Antiviral and Immunological Benefits in HIV Patients Receiving Peptide T: Flushing of Viral Reservoirs.

Maria T. Polianova1,2, Francis W. Ruscetti1, Candace B. Pert2, Rochelle E. Tractenberg3, Gifford Leoung4, Scott Strang4, Michael Ruff 2.

1NCI-FCRDC, Frederick, MD 21702 (USA), 2School of Medicine, Georgetown University, Box 571460, Washington, D.C. 20057 (USA), 3University of California, San Francisco, CA 94143 (USA).

Background: Current HAART therapies do not eliminate viral reservoirs, even in the face of effective suppression of plasma viral RNA.  D-Ala-Peptide T-amide (DAPTA), was the first described entry inhibitor and selectively blocks infection mediated by chemokine (CCR5) receptors, with minimal effect on lab adapted X4-tropic HIV-1 isolates. Material and Methods: DAPTA, with or without HAART, was administered by nasal spray (6 mgs/day) for up to 32 weeks to eleven long-term infected (mean=17 years) patients with stable persistent plasma HIV RNA between 1000 and 25,000 copies/mL and CD4> 300.  Viral RNA (Amplicor), CD4 cells, infectious virus by co-culture of PBMCs, active viral replication in blood monocytes by p24 expression, and IFNg secretion by CD8 T cells were determined at baseline and after therapy. Results: DAPTA administration did not change plasma HIV RNA.  Infectious virus could not be isolated from plasma suggesting it was devoid of replicative capacity.  Progressively less virus could be isolated from PBMC’s and all patients which were positive for virus isolation by co-culture at baseline (6/11) became co-culture negative at 24 weeks.  DAPTA also flushed the persistently infected monocyte reservoir to undetectable viral levels in most patients. The combination of DAPTA with HAART was most effective in suppressing active monocyte infection. Integrated HIV in PBMC’s became undetectable after 44 weeks in one patient we have followed.  Five of eleven had a mean CD4 increase of 33% at 24 weeks.  Immune benefits also included a four-fold increase in gamma-interferon-secreting T-cells (antiviral cytotoxic T cells) which peaked at 8-12 weeks and preceded viral declines. Conclusion: Peptide T has immunomodulatory benefits with anti-viral effects on reservoir cell populations, such as PBMCs and monocytes, with no toxicities.  Future placebo-controlled studies will test DAPTA in a treatment naďve cohort not yet eligible for therapy (viral load <55,000 copies/mL) as a primary immunomodulatory therapy with antiviral effects on plasma RNA and in persistent reservoir populations.