Catching Up With Pathogenesis and Cure Research From CROI 2014
May 16, 2014
HIV-Specific CD4 T-Cell Responses in the VISCONTI Cohort
The VISCONTI cohort comprises individuals treated very early after acquiring HIV infection (for an average of around three years) who have maintained undetectable or extremely low HIV viral loads after interrupting ART. At the last published accounting, there were 14 members, although anecdotally it has been mentioned that there may now be as many as 20. The cohort appears to lack the robust HIV-specific CD8 T-cell responses observed in most elite controllers, but until CROI no data had been presented on their HIV-specific CD4 T-cell responses. Assia Samri reported in a poster that HIV p24-specific CD4 T cells are detectable at "relatively high frequencies" in the cohort and have a more polyfunctional profile -- but are not more abundant -- compared to individuals on ART. However, the data are cross-sectional and cannot answer the question of whether the presence of these responses is a cause or effect of the persistently low viral load in the absence of ART.
Hospitalization Among Elite Controllers
Elite controllers are sometimes cited as a model of a "functional cure" of HIV infection, because they naturally maintain extremely low viral loads in the absence of ART. However, in recent years it has become apparent that most elite controllers have elevated levels of immune activation and inflammation compared to comparable HIV-negative people, and are not entirely free from the risk of disease progression. Trevor Crowell presented a poster looking at hospitalization rates among 149 elite controllers compared to 4,704 HIV-positive individuals with suppressed viral loads on ART. Elite control was associated with a significantly higher rate of hospitalization (approximately two-thirds greater), primarily for cardiovascular and pulmonary disease, compared to the cohort on ART. The data are consistent with research indicating that ART may be beneficial for at least some elite controllers, and also has implications for HIV cure research because it argues that the achievement of virological control in the absence of ART does not necessarily equate to ideal health.
Anti-PD-L1 Antibody in Macaques
Targeting the PD-1 receptor pathway has been proposed as a method for both reversing HIV latency and reinvigorating exhausted HIV-specific T-cell responses. The AIDS Clinical Trials Group is on the verge of launching a clinical trial of an antibody against the PD1 ligand, PD-L1. At CROI, Stephen Mason described results of a preclinical study of the anti-PD-L1 antibody in ART-treated SIV-infected macaques. Administration was found to be safe and associated with a significant but short-term reduction in viral rebound after an ART interruption.
EraMune 02 Results
Two of the first clinical trials launched to specifically attempt therapeutic reduction of HIV reservoirs were EraMune 01 and 02, sponsored by the French Objectif Recherche Vaccins SIDA collaboration. Both investigated intensified ART, combined with IL-7 (EraMune 01) or a DNA/Ad5 prime-boost therapeutic HIV vaccine (EraMune 02). Results from study 01 were presented at a prior CROI, showing no significant HIV reservoir reduction and some evidence of an IL-7-mediated increase in HIV DNA resulting from the proliferation of latently infected cells. Results from study 02 debuted as a poster this year, also showing no significant reduction in levels of HIV DNA. However, the vaccine did successfully induce significant T-cell responses against HIV Gag, Pol and Env antigens in individuals on ART.
Evidence Prednisolone Can Increase CD4 T-Cell Counts and Slow Progression in the Absence of ART
In the early 1990s, there was some excitement about results from an uncontrolled, open-label study of the immune suppressant drug prednisolone in people with HIV infection. The investigators reported that administration of the drug led to sizable increases in CD4 T-cell counts that had not been seen with the antiretroviral drugs that were being given as monotherapy or dual therapies at the time. The advent of three-drug ART consigned this prednisolone study to the haze of history, but at CROI there was a flashback in the form of results from a randomized clinical trial, which suggest that the prior data were not a fluke. The trial was conducted in Tanzania during a period when ART was only indicated for people with low CD4 T-cell counts. Treating individuals for whom ART was not yet indicated with prednisolone was associated with a significant increase in CD4 T-cell counts and a reduced risk of clinical progression. The results underscore the causative role of immune activation in the progression of HIV infection, since prednisolone acts via this pathway without directly inhibiting the virus. The researchers suggest the drug may be able to inhibit immune activation and improve immune reconstitution in immunological non-responders on ART, and perhaps could have a role as an early therapy for asymptomatic HIV infection in resource-limited settings (the latter suggestion is likely to be controversial given the understandable emphasis on trying to improve global access to ART, the efficacy of which is proven).
Richard Jefferys is the coordinator of the Michael Palm HIV Basic Science, Vaccines & Prevention Project Weblog at the Treatment Action Group (TAG). The original blog post may be viewed here.
This article was provided by Treatment Action Group. It is a part of the publication Michael Palm HIV Basic Science, Vaccines & Cure Project.
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