CROI 2009: A new strategy to purge latent HIV-1 reservoir

[John2038]

Gisslen and colleagues (abstr. 88) presented provocative findings suggesting the IV immunoglobulin therapy could reduce the frequency of latent HIV-1 infection. Like many great ideas in medicine, this trial was sparked by a clinical observation: a patient on ART was treated with IV Ig for an autoimmune disease, stopped ART, and remained aviremic for several months. The idea was that the mild immune and complement activation induced by IV Ig might ignite replication of latent HIV, and its clearance.
 
9 subjects on ART were treated with 30 gm IV Ig for 5 days. Highly purified resting memory CD4+ T cells were isolated and activated, and replication-competent HIV-1 was quantified. Replication-competent HIV-1 was detected in resting T cells in 7 of the 9 subjects. IVIG was said to decrease the frequency of resting CD4 cell infection by more than 68% during the study period (8 to 12 weeks) in 5 of 9 subjects. The investigators also observed a transitory increase in plasma HIV-1 RNA using a sensitive assay (LOD 2 copies/ml), and in increase in serum IL-7 levels.
 
This study was provocative and interesting, especially given the safety record of IV Ig. However, the frequency of resting cell infection appeared to vary over a range of 50 to 0.1 per million in the patients studied, and the quantitative measurements of infection could not be explained by the presenter. It was not clear how many replicate cultures were studied, and what quantitative change in viral recovery led to the conclusion that resting cell infection had decreased three-fold. These findings would need to be clarified, but if shown to be credible the further testing and validation of this pilot study might be worthwhile.

Here is the abstract:

Background:  The latency of HIV-1 in resting CD4+ T lymphocytes constitutes a major obstacle for the eradication of the virus in patients on ART. As yet, no approach to reduce this viral reservoir has proven effective.

Methods:  We treated 9 subjects on effective ART with high-dose intravenous immunoglobulin (IVIG) for 5 consecutive days. Highly purified resting memory CD4+ T cells were isolated and activated. Cells containing replication-competent HIV-1 were quantified. We also quantified HIV-1 RNA in plasma by an ultrasensitive test with detection limit of 2 copies/mL. HIV-1 from plasma and activated memory CD4+ T cells were compared with single genome sequencing (SGS) of the gag region. T lymphocyte activation markers and serum interleukins were measured.

Results:  Replication-competent HIV-1 was detected in resting T cells in 7 of the 9 subjects. IVIG had a profound effect on the latent HIV-1 pool which decreased by more than 68% during the study period (8 to 12 weeks) in 5 subjects when added to an effective ART. The decrease was preceded by a transitory low-level increase in plasma HIV-1 RNA and serum interleukin 7 (IL-7) levels, and followed by an expansion of T regulatory cells. The magnitude of the viral increase in plasma correlated to the size of the latent HIV-1 pool. SGS of the gag region showed that viral clones from plasma clustered together with virus from activated memory T cells.

Conclusions:  Our findings indicate that the latent HIV-1 reservoir became accessible by IVIG through activation of HIV-1 gene expression in latently-infected resting CD4+ T cells, possibly mediated by IL-7.