Chasing down the viral reservoir

“To know your Enemy, you must become your Enemy.” The quote by Sun Tzu perfectly captures the theme of the session titled Defining and Targeting Residual Virus on cART.

And so Dr Keele presented an innovative molecular tag of SIV to help better understand the location, size and variability of persistent SIV infection in non-human primates. The “barcode” approach presented allows multiple viral variants to establish infection and then be identified over the course of disease progression. This will hopefully lead to the researchers tracking down the actively replicating viruses that are responsible for maintaining the reservoir and studying how this morphs once ART is introduced and subsequently ceased. Although non-human primate models seem far removed from the clinic, these models are essential for a better understanding of how and where HIV is hiding in the body.

Much closer to home comes the follow-up of a unique patient known as C135 who was part of the Sydney Blood Bank Cohort (SBBC) and infected with HIV 33 years ago. Infected with an attenuated ∆-nef strain of virus, C135 presented as an elite controller with 3 genetic polymorphisms associated with viral control, including protective HLA class I and HLA class II alleles, and CCR5∆32 heterozygosity – a truly distinct combination when accounting for the attenuated virus. Samples taken 15 years after blood transfusion indicated established HIV-1 infection, but in samples from 1997 onwards infectious HIV-1 has never been recovered from PBMC cultures and no HIV-1 DNA found in CD4+ T cells from either PBMC or gut biopsies. The patient has remained off ART since infection and presents a strong case for either viral clearance or at least sustained virological remission. Unfortunately, the current difficulty of sampling all possible reservoir sites in the body such as the CNS makes confirming viral clearance particularly challenging.

The session concluded with a late breaker from Dr Søgaard from Denmark, who presented the results of a clinical trial to assess the effects of romidepsin (an HDAC inhibitor) on the latent reservoir in 6 HIV-infected patients. The phase I/II clinical trial,  gave six aviremic HIV-infected adults intravenous romidepsin (5 mg/m²) once weekly for 3 weeks while maintaining cART. 36 adverse events were reported although the majority were mild and resolved spontaneously. Viral load increased from undetectable at baseline to readily quantifiable levels at multiple post-infusion timepoints in 5 of 6 patients (range 46-103 copies/mL after 2^nd infusion, p=0.007) – the first time this has been seen with an HDAC inhibitor. Furthermore, the emergence of quantifiable plasma HIV-1-RNA corresponded directly with the cyclic romidepsin infusions. However, the HIV-1 RNA levels returned to baseline a few days post infusion and no significant change was detected in total viral DNA across the 6 patients suggesting a transient effect of the drug and no permanent decrease in the size of the viral reservoir. Further trials with larger numbers of patients and/or in conjunction with other therapeutic interventions are eagerly awaited.