18th International HIV Drug Resistance Workshop Basic Principles & Clinical Implications June 9–13 2009, Fort Myers, Florida, USA

HIV-SPECIFIC CD4+ T-CELLS MAY CONTRIBUTE TO VIRAL PERSISTENCE IN HIV-INFECTED ELITE CONTROLLERS

Antivir Ther 2009; 14 Suppl 1:A7 (abstract no. 5)

PW Hunt¹, H Hatano¹, E Sinclair¹, EL Delwart^1,2, TH Lee², MP Busch^1,2, R Hoh¹, Z Grossman³, JN Martin¹ and SG Deeks^1
1University of California, San Francisco, CA, USA; ²Blood Systems Research Institute, San Francisco, CA, USA; ³National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA

BACKGROUND: HIV-infected ‘elite’ controllers maintain plasma HIV RNA levels <75 copies/ml in the absence of antiretroviral therapy and have been proposed as models for a functional cure. However, most elite controllers have detectable viremia using ultrasensitive methods and many have evidence of viral evolution. We hypothesized that HIV-specific CD4+ T cells, while supporting cytotoxic HIV-specific CD8+ T-cells, might also serve as target cells contributing to viral persistence.

METHODS: We sampled HIV-infected elite controllers with plasma HIV RNA levels <75 copies/ml in the absence of antiretroviral therapy from the SCOPE cohort and measured ultrasensitive plasma and cell-associated HIV RNA levels with a transcription-mediated amplification assay (TMA; GenProbe), cell-associated HIV DNA levels and the %activated (CD38+HLA-DR+) and %IFN-γ+IL-2+ HIV Gag- and CMV pp65-specific CD4+ and CD8+ T-cells.

RESULTS: Of 38 elite controllers, most (55%) were men. The median CD4+ T-cell count was 746 cells/mm³. Thirty-one elite controllers (82%) had detectable plasma HIV RNA levels by TMA, 16/20 (80%) had detectable cell-associated HIV RNA levels and 15/20 (75%) had detectable proviral DNA levels (median 22 copies/million PBMCs). The only host response that correlated with plasma HIV RNA levels was the %activated CD8+ T-cells (rho 0.32; P=0.048). By contrast, cell-based measures of viral load (proviral DNA and cell-based RNA) were strongly and consistently correlated with the %activated CD4+ T-cells and %HIV-specific CD4+ cells, but not with CD8+ T-cell responses or with CMV-specific responses. Specifically, higher HIV DNA levels correlated with higher %HIV-specific CD4+ T-cells (rho 0.53; P=0.019) and %activated CD4+ T-cells (rho 0.49; P=0.027), and higher cell-associated HIV RNA levels correlated with higher %activated CD4+ T-cells (rho 0.56; P=0.01) and %HIV-specific CD4+ T-cells (rho 0.43; P=0.066).

CONCLUSIONS: The cell-associated viral burden (DNA and RNA) in HIV-infected elite controllers is strongly associated with level of potential target cells (activated CD4+ T-cells and HIV-specific CD4+ T-cells), but not with other host responses. Plasma HIV RNA levels were only associated with the %activated CD8+ T-cells. Collectively, these data suggest that activated and/or HIV-specific CD4+ T-cells are major contributors to viral persistence in this setting.

2009-06-09
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