135 HIV-associated immunodeficiency despite potent antiretroviral therapy with CD4 T cell reconstitution

CD4 T cell reconstitution in patients with HIV is associated with increased responses to conventional vaccines and improved resistance to opportunistic infections. However, prolonged therapy fails to replenish a capacity for immune control over HIV and patients who interrupt therapy inevitably rebound to pre-treatment viral burden in plasma. Only elite patients, termed NVS or natural virus suppressors (1), control viremia to undetectable levels in the absence of therapy. Our earlier studies on NVS patients showed that this group was distinguished from all other HIV patients by the presence of normal levels of CD56+ V 2V 2 T cells in blood (2) reflecting reconstitution of the T cell receptor repertoire through new cell synthesis (3). The CD56 marker identifies cytotoxic effector lymphocytes including NK, CD8, T and NKT subsets, but it’s function remains unknown. We have now shown persistent depression of CD56 expression on CD8 T cells from HIV+ individuals except for NVS patients where the levels approach those found in normal controls. The CD56(+) CD8 T cell subset is highly responsive to stimulus, expresses high levels of perforin/granzyme and the small population remaining in HIV patients on therapy, also express the immune exhaustion marker TIM-3, indicating cells may be lost through an apoptosis mechanism. The persisting defect in CD56 expression for 2 T cells subsets is consistent with a lack of cytolytic effector function and is present in patients with complete virus suppression for many years due to treatment, long after the T cell population is refreshed by new cell synthesis. The block to lytic effector function may explain why treated patients fail to eradicate viral reservoirs; this mechanism is a key target for new therapies designed to cure HIV disease. 1. M. M. Sajadi, A. Heredia, N. Le, N. T. Constantine, R. R. Redfield, HIV-1 natural viral suppressors: control of viral replication in the absence of therapy. AIDS 21, 517 (2007). 2. D. J. Riedel et al. Natural viral suppressors of HIV-1 have a unique capacity to maintain gamma delta T cells. AIDS 23, 1955 (2009). 3. S. Chaudhry, C. Cairo, V. Venturi, C. D. Pauza, The gamma delta T cell receptor repertoire is reconstituted in HIV patients after prolonged antiretroviral therapy. AIDS epub ahead of print, (2013).