HIV reservoir size in relation to the expression and usage of coreceptors

Abstract

Previous findings indicate that the majority of HIV-1 (subtype B and C) infections occur via CCR5 coreceptor usage. Among other factors, this may be related to the selective expression of CCR5 coreceptor on the surface of CD4+ target cells in the genital mucosa (HIV-1 is often sexually transmitted). Using this CCR5 coreceptor HIV-1 is able to establish viral reservoirs during the early onset of primary infection in both myeloid as well as lymphoid lineages and are widely disseminated throughout the whole body. During the chronic phase, the largest reservoir resides in resting CD4+ memory T cells, which have a long life-span, creating a solid barrier for virus eradication. There are indications that R5 viruses have the ability to switch to usage of an alternative co-receptor CXCR4, which is primarily determined by the V3 loop of glycoprotein 160. Since CXCR4 is expressed on different cells, this may play a role in the size and composition of the viral reservoir. With this study, we aim to gain more insight in the dynamics of the HIV reservoirs in relation to the use of different coreceptors in separate compartments HIV latency is established in cellular- and anatomical reservoirs. Several T cell subsets, mainly resting CD4+ T memory cells are considered to be the largest (cellular) reservoir. Anatomical reservoirs include the GALT, genital tract, central nervous system, lungs, liver and kidneys. HIV uses reservoirs to avoid viral cytopathic effects and host immune clearance, since no viral protein is produced in latently infected cells. Viremia is suppressed by combined antiretroviral treatment, which is an intensive targeting combination of three different antivirals, to below a detection limit of 20-50 copies/ml plasma. However antiretroviral therapy is not sufficient to eliminate HIV reservoirs. Therefore reactivation (followed by elimination) of latent HIV provide promising perspectives. However total eradication of HIV is an extremely challenging process due to the stability of reservoirs, variation in reservoir sizes and the possible effects of the potential coreceptor switch to CXCR4. Gaining profound knowledge on reservoir dynamics may provide clues towards the development of novel therapies to not only suppress viral replication, but to eventually target and perhaps successfully eliminate HIV worldwide in the future.