HIV Science Update from Rome to Addis : Basic Science Coumba Toure Kane Dakar University Senegal

Introduction Basic science research  valuable scientific information Questions still remain about: – the molecular interactions involved in the regulation of HIV expression and replication in human immune cells, – why the host immune response is not fully effective in controlling the infection, and – how reservoirs of infection persist in the body despite highly active antiretroviral treatment (HAART)

Key Outcomes Prevention Mechanisms of disease progression Immune Activation /inflammation and HIV disease Antiviral immunity and transmission HIV coinfection Drug developpmement and resistance Joint –Bridging sessions Reservoirs /strategies to eliminate reservoirs

Prevention New prevention strategies In the era of PrEP and treatment as prevention, do we still need vaccine? Vaccine: Given once Durable protection Cost-effectiveness

Prevention : Vaccine Research The changing face of HIV vaccine research some promising scientific developments – high diversity of HIV envelope and the importance of glycans, which mask HIV envelope and creates an even more moving and evasive target – Development of resurfaced stabilized cores that can be used as probes for Human neutralizing antibodies and templates for immunogens. – VRC01 that not only neutralizes 90% of natural circulating viruses but also confers sterile protection against mucosal challenge in non-Human primates.

Prevention : Vaccine Research The changing face of HIV vaccine research News from Bangkok Emerge Molecular Clues to Explain First Successful HIV Vaccine Experiments: Results of HIV vaccine ALVAC and AIDSVAX Immune responses of patients could point way forward for future vaccines.

Prevention:Time to consider a combination approach to biomedical interventions Mucosal exposure in the context of PrEP influence immune response (animal models) VAXPrEP could deliver better protection by providing protection during immunization period, reducing infectious challenge, and increasing eclipse phase providing an extended opportunity for adaptive immunity to respond. Vaccine candidates can be co-formulated with microbicides – Gp120 stable within genital gels – mucosal vaccination boost localized immunity

Mechanisms of disease progression Naïve T cell recruitment is not the major source of CD4+ memory T cell production after infection; CD4+ memory T cells are intrinsically capable of self-renewal Intestinal microbioma as driver of inflammation? Greater representation of proinflammatory/inflammation-thriving class-level bacteria. Tryptophan catabolism as correlate of HIV disease progression and mortality? Lower pretreatment tryptophan predict slower CD4+ recovery after 12 months therapy; lower pretreatment/month 6 tryptophan predict death, also adjusting for self-reported dietary protein intake

Immune activation/inflammation and HIV disease The facts: Immune activation predicts disease progression and response to HAART; Immune activation persists on virologically-suppressive HAART; Immune activation/inflammation on HAART associates to non- infectious complications The questions: o What drives immune activation on HAART? o How can we target immune activation as an anti-HIV therapy?

Immune activation/inflammation and HIV disease How do we move forward? Models of protection Why do elite controllers have high T-cell activation but low HIV RNA? Non-pathogenicity of SIV-1 for African monkeys (get infected, present viremia, present immune activation only during acute infection0 Viral determinants of AIDS pathogenesi Interventional trials “Interventional Trials targeting key pathways of “activation” can concurrently test hypotheses of pathogenesis and also explore promising treatment strategies for persons at risk for morbidity” ( “Interventional Trials targeting key pathways of “activation” can concurrently test hypotheses of pathogenesis and also explore promising treatment strategies for persons at risk for morbidity” (PANEL CONSENSUS) Approaches to block inflammation/immune activation

Antiviral immunity Human stem cell-based gene therapy to engineer HIV-specific T-cell immunity can elicit functional anti-viral CTL in vivo - Transmission Non-human primate model of penile transmission (RM- SIVMAC251): SIV can be transmitted by penile SIV exposure but is ~50% less efficient than vaginal challenge Antiviral immunity and transmission

HIV co-infections: the axis of the evil GBV-C /HIV – GBV-C infection reduces B/NK activation and monocyte CCR5 surface expression HIV/ Toxoplasma gondii- – Destruction of nervous cells is potentiated in the simultaneous presence of gp41 and Toxoplasma gondii- HIV/Malaria – Placenta malaria associated with increased risk of MTCT of HIV- 1 (aOR = 6.5; ), especially among primigravidae (aOR = 12.0; ; p< 0.05)

Tenofovir gel 1% Tenofovir gel (CAPRSA 004), has a direct anti- herpetic activity: (i) it inhibits HSV-1 and HSV-2; (ii) reduces HSV-1 and HSV-2 replication at different sites; Topical drug administration appears to be a key requirement to enable this dual prophylactic effect of tenofovir - Drug development and Resistance

Joint Sessions (Track A and B) – TB paradox – Basic Sciences  Clinical – investigating the signaling pathways involved in unmasking TB pathogenesis. CREB pathway(s) Increased expression of cytokines and acute-phase reactants regulated by the cAMP/CREB pathway supporting the role for an activation of the CREB pathway(s) in the pathogenesis of IRIS. – new strategies to treat TB and MDR-TB in resource limited settings and the importance of IRIS in the approach to HIV ART and treating TB coinfection.

Bridging Sessions Drug resistance – Basic Sciences  Operational Research Correlation : Emergence DR and Increased Risk of Mortality Clinical relevance of DR in both develpped and developping countries  Improvment of ART regimens to Prevent DR in PMTCT Need of Population based surveillance of HIV DR  prevent the Emergence of Resistance itself Need to setup patient’s adherence to treatment and setup operationnal research to identify best clinical practise.

Reservoirs and strategies to eliminate Reservoirs CCR6: marker for memory T-cells imprinted with a transcriptional program favorable to HIV replication Lymph nodes reservoirs and alteration/dysregulation TH22 cells: gut HIV reservoir and immune activation on HAART

Cure and eradication research comprehensive overview – HAART cannot eradicate HIV infection and people on HAART show significant higher prevalence of morbidities, which may be linked with residual HIV replication and immune activation. – The reasons for finding a cure are multiple. Elite controllers and CCR5delta32/delta32 stem cells transplantation  2 examples of respectively -non sterilising (functional) and sterilising cure.

Cure and eradication research comprehensive overview – Latency, persistent infection and sanctuaries are the causes of persistent HIV RNA production in patients. – Concerning the roadmap to a cure, intensification, therapeutic vaccination, elimination of latency infected cells and gene therapies are considered as possible strategies.

Implications for Africa interactions between the virus and the host immune system, and implications in terms of AIDS therapy and Prevention  Favourable Research environment ++++ – Prevention Commitment to a Highly active HIV prevention that can be achieved by combination of behavioral changes, ART, social justice and human rights, and Biomedical strategies More studies are needed +++  deliver of innovation – Therapy Optimal management More studies +++ (from basic to operational Research) Assessment strategies and interventions

Conclusions ”Now let Science inform Policy”, – referring in particular to HPTN 052 (96% - reduction of HIV-infections in heterosexual serodiscordant couples). – The new scientific targets outlined are a preventative vaccine (trying to solve the dilemma: "Will a neutralizing epitotope also be an immunogen?”) and a cure (sterilizing or functional, that means no eradication but full control without drugs).

Conclusions ”Now let Science inform Policy”, – Basic scientific information is critical to feeding the pipeline that generates new targets against which therapeutic interventions and vaccines can be directed.

Thank you for your attention