HIV reservoir size and persistence are driven by T cell survival and homeostatic proliferation

Chomont, N., et al. 2009. Nature Medicine 15, 893-900

Speaker: Yu-Ting Liao (廖郁婷)                                    Time: 13:10~14:00, Nov. 25, 2009

Commentator: Dr. Yea-Lih Lin (林雅俐老師)              Place: Room 601

Abstract:

Finding a new therapeutic target to eradicate HIV is still an important topic concerned in recent years. Although highly active antiretroviral therapy (HAART) has been successful in reducing the rate of progression to acquired immune deficiency syndrome (AIDS), a cure has not yet been achieved. Latent infection of CD4⁺ T cells provides a mechanism for persistence HIV reservoir and become an obstacle to viral eradication in individuals under HAART. New tools are required to delay progression of infection or to block the replication cycle of HIV. In this article, the author found two major and distinct HIV reservoirs, central memory (T_CM) and transitional memory (T_TM) CD4⁺ T cell, maintained by two different mechanisms. First, they identified that integrated viral DNA is the most stable molecular form of HIV in T_CM and T_TM cells after initiation of HAART. CD4⁺ T cells subsets harboring HIV proviral DNA are able to produce infectious virus after co-culture and stimulation with IL-2 and phytohemagglutinin-activated CD4⁺ T cells from HIV-negative donors. T_CM cells constituted the major reservoir for HIV in subjects with high CD4⁺ counts, whereas T_TM cells were infected in subjects with low CD4⁺ counts. According to the Ki67 and PD-1 expression level in CD4⁺ T cells, the results indicate that HIV preferentially persists in T_CM and T_TM cells that proliferate at low levels. They compared HIV sequences obtained from both cell reservoirs by performing phylogenetic analyses and found that proliferation of T_TM cells is associated with genetic stability of the HIV reservoir. Moreover, high proliferation levels in T_TM cells are connected to a limited genetic divergence of the reservoir. Percentage of CD4⁺ T cells expressing Ki67 are increased after IL-7 stimulation without modifying the diversity of the viral reservoir. Collectively, these results suggest that new therapies should target the IL-7-dependent proliferation and memory CD4⁺ T-cell subsets in connection with HAART.

References:

1.        Alexaki, A., et al. 2008. Cellular Reservoirs of HIV-1 and their Role in Viral Persistence. Curr HIV Res. 6, 388–400

2.        Napolitano, L.A., et al. 2001. Increased production of IL-7 accompanies HIV-1–mediated T-cell depletion: implications for T-cell homeostasis. Nat. Med. 7, 73–79