Date Published: April 4, 2012
Publisher: Hindawi Publishing Corporation
Author(s): W. Abbas, G. Herbein.
The introduction of highly active antiretroviral therapy (HAART) has been an important breakthrough in the treatment of HIV-1 infection and has also a powerful tool to upset the equilibrium of viral production and HIV-1 pathogenesis. Despite the advent of potent combinations of this therapy, the long-lived HIV-1 reservoirs like cells from monocyte-macrophage lineage and resting memory CD4+ T cells which are established early during primary infection constitute a major obstacle to virus eradication. Further HAART interruption leads to immediate rebound viremia from latent reservoirs. This paper focuses on the essentials of the molecular mechanisms for the establishment of HIV-1 latency with special concern to present and future possible treatment strategies to completely purge and target viral persistence in the reservoirs.
Infection with HIV-1, which was first isolated in 1983, causes AIDS, a syndrome that was first reported in 1981 . The HIV-1 pandemic represents one of the great plagues in the history of mankind and a major challenge for medicine, public health, and medical research . The majority of people living with HIV-1 belong to low- and middle-income countries. For example, sub-Saharan Africa accounts for two third of all infected people with HIV-1, where in few countries more than one in five adults are infected with HIV. South and south East Asia have second highest number of people living with HIV-1. Furthermore the epidemic is spreading most rapidly in Eastern Europe and central Asia, where the number of people living with HIV increased by 54.2% between 2001 and 2009. UNAIDS estimated that 33.3 million people were infected with HIV at the end 2009 compared to 26.2 million in 1999, a 27% increase in HIV infection. Each year 2.6 million people are infected with HIV-1 and 1.8 million die of AIDS (UNAIDS 2010). Much has been learned about the science of AIDS and continuous research has allowed the development of 25 different active compounds belonging to six different drug families shifting the HIV-1 infection from a fatal illness into a chronic disease [3, 4].
Two forms of viral latency have been seen on the basis whether or not HIV-1 genome has integrated into the host cell genomes: preintegration and postintegration latency . Preintegration latency results in partial or complete blockade of viral life cycle prior to integration of virus genome into host genome. It could result from incomplete reverse transcription or from restriction by factors such as APOBEC3G (cellular deoxycytidinedeaminase whose function can be counteracted by viral vif protein) [39, 40]. Further the preintegration latency does not appear to be of clinical significance because unintegrated forms persist in the cytoplasm for only one day and cannot account for long-term latently infected CD4+ T-cell reservoirs but this unintegrated form of DNA remains stable for at least one month in nondividing metabolically active macrophages [41, 42]. Postintegration latency occurs when HIV-1 genome integrated into host genome is reversibly silenced and is limited only by the life span of the infected cells and its progeny. Most mechanisms to maintain HIV-1 latency operate at transcriptional level.
HIV-1 uses different strategies to survive within infected individuals. The macrophages, dendritic cells (DCs), and CD4+ T lymphocytes are considered reservoirs for HIV-1 infection. In CD4+ T cells, the viral replication is dependent upon the cell cycle of the host cell and HIV-1 entry into activated CD4+ T lymphocytes leads to productive infection. Virions found within monocyte-derived macrophages persist and retain infectivity for weeks, thus providing an environment for viral persistence. Dendritic cells capture and internalize extracellular virions via DC-SIGN which can be subsequently transmitted to T cells in trans. HIV-1 hidden in DCs and macrophages certainly play an important role for viral spread and cell-to-cell transmission, and its involvement in long-term viral persistence will be discussed here.
The implementation of HAART therapy has improved the survival and quality of life of HIV-1-infected individual, but it has unable to eradicate the virus from latently infected reservoirs like memory CD4+ T cells and macrophages constituting a major obstacle in HIV-1 eradication . The frequency of HIV-1-infected cells, in the patients on HAART, has been reduced to less than one cell per 106 resting CD4 T cells, but after many years of treatment, the frequency of these infected cells is not decreasing further [152, 156]. Moreover, some reservoirs are found in tissue sanctuary sites, like the brain, that are protected from drug penetration .
HIV-1 infection is currently controlled by HAART but it has long-term toxicity and does not eradicate HIV-1 latent reservoir. It is now increasingly clear that epigenetic restriction poses an initial hurdle to viral transcription and cause of maintenance of viral latency. HIV-1 latency is regulated by both cellular and viral factors. A better understanding of epigenetic regulation of HIV-1 latency and identification of new pharmacological targets would open the doors to clear the viral reservoirs.