Addressing key gaps in cure research through identification and treatment of hyperacute HIV infection in a resource-limited setting

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1 Addressing key gaps in cure research through identification and treatment of hyperacute HIV infection in a resource-limited setting Thumbi Ndung u, BVM, PhD KwaZulu-Natal Research Institute for Tuberculosis and HIV (K-RITH) and HIV Pathogenesis Programme (HPP) Nelson R. Mandela School of Medicine University of KwaZulu-Natal IAS 2016 Towards an HIV Cure Symposium Durban, South Africa

2 Outline Why cure research despite improved prevention and treatment strategies? The FRESH cohort- a unique cohort to address gaps in HIV prevention, pathogenesis and cure research Impact of treatment during hyperacute HIV infection on virologic and immunologic factors Implications for HIV cure research in resource-limited settings

3 Eastern and southern Africa: high new HIV infections among young women aged years There is a need to better understand the reasons for high incidence among young women Current strategies are suboptimal- new biomedical interventions such as vaccines or a functional cure are needed

4 Strategies for cure Eliminate latently infected cells (Ablative chemotherapy, shock and kill strategies- reviewed by Siliciano and Siliciano, JCI, 2016) Engineer cells to become refractory to HIV infection (Hutter et al., N Engl J Med, 2009; Henrich et al, JID, 2013: Shimizu et al, Mol Ther Nucl Acids, 2015) Optimise cart Early treatment and/or intensification (Persaud et al, N Engl J Med, 2013; Saez-Cirion et al, PLoS Path, 2013; Frange et al, Lancet HIV, 2016)

5 Acute HIV infections- an opportunity for early interventions? Viral set point is a predictor for: - Rate of disease progression -Risk of transmission Year 1 Can we identify hyperacute HIV infections? What will be the impact of early treatment on immune responses and the viral reservoir?

6 FRESH study cohort FRESH: Females Rising through Education, Support and Health Recruit women 18 to 23 at very high risk of HIV infection Provide an intensive empowerment, life-skills and job readiness curriculum that coincides with the sample collection protocol. Identify persons in the earliest stages of acute infection by testing them twice weekly for one year, and collect serial pre- and post-infection samples. Study antiviral immune mechanisms

7 Study setup and sample collection Phase I: Surveillance Twice weekly HIV RNA PCR testing via finger stick blood draws Quarterly blood and mucosal sampling of the female genital tract Phase II: Acute Infection WEEK PBMC Plasma Swabs CVL Cytobrush LN excision X X X X X X X X X X X X X X X X X X X X X X X X X X X X

8 Acute infections detected (N=42) As of as of June 30, 2016: 14 untreated, 11/14 (79%) Fiebig I 28 treated early, 24/28 (85.7%) Fiebig I Incidence 8.5 (95% CI= ) per 100 p/y Median: 124 days; range 0-684

9 P la s m a R N A (c o p ie s /m l) C D 4 C o u n t (U /L ) P la s m a R N A (c o p ie s /m l) C D 4 C o u n t (U /L ) Typical treated and untreated acute HIV-1 infection F R E S H A c u te 1 F R E S H R x P a tie n t R N A C D P la sm a R N A C D 4 C o u n t D a y s D a y s

10 Treatment during hyperacute phase blunts peak viremia

11 Very early ART limits CD4 T cell loss CD4 Count (cell/mm 3 ) Untreated p=0.001 p= p=0.01 CD4 Count (cell/mm 3 ) Early treated ns ns p= Preinfection Nadir CD4 Rebound CD4 0 Preinfection Nadir CD4 Rebound CD4

12 How does timing of cart initiation (Fiebig I/II versus III onwards) or peak viremia affect immune responses? Viral RNA and/or P24 antigen pos (but antibody neg)

13 Most treated participants do not seroconvert* *WB- Biorad GS kit

14 CD4 counts (cells/ml) Some patients started on cart in Fiebig I do not make detectable HIV-specific tetramer CD8 + T cell responses PID Viral load (copies/ml) Cobas combi ELISA Western blot P24 antigen Unigold Determine Days since detection No tetramer response detected and no memory responses detected by CFSE dilution

15 CD8 + T cell responses in early treated subject PID 442 Fiebig V

16 HIV-specific CD8 T cells show defects of cytokine secretion and long-term memory during untreated acute HIV infection % of teramer+ cells secreting IFN-g CD127+Tetramer+ CD8 T cells Kruskal-Wallis p=0.001 P=0.01 P=0.01 P=0.01 P=0.02 HIV HIV CMV CMVEBV Flu

17 Tetramer Tetramer Tetramer Tetramer HIV-specific CD8 + T cells in early treated subjects are more functionally competent Treated CD8 IFN-gamma Untreated CD8 IFN-gamma

18 Frequency of individual tetramers + CD8 + cells is lower in early treated but cells upregulate survival molecules Frequency CD127 + Tetramer of single + tetramer+ CD8 + cells cells (%of total CD8+PBMC) p= Treated p=0.01 Untreated

19 Conclusions We have demonstrated the feasibility of identifying individuals with acute HIV infection and linking them to care FRESH study participants initiated on cart during hyperacute HIV infection may offer new insights on longterm viral remission Understanding of immune responses following cart initiation may be useful for future intervention studies Ideal platform for future interventions aimed at cure?

20 Acknowledgements K/RITH and HPP- UKZN Krista Dong Amber Moodley Zaza Ndhlovu Jenn Maroa Kamini Gounder Daniel Muema Nikoshia Mewalal Thandeka Nkosi Karyn Pretorius Nasreen Ismael FRESH study participants FRESH study team Harvard/MGH Bruce Walker Douglas Kwon Musie Ghebremichael Funding Bill and Melinda Gates Foundation IAVI NIH South African DST/NRF Mark and Lisa Schwartz Foundation HHMI Victor Daitz Foundation