific translocation of Gram-negative bacteria could enhance disruption of intestinal CD4 T cell homeostasis via CCR5 axis and a productive R5-tropic HIV-1 infection.
Jennifer Manuzak interestingly demonstrated that continuous administration of probiotics to healthy macaques induces beneficial immunological changes in mucosal and lymphoid tissues (increased frequency of IgA+ B and Tfh cells, down-regulation of TLR signaling) that could enhance local immune function. Finally, Ma Somsouk from San Francisco showed how fecal microbial transplantation of 6 participants was well tolerated and has been able to transiently and partially shift recipient microbiome.
Suzanne Crowe opened the ball of the session S-6 symposium with a very clear presentation about immunopathogenesis of metabolic complications in treated HIV infection. In the context of persistent inflammation (plasma LPS and IL-6, sCD14, TNF, sTNFR1) and immune activation, blood monocytes show evidence of immune and metabolic activation (Glut1+ monocytes), along with M1 pro-inflammatory macrophages and despite viral suppression. Tissue macrophages, glycolytic metabolism, as well as oxidative stress are critical in metabolic pathogenesis. Gut microbiome is also linked via inflammatory pathways to visceral adiposity, and inflammasome activation in the liver enhances NASH. These observations can explain how systemic and local innate immune changes can underpin the development of metabolic co-morbidities (visceral adiposity, insulin resistance, T2D, cardiometabolic disease) in HIV-infected individuals.
Professor Grace McComsey from Ohio talked about visceral adiposity in the modern HIV treatment era. Even in the current era of earlier treatment and safer antiretrovirals, visceral adipose tissue (VAT) increases by 25-35% during the initial 2 years of ART, with a minimal impact of ART selection. VAT and SAT (subcutaneous adipose tissue) are very different fat depots with VAT being more proinflammatory, as well as a better predictor of complications than SAT or BMI. This VAT accumulation is independently associated with increased cardiovascular morbidity and mortality in suppressed HIV-infected individuals. Concerning first-line ART, it seems to be no effect of NRTI or type of last generation PIs on VAT, as well as no difference on VAT gains between PI/r and NNRTI (ACTG 5224s). Switches do not seem to work either in order to improve VAT (SMART). Determinants of VAT gains on ART are multifactorial, including baseline HIV-1 RNA and CD4 T cell count, BMI and marijuana use (A5260s). Interventions targeting VAT should be based on lifestyle and nutrition.
Elisabeth Verna did a comprehensive presentation on pathophysiologic mechanisms of NAFLD and NASH in HIV infection. Overall NAFLD prevalence in the US is estimated to be 10-46% and appears to be rising over time. In the modern ART era current estimates of NAFLD are 30-40%, it increases risk of metabolic complications (including CVD), and is responsible of 13% of deaths from liver disease in the D:A:D cohort. Fatty liver pathogenesis in HIV is multifactorial, but mainly associated with persistent immune activation, and should be treated by combination therapies tailored to NAFLD phenotype of each patient (vitamin E ++). Novel therapeutic trials currently evaluate molecules such as aramchol and tesamorelin in HIV-associated NAFLD.
The presentation of Paddy Mallon was outstanding analyzing influence of ART on bone. He argued against the 'conventional wisdoms', to rationally precise that ART is associated with avoidable BMD loss only during initiation of treatment (use of NRTI++), that TDF causes more BMD loss at ART initiation and switch, that raltegravir causes less BMD loss but we cannot assert that this is a generalized Integrase Inhibitor-class effect, and that we cannot formally be certain of the effect of last generation protease inhibitors on BMD loss. He closed the presentation highlighting the important role of age on bone turnover and bone complications, especially in suppressed HIV-infected patients.
The ISHEID at CROI
Key words: ART, Christina Psomas, HAART, HIV, HIV cure, HIV reservoirs, ISHEID, PrEP, anti-retroviral therapy, cART